Untitled record

The application claims the benefit of US Provisional Application No. 61 / 550,352, filed October 21, 2011, US Provisional Application No. 61 / 562,181, filed November 21, 2011, US Provisional Application No. 61 / 587,225 on January 17, 2012, US Provisional Application No. 61 / 600,276, filed February 17, 2012, US Provisional Application No. 61 / 619,870, filed April 3, 2012, US Provisional Application No. 61 / 656,251, submitted on 06. June 2012, and U.S. Provisional Application No. 61 / 711,830, filed 2012.

FIELD OF THE INVENTION

The present invention relates to the interferon-free treatment of the hepatitis C virus (HCV).

BACKGROUND OF THE INVENTION

The HCV is an RNA virus that belongs to the genus Hepacivirus in the Flaviviridae family. The enveloped HCV virion contains a positive-stranded RNA genome that encodes all known virus-specific proteins in a single, uninterrupted, open reading frame. The open reading frame is approximately 9500 nucleotides and encodes a single large polyprotein of approximately 3000 amino acids. The polyprotein comprises a core protein, envelope proteins E1 and E2, a membrane-bound protein p7 and the non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.

Chronic HCV infection is associated with progressive liver pathology, including cirrhosis and hepatocellular carcinoma. Chronic hepatitis C can be treated with peginterferon-alpha in combination with ribavirin. There remain substantial limitations in terms of effectiveness and tolerance, since many users suffer from side effects, and the

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viral elimination from the body is often incomplete. Therefore, there is a need for new therapies to treat HCV infection.

BRIEF SUMMARY OF THE INVENTION

As one aspect of the present invention, methods of treating HCV infection in a subject are provided. The methods include the administration of at least two direct acting antiviral agents (DAAs) and ribavirin for a duration of no more than twelve weeks, or for another duration as set forth herein. Preferably the duration of treatment is twelve weeks. The duration of treatment can also not be more than eight weeks. Preferably, the two or more direct acting antiviral agents (DAAs) and ribavirin are administered in amounts effective to provide a sustained virological response (SVR) or other desired level of effectiveness in a subject. Interferon is not administered to the subject during the treatment regimen. In other words, the methods preclude the administration of interferon to the subject, thereby avoiding the side effects associated with interferon. In some embodiments, the methods further include administering a cytochrome P-450 inhibitor (such as ritonavir) to the subject to improve the pharmacokinetics or bioavailability of one or more of the DAAs.

As another aspect, methods of treating HCV infection in a subject are provided. The methods comprise the administration of (a) therapeutic agent 1, (b) at least one polymerase inhibitor selected from the group consisting of therapeutic agent 2, therapeutic agent 3 and combinations thereof, (c) ribavirin and (d) a cytochrome P-450 inhibitor to the subject for a period of no more than twelve weeks or for any other duration as set forth herein (for example, the treatment regimen may continue for a period of no more than eight weeks). Therapeutic active substance 1,

3/229 • · * ·· * · · * »· · ·· ··· the polymerase inhibitor (s), ribavirin, and the cytochrome P450 inhibitor are administered in amounts effective to prevent high rates of SVR or another To provide a measure of effectiveness in the subject. As non-limiting examples, therapeutic agent 1 and the cytochrome P-450 inhibitor can be co-formulated and administered once daily, and the polymerase inhibitor (s) can be administered once daily or twice daily, and the treatment regimen is preferably twelve Weeks (the treatment regimen can also last, for example, eight weeks).

As yet another aspect, methods of treating a population of subjects who have HCV infection are provided. The methods involve administering at least two DAAs, along with ribavirin, to the subjects for a period of no more than twelve weeks. Preferably, the at least two DAAs are administered to the subjects in amounts effective to result in SVR or other measure of effectiveness in at least about 50% of the population, preferably at least about 70% of the population.

In the aforementioned methods, as well as in the methods described herein below, the DAAs can be selected from the group consisting of protease inhibitors, nucleoside or nucleotide polymerase inhibitors, non-nucleoside polymerase inhibitors, NS3B inhibitors, NS4A inhibitors, NS5A inhibitors , NS5B inhibitors, cyclophilin inhibitors, and combinations of any of the foregoing. For example, the DAAs used in the present methods comprise or consist of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor. The HCV polymerase inhibitor can be a nucleotide or nucleoside polymerase inhibitor or a non-nucleoside polymerase inhibitor. The HCV polymerase inhibitor can also be a non-nucleotide polymerase inhibitor.

In some embodiments, the HCV protease inhibitor is therapeutic agent 1 (described below) and the HCV polymerase inhibitor is therapeutic agent 2 and / or therapeutic agent 3 (also described below). As

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For example, the therapeutic agent 1 is administered in a total daily dose of about 100 mg to about 250 mg, or at least once daily at a dose of about 150 mg to about 250 mg, and the therapeutic agent 2 is administered in a total daily dose of about 300 mg to about 1800 mg is administered or is administered at least twice daily at doses of about 200 mg to about 400 mg. For some embodiments, the HCV protease inhibitor is therapeutic agent 1 and the non-nucleoside HCV polymerase inhibitor is therapeutic agent 3. As an example, therapeutic agent 1 can be administered at a total daily dose of 100 mg, alternatively about 200 mg, or alternatively about 250 mg; and the therapeutic agent 3 is administered at a total daily dose of about 400 mg. Ritonavir (or another cytochrome P-450 3A4 inhibitor) can be co-administered with Therapeutic Agent 1 to improve the pharmocokinetics and bioavailability of Therapeutic Agent 1.

In some embodiments, the at least two DAAs comprise at least one HCV protease inhibitor and at least one NS5A inhibitor. Preferably, the HCV protease inhibitor is therapeutic agent 1 and the NS5A inhibitor is therapeutic agent 4. As an example, therapeutic agent 1 can be administered in a total daily dose of about 100 mg to about 250 mg, and therapeutic agent 4 can be administered in a total daily dose of about 25 mg to about 200 mg. Ritonavir (or another cytochrome P-450 3A4 inhibitor) can be co-administered with Therapeutic Agent 1 to improve the pharmacokinetics and bioavailability of Therapeutic Agent 1.

In the aforementioned methods, as well as in the methods described herein, the DAAs and ribavirin can be administered at any effective dosage regimen and / or frequency, for example, they can each be administered daily. Each DAA can either be used separately or in

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Combination can be administered, and each DAA can be administered at least once a day, at least twice a day, or at least three times a day. Similarly, the ribavirin can be administered at least once a day, at least twice a day, or at least three times a day, either separately or in combination with one or more of the DAAs. In some preferred embodiments, therapeutic agent 3 is administered once daily (QD) or twice daily (BID) and therapeutic agent 1 is administered once daily.

In some aspects, the present technology provides a method of treating HCV infection comprising administering to a subject in need thereof at least two DAAs and ribavirin for a period of no more than twelve weeks, wherein the subject is not interferon during this Duration is administered. In some aspects, the at least two DAAs and ribavirin are administered in an amount effective to result in SVR. Some methods further include administering a cytochrome P450 inhibitor to the subject. In some aspects, the duration is no more than eight weeks.

In some aspects of the present technology, the at least two direct acting antiviral agents comprise (i) Compound 1, or a pharmaceutically acceptable salt thereof, being co-administered, or and (ii) Compound 2, acceptable salt thereof.

In other aspects, the at least two direct acting antiviral agents comprise (i) Compound 1 or a pharmaceutically acceptable salt thereof which is administered or co-formulated with ritonavir, and

Compound 3 or a pharmaceutically acceptable salt thereof.

In yet another aspect, the at least two direct acting antiviral agents comprise (i) Compound 1 or a pharmaceutically acceptable salt thereof, which (s) is co-administered or co-formulated with ritonavir, and (ii) Compound 4 or a pharmaceutically acceptable salt thereof .

In yet another aspect, the at least two direct acting antiviral agents comprise (i) Compound 1 co-formulated with or a pharmaceutical which (s) ritonavir, codi)

6/229 • ·: -6 ···· ·· · * · · · · · ·· · ·· · · · or a pharmaceutically acceptable salt thereof which is co-administered or co-formulated with ritonavir, (ii) Compound 2 or a pharmaceutically acceptable salt thereof; and (iii) Compound 4 or a pharmaceutically acceptable salt thereof.

In yet another aspect, the at least two directly acting antiviral agents comprise a drug combination selected from the group consisting of: a combination of PSI-7977 and PSI-938, a combination of BMS-790052 and BMS-650032, a combination of GS-5885 and GS-9451, a combination of GS-5885, GS-9190 and GS-9451, a combination from BI-201335 and BI-27127, a combination of telaprevir and VX-222, a combination of PSI-7977 and TMC-435, and a combination of danoprevir and R7128. In another aspect, the at least two direct acting antiviral agents comprise a combination of PSI-7977 and BMS790052 (daclatasvir). In yet another aspect, the at least two direct acting antiviral agents comprise a combination of PSI-7977 and BMS-650032 (asunaprevir). In yet another aspect, the at least two direct acting antiviral agents comprise a combination of PSI-7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another aspect, the at least two direct acting antiviral agents comprise a combination of TMC-435 and daclatasvir.

In other aspects, the present technology provides a method of treating HCV infection in a subject comprising administering (a) therapeutic agent 1, (b) at least one polymerase inhibitor selected from the group consisting of therapeutic agent 2, therapeutic agent 3 and combinations thereof, (c) ribavirin and (d) a cytochrome P450 inhibitor to the subject and for a duration of no more than twelve weeks, wherein the therapeutic agent 1, the at least one polymerase inhibitor, the ribavirin and the cytochrome P450 inhibitor are administered in amounts effective to result in SVR in the subject.

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In yet another aspect, the present technology provides a method of treating a population of subjects who have HCV infection, the method comprising administering to the subjects at least two DAAs for a period of no more than 12 weeks, wherein the at least two DAAs are administered to the subjects in amounts and for a duration effective to result in SVR in at least about 70% of the population.

In another aspect, the present technology provides a combination of at least two DAAs for use in the treatment of HCV infection, wherein the duration of the treatment regimen is no more than twelve weeks (for example, the duration is 12 weeks; or the duration is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks). Treatment involves administering the at least two DAAs to an individual infected with HCV. Preferably the duration of the treatment regimen is twelve weeks. The duration of the treatment can also last, for example, for no more than eight weeks (for example, di the duration is 8 weeks; or the duration is 7, 6, 5, 4 or 3 weeks). Treatment includes administration of ribavirin but not administration of interferon. Treatment may also include administration of ritonavir or another CYP3A4 inhibitor (for example, cobicistat) if any of the DAAs require pharmacokinetic enhancement. The at least two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and another DAA can be administered twice a day. As another example, the two DAAs are administered once a day. Again, as another example, the two DAAs are co-formulated in a single composition and administered simultaneously (e.g., once a day). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment naïve patient, an HCV treatment experienced patient

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Patient, an interferon non-responder (e.g., a null responder, a partial responder, or a relapser), or he may be a non-candidate for interferon treatment.

In another aspect, the present technology provides a combination of a compound acceptable salt thereof) and (or a pharmaceutically acceptable compound 2 (or a (for example (or the salt for example Compound 2 pharmaceutically acceptable salt thereof) for use in the treatment of an HCV- Treatment involves administering the DAAs to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (for example, the duration is twelve weeks); or the duration is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks). Preferably the

Duration of the treatment regimen twelve weeks. The duration of treatment can also last, for example, for no more than eight weeks (for example, the duration is 8 weeks; or the duration is 7, 6, 5, 4 or 3 weeks). Treatment includes that

Administration of ribavirin, but not interferon; and ritonavir or another CYP3A4 inhibitor

Cobicistat) is administered with compound 1 thereof) to improve the pharmacokinetics of the latter. Compound 1 (or the salt thereof) and Compound 2 (or the salt thereof) can be administered simultaneously or sequentially. For example, Compound 1 (or the salt thereof) can be administered once daily, along with ritonavir or another CYP3A4 inhibitor (e.g. cobicistat) and Compound 2 (or the salt thereof) can be administered twice daily. As yet another example, Compound 1 (or the salt thereof) and ritonavir (or another CYP3A4 inhibitor, e.g., cobicistat) are co-formulated in a single composition and are administered simultaneously (e.g., once a day). As yet another example, Compound 1 (or the salt thereof) is coformulated with ritonavir (or another CYP3A4 inhibitor, cobicistat) administered once daily (or the salt thereof). As a non-limiting example, the HCV genotype 1 patient treated, such as genotype; and twice a day

9/229 «· ·· ·· · ·· ··· la or lb, be infected. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a null responder), or may not be a candidate for interferon treatment. In one example, treatment lasts for twelve weeks and the subject being treated is a naive patient infected with HCV genotype 1. In another example, treatment lasts for 11 weeks and the subject treated is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 10 weeks and the subject treated is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 9 weeks and the treated subject is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 8 weeks and the treated subject is a naive patient, infected with HCV genotype 1. In yet another example, treatment lasts for 12 weeks and the subject treated is a naive patient infected with HCV genotype 2. In another example, treatment lasts for 11 weeks and the treated subject is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 10 weeks and the treated subject is a naive patient, infected with HCV genotype 2. In yet another example, treatment lasts for 9 weeks and the subject treated is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 8 weeks and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 12 weeks and the subject being treated is a naive patient , infected with HCV genotype 3. In another example, treatment lasts for 11 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 10 weeks,

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10 and the treated subject is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 9 weeks and the treated subject is a naive patient infected with HCV genotype 3. In yet another example treatment continues for 8 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, treatment lasts for 12 weeks and the subject being treated is a non-responder (e.g. a null responder) infected with HCV genotype 1. In another example, treatment lasts for 11 weeks, and that treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 10 weeks and the treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 8 weeks and the subject treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.

In another aspect, the present technology provides a combination of Compound 1 (or a pharmaceutically acceptable salt thereof) and Compound 3 (or a pharmaceutically acceptable salt thereof) for use in the treatment of HCV infection. Treatment involves administering the DAAs to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (for example, the duration is 12 weeks; or the duration is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks). Preferably the duration of the treatment regimen is twelve weeks. The duration of treatment can also last, for example, for no more than eight weeks (for example, the duration is eight weeks; or the duration is 7, 6, 5, 4, or 3 weeks). Treatment includes administration of ribavirin, but not interferon, and ritonavir or another CYP3A4 inhibitor (for example, cobicistat)

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-11.«· ·· ·· · ·· ...

Compound 1 (or the salt thereof) administered to improve the pharmacokinetics of the latter. Compound 1 (or the salt thereof) and Compound 3 (or the salt thereof) can be administered simultaneously or sequentially. For example, Compound 1 (or the salt thereof) can be administered once a day, along with ritonavir or another CYP3A4 inhibitor (e.g. cobicistat), and Compound 3 (or the salt thereof) can be administered twice a day. As another example, Compound 1 (or the salt thereof) and Compound 3 (or the salt thereof) are administered once a day. As yet another example, Compound 1 (or the salt thereof) and ritonavir (or another CYP3A4 inhibitor, e.g., cobicistat) are co-formulated in a single composition and administered simultaneously (e.g., once a day). As yet another example, Compound 1 (or the salt thereof), ritonavir (or another CYP3A4 inhibitor, e.g. cobicistat), and Compound 3 (or the salt thereof) are co-formulated in a single composition and are administered simultaneously ( for example once a day). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a null responder), or not a candidate for interferon treatment. In one example, treatment lasts for 12 weeks and the treated subject is a naive patient infected with HCV genotype 1. In another example, treatment lasts for 11 weeks and the treated subject is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 10 weeks and the subject treated is a naive patient infected with HCV genotype 1. In yet another example, treatment continues for 9 weeks and the subject treated is a naive patient infected with HCV12 / 229 • · · · _{Ί o} · · • · · · · » • · · · · · · • · · · · · · • ···

Genotype 1. In yet another example, the treatment lasts for 8 weeks and the treated subject is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks and the treated subject is a naive Patient infected with HCV genotype 2. In another example, treatment lasts for 11 weeks and the subject treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 10 weeks and the treated subject is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 9 weeks and the treated subject is a naive patient, infected with HCV genotype 2. In yet another example, treatment lasts for 8 weeks and the subject treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 12 weeks and the treated subject is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 11 weeks and the treated subject is a naive patient, infected with HCV genotype 3. In yet another example, treatment lasts for 10 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 9 weeks and the treated subject is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 8 weeks and the treated subject is a naive patient, infected with HCV genotype 3. In yet another example, treatment lasts for 12 weeks and the subject treated is a non-responder (e.g. a null responder) infected with HCV genotype 1. In another example, treatment lasts for 11 weeks and the subject treated is a NonResponder (e.g., a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 10 weeks and the subject treated is a Non-responders (for example a null responder) infected with HCV genotype 1. In yet another example, it lasts

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Treatment for 9 weeks and the treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 8 weeks and the treated subject is a non- Responders (for example, a null responder) infected with HCV genotype 1.

In another aspect, the present technology provides a combination of Compound 1 (or a pharmaceutically acceptable salt thereof) and Compound 4 (or a pharmaceutically acceptable salt thereof) for use in the treatment of HCV infection. Treatment involves administering the DAAs to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (for example, the duration is 12 weeks; or the duration is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks). Preferably the duration of the treatment regimen is twelve weeks. The duration of treatment can also last, for example, for no more than eight weeks (for example, the duration is eight weeks; or the duration is 7, 6, 5, 4 or 3 weeks). Treatment includes administration of ribavirin, but not interferon, and ritonavir or another CYP3A4 inhibitor (e.g. cobicistat) is administered with compound 1 (or the salt thereof) to improve the pharmacokinetics of the latter. Compound 1 (or the salt thereof) and Compound 4 (or the salt thereof) can be administered simultaneously or sequentially. For example, Compound 1 (or the salt thereof) can be administered once daily, along with ritonavir or another CYP3A4 inhibitor (e.g. cobicistat), and Compound 4 (or the salt thereof) can be administered twice daily. As another example, Compound 1 (or the salt thereof) and Compound 4 (or the salt thereof) are administered once a day. As yet another example, Compound 1 (or the salt thereof) and ritonavir (or another CYP3A4 inhibitor, e.g., cobicistat) are co-formulated in a single composition and are administered simultaneously (e.g., once daily). Yet another example is compound 1 (or the salt thereof), ritonavir / 229

<img file="AT514003A2_D0004.tif" />

(Or another CYP3A4 inhibitor, for example cobicistat), and Compound 4 (or the salt thereof) are co-formulated in a single composition at the same time (for example, once a day) administered.

As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient may be infected with genotype 2 or HCV

3. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a null responder), or no candidate for interferon treatment. In one example, treatment lasts for twelve weeks and the subject treated is a naive patient infected with HCV genotype 1. In another example, treatment lasts for eleven weeks and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 10 weeks and the subject treated is a naive patient, infected with HCV genotype 1. In yet another example, treatment lasts for 9 weeks and the subject treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks and the treated subject is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks and the treated subject is a naive patient, infected with HCV genotype 2. In another example, treatment lasts for 11 weeks and the subject treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 10 weeks and the treated subject is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 9 weeks and the treated subject is a naive patient, infected with HCV genotype 2. In yet another example, the

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• ·· ·· ·· · · ·· ·· ·· · ·· ···

Treatment for 8 weeks and the treated subject is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 12 weeks and the treated subject is a naive patient infected with HCV genotype 3. In In another example, treatment lasts for 11 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 10 weeks and the treated subject is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 9 weeks and the treated subject is a naive patient, infected with HCV genotype 3. In yet another example, treatment lasts for 8 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 12 weeks and the treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and that treated subject is a non-responder (e.g. null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 10 weeks and the treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks, and that treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 8 weeks and the subject treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.

In another aspect, the present technology provides a combination of Compound 1 (or a pharmaceutically acceptable salt thereof), Compound 2 (or a pharmaceutically acceptable salt thereof), and Compound 4 (or a pharmaceutically acceptable salt thereof) for use in the treatment of HCV -infection. Treatment involves administering the DAAs to the subject infected with HCV. The duration of the treatment regimen is no more than 12

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Weeks (for example, the duration is 12 weeks; or the duration is 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably the duration of the treatment regimen is twelve weeks. The duration of treatment can also last, for example, for no more than eight weeks (for example, the duration is 8 weeks; or the duration is 7, 6, 5, 4, or 3 weeks). Treatment includes administration of ribavirin, but not interferon; and ritonavir or another CYP3A4 inhibitor (e.g. cobicistat) is administered with compound 1 (or the salt thereof) to improve the pharmacokinetics of the latter. Compound 1 (or the salt thereof), Compound 2 (or the salt thereof) and Compound 4 (or the salt thereof) can be administered simultaneously or sequentially. For example, Compound 1 (or the salt thereof) can be administered once a day, along with ritonavir or another CYP3A4 inhibitor (e.g. cobicistat), and Compound 4 (or the salt thereof) can be administered once a day and Compound 2 (or the salt thereof) can be given twice a day. As another example, Compound 1 (or the salt thereof), Compound 4 (or the salt thereof) and ritonavir (or another CYP3A4 inhibitor, for example cobicistat) are co-formulated in a single composition and simultaneously (for example, once a day ) administered. As yet another example, Compound 1 (or the salt thereof), roitonavir (or another CYP3A4 inhibitor, for example cobicistat), and Compound 4 (or the salt thereof) are coformulated in a single composition and are administered simultaneously (for example once a day); and Compound 2 (or the salt thereof) are administered twice a day. As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a null responder), or none / 229

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»17.• · ·· • ···

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Candidate for interferon treatment. In one example, treatment lasts for twelve weeks and the subject being treated is a naive patient infected with HCV genotype 1. In another example, treatment lasts for 11 weeks and the subject treated is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 10 weeks and the subject treated is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 9 weeks and the treated subject is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 8 weeks and the treated subject is a naive patient, infected with HCV genotype 1. In yet another example, treatment lasts for 12 weeks and the subject treated is a naive patient infected with HCV genotype 2. In another example, treatment lasts for 11 weeks and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 10 weeks and the subject being treated is a naive patient, infected with HCV genotype 2. In yet another example, treatment lasts for 9 weeks and the subject treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 8 weeks and the treated subject is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 12 weeks and the treated subject is a naive patient, infected with HCV genotype 3. In another example, treatment lasts for 11 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, treatment lasts for 10 weeks and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, treatment lasts for 9 weeks and the subject being treated is a naive patient , infected with HCV genotype 3. In yet another example, treatment lasts for 8 weeks and the treated subject is a naive patient infected with HCV18 / 229

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« ··· • · ·· ·#·

Genotype 3. In yet another example, treatment lasts for 12 weeks and the subject treated is a non-responder (e.g. a null responder) infected with HCV genotype 1. In another example, treatment lasts for 11 weeks , and the subject being treated is a NonResponder (e.g. a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 10 weeks and the subject being treated is a

Non-responders (for example a null responder) infected with

HCV genotype 1. In yet another example, the lasts

Treatment for 9 weeks and the subject treated is a

Non-responders (e.g. a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 8 weeks and the treated subject is a non-responder (e.g. a null responder) infected with HCV- Genotype 1.

In another aspect, the present technology features a combination of at least two DAAs for use in treating HCV infection, wherein the combination comprises a combination selected from:

a combination of PSI-7977 and PSI-938, a combination of BMS-790052 and BMS-650032, a combination of GS-5885 and GS-9451, a combination of GS-5885, GS-9190 and GS-9451, a combination composed of BI-201335 and BI-27127, a combination of telaprevir and VX-222, a combination of PSI-7977 and TMC-435, and a combination of danoprevir and R7128.

Treatment involves administering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (for example, the duration is 12 weeks; or the duration is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks). Preferably the duration of the treatment regimen is twelve weeks. The duration of treatment can also, for example, last for no more than eight weeks (for example the duration is 8 weeks; or the duration is 7, 6, 5, 4

19/229 • · · · 1 Q ± • · · «- ± bi-« • · · »· · • ·· · · · ·· ·· ·· · ·· ··· or 3 weeks). Treatment includes administration of ribavirin, but not interferon. Treatment may also include administration of ritonavir or another CYP3A4 inhibitor (for example, cobicistat) if any of the DAAs require pharmacokinetic improvement. The at least two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and another DAA can be administered twice a day. As another example, the two DAAs are administered once a day. As yet another example, the two DAAs are co-formulated into a single composition and are administered simultaneously (e.g., once a day). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a null responder), or no candidate for interferon treatment.

In yet another aspect, the present technology features a combination of at least two DAAs for use in treating HCV infection, wherein the combination comprises a combination selected from:

<td>a</td><td>combination</td><td>out</td>

<td>a</td><td>combination</td><td>out</td>

<td>a</td><td>combination</td><td>out</td>

<td>a</td><td>combination</td><td>out</td>

<td>a</td><td>combination</td><td>out</td>

<td>a</td><td>combination</td><td>out</td>

PSI-7977 and BMS-790052

PSI-7977 and BMS-650032,

PSI-7977, BMS-790052 and BMS-650032, INX-189 and BMS-790052 INX-189 and BMS-650032 or INX-189, BMS-790052 and BMS-650032.

Treatment involves administering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (for example, the duration is 12 weeks; or the duration is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks). Preferably the duration of / 229 · · • 9 9

9 9

9 9 ···· ···· 9999 9999 or \ · · *&gt; ·

-2Ci- · · ··· • · · · ·· · »···

Treatment regime twelve weeks. The duration of treatment can also last, for example, for no more than eight weeks (for example the duration is 8 weeks; or the duration is 7, 6, 5, 4 or 3 weeks). Treatment includes administration of ribavirin, but not interferon. Treatment may include administration of ritonavir or another CYP3A4 inhibitor (e.g. cobicistat) if any of the DAAs are in need of pharmacokinetic enhancement. The at least two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and another DAA can be administered twice a day. As another example, the two DAAs are administered once a day. As yet another example, the two DAAs are co-formulated in a single composition and are administered simultaneously (e.g., once a day). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a null responder), or not a candidate for interferon treatment.

In yet another aspect, the present technology features PSI-7977, or a combination of at least two DAAs for use in the treatment of HCV infection, wherein the combination comprises a combination selected from:

a combination of mericitabine and danoprevir, a combination of INX-189, daclatasvir and BMS-791325, and a combination of PSI-7977 and GS-5885.

Treatment includes administering PSI-7977 or the

DAA combination to a subject infected with HCV. The

Duration of the treatment regimen is no more than twelve weeks (for example the duration is 12 weeks, or the duration is 11,

21/229

-2110, 9, 8, 7, 6, 5, 4 or 3 weeks). For example, the duration of the treatment regimen is no more than eight weeks (for example, the duration is 8 weeks; or the duration is 7, 6, 5, 4, or 3

Weeks). Treatment includes administration of ribavirin, but not interferon. Treatment may include administration of ritonavir or another CYP3A4 inhibitor (for example, cobicistat) if any of the DAAs require pharmacokinetic enhancement. The at least two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and another DAA can be administered twice a day. As another example, the two DAAs can be administered once a day. As yet another example, the two DAAs are co-formulated in a single composition and are administered simultaneously (e.g., once a day). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a null responder), or no candidate for interferon treatment.

In yet another aspect, the present technology features PSI-7977, or a combination of at least two DAAs, for use in treating HCV infection, wherein the combination comprises a combination selected from:

a combination of mericitabine and danoprevir, a combination of INX-189, daclatasvir and BMS-791325, and a combination of PSI-7977 and GS-5885.

Treatment includes administering PSI-7977 or the

DAA combination to a subject infected with HCV. The

Duration of the treatment regimen is no more than twelve weeks (for example the duration is 12 weeks; or the duration is 11, / 229

-22······· ·· · ·· ·· ·· · ·· ···

10, 9, 8, 7, 6, 5, 4 or 3 weeks). Preferably the duration of the treatment regimen is twelve weeks. The duration of treatment can also, for example, last for no more than eight weeks (for example the duration is 8 weeks; or the duration is 7, 6,

5, 4 or 3 weeks). Treatment includes giving ribavirin, but not interferon. Treatment may include administration of ritonavir or another CYP3A4 inhibitor (for example, cobicistat) if any of the DAAs require pharmacokinetic enhancement. The at least two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and another DAA can be administered twice a day. As another example, the two DAAs are administered once a day. As yet another example, the two DAAs are co-formulated in a single composition and are administered simultaneously (e.g., once a day). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a null responder), or no candidate for interferon treatment.

In yet another aspect, the present technology features a combination of at least two DAAs for use in treating HCV infection, wherein the combination comprises a combination selected from:

a combination of tegobuvir and GS-9256, a combination of BMS-791325, asunaprevir and daclatasvir, and a combination of TMC-435 and daclatasvir.

Treatment involves administering the DAA combination to a subject infected with HCV. The duration of the

Treatment regimen is no more than twelve weeks (for example, the duration is 12 weeks; or the duration is 11, 10, 9, 8, 7, 6, / 229

-235, 4 or 3 weeks). Preferably the duration of the treatment regimen is twelve weeks. The duration of treatment can also last, for example, for no more than eight weeks (for example the duration is 8 weeks; or the duration is 7, 6, 5, 4 or 3 weeks). Treatment includes giving ribavirin, but not interferon. Treatment may include administration of ritonavir or another CYP3A4 inhibitor (e.g. cobicistat) if any of the DAAs require pharmacokinetic enhancement. The at least two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and another DAA can be administered twice a day. As another example, the two DAAs are administered once a day. As yet another example, the two DAAs are co-formulated into a single composition and are administered simultaneously (e.g., once a day). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a null responder), or no candidate for interferon treatment.

In yet another aspect, the present technology features a combination of PSI-7977 and BMS-790052 for use in treating HCV infection. Treatment involves administering the DAA combination to a subject infected with HCV. The duration of treatment can, for example, be no more than twelve weeks (for example the duration is 12 weeks; or the duration is 11, 10, 9, 8, 7, 6, 5, 4 the

Duration of or 3 weeks). Preferably, treatment regimen is twelve weeks. The duration of treatment can also last, for example, for no more than eight weeks (for example the duration is 8 weeks; or the duration is 7, 6, 5, 4 or 3 weeks). Treatment includes administering / 229 • ·

-24ribavirin, but not from interferon. Treatment may include administration of ritonavir or another CYP3A4 inhibitor (e.g. cobicistat) if any of the DAAs require pharmacokinetic enhancement. The two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and the other DAA can be administered twice a day. As another example, the two DAAs are administered once a day. As yet another example, the two DAAs are co-formulated in a single composition and are administered simultaneously (e.g., once a day). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a null responder), or no candidate for interferon treatment. In one example, treatment continues for twelve weeks and the subject treated is a naive patient infected with HCV genotype 1. In another example, treatment lasts for eleven weeks and the subject treated is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for ten weeks and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for nine weeks and the subject being treated is a naive patient , infected with HCV genotype 1. In yet another example, treatment lasts for 8 weeks and the patient being treated is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 12 weeks and the subject being treated is a naive patient , infected with HCV genotype 2. In another example, treatment continues for 11 weeks and the subject treated is a naive patient infected with HCV genotype 2. In yet another example / 229 • · ·· ···· ···· ···· ί ***

<img file="AT514003A2_D0009.tif" />

treatment lasts for 10 weeks and the treated subject is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 9 weeks and the treated subject is a naive patient infected with HCV- Genotype 2. In yet another example, treatment lasts for 8 weeks and the subject treated is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 12 weeks and the subject being treated is a naive patient infected with HCV genotype 3. In another example, treatment lasts for 11 weeks and the subject being treated is a naive patient, infected with HCV genotype 3. In yet another example, treatment lasts for 10 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, treatment lasts for 9 weeks and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, treatment lasts for 8 weeks and the subject being treated is a naive patient , infected with HCV genotype 3. In yet another example, treatment lasts for 12 weeks and the subject treated is a non-responder (e.g. a null responder) infected with HCV genotype 1. In another example, treatment lasts for 11 weeks and the subject treated is a NonResponder (e.g., a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 10 weeks and the subject treated is a Non-responders (e.g. a null responder) infected with HCV genotype 1. In another example, treatment lasts for 9 weeks and the treated subject is a NonResponder (e.g. a null responder) infected with HCV genotype 1. In another example, treatment lasts for 8 weeks and the treated subject is a Non Responders (for example a null responder) infected with HCV genotype 1.

In yet another aspect, the present technology features a combination of PSI-7977 and TMC-435 for use in the treatment of HCV infection. The treatment / 229

<img file="AT514003A2_D0010.tif" />

·· ·· ·· · ·· ··· involves administering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (for example, the duration is 12 weeks; or the duration is 11, 10, 9, 8, 7, 6, 5, 4 or 3

Weeks). Preferably the duration of the treatment regimen is twelve weeks. The duration of treatment can also last, for example, for no more than eight weeks (for example the duration is 8 weeks; or the duration is 7, 6, 5, 4 or 3 weeks). Treatment includes giving ribavirin, but not interferon. Treatment may include administration of ritonavir or another CYP3A4 inhibitor (for example, cobicistat) if any of the DAAs require pharmacokinetic enhancement. The two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and the other DAA can be administered twice a day. As another example, the two DAAs are administered once a day. As yet another example, the two DAAs are co-formulated in a single composition and are administered simultaneously (e.g., once a day). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a null responder), or no candidate for interferon treatment. In one example, treatment lasts for 12 weeks and the subject treated is a naive patient infected with HCV genotype 1. In another example, treatment lasts for 11 weeks and the treated subject is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 10 weeks and the treated subject is a naive patient, infected with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks and the treated / 229, · * ·········

-2.Ί ,, ,, ·· · ·· ··

The subject is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 8 weeks and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 12 weeks and the subject being treated is a naive patient infected with HCV genotype 2. In another example, treatment lasts for 11 weeks and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 10 weeks and the subject being treated is a naive patient, infected with HCV genotype 2. In yet another example, treatment lasts for 9 weeks and the subject treated is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 8 weeks and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 12 weeks and the subject being treated is a naive patient , infected with HCV genotype 3. In another example, treatment lasts for 11 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 10 weeks and the treated subject is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 9 weeks and the treated subject is a naive patient , infected with HCV genotype 3. In yet another example, treatment lasts for 8 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 12 weeks and the treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and that treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 10 weeks and the treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In again / 229 ·· ···· ···· ···· ···· In another example, treatment lasts for 9 weeks and the treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 8 weeks and the subject treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.

In yet another aspect, the present technology provides a combination of danoprevir and mercitabine for use in the treatment of HCV infection. Treatment involves administering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is no more than sixteen weeks (for example, the duration is 16 weeks; or the duration is 14, 12 or 10 weeks). The duration of the treatment regimen can also be less than ten weeks. Treatment includes administering ribavirin, but not either interferon. Treatment also includes co-administration of ritonavir or another CYP3A4 inhibitor (e.g. cobicistat) with danoprevir to improve the pharmacokinetics of danoprevir. The two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and the other DAA can be administered twice a day. As another example, the two DAAs are administered once a day. As yet another example, the two DAAs are co-formulated in a single composition and are administered simultaneously (e.g., once a day). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a null responder), or no candidate for interferon treatment. In one example, the treatment lasts / 229

-2 9-:

• ··· • 4

I · 4 ·· ··· ·· ·· ·· for 16 weeks, and the treated subject is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 15 weeks and the treated subject is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 14 weeks and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 13 weeks and the treated subject is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks and the treated subject is a naive patient, infected with HCV genotype 1. In yet another example, treatment lasts for 12 weeks and the subject treated is a naive patient infected with HCV genotype 2. In another example, treatment lasts for 11 weeks and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 10 weeks and the subject being treated is a naive patient, infected with HCV genotype 2. In yet another example, treatment lasts for 9 weeks and the subject treated is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 8 weeks and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 16 weeks and the subject being treated is a naive patient , infected with HCV genotype 3. In another example, treatment lasts for 15 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, treatment lasts for 14 weeks and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, treatment lasts for 13 weeks and the subject being treated is a naive patient , infected with HCV genotype 3. In yet another example, treatment lasts for 12 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 16/229

<img file="AT514003A2_D0011.tif" />

·· ···· ··*♦ ···· ···· • · ··

<img file="AT514003A2_D0012.tif" />

Weeks on and the subject being treated is a non-responder (e.g. a null responder) infected with HCV genotype 1. In another example, treatment lasts for 15 weeks and the subject being treated is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 14 weeks and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 13 weeks and the subject treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 12 weeks, and the subject being treated is a non-responder (e.g. a null responder) infected with HCV genotype 1.

In yet another aspect, the present technology features a combination of INX-189, daclatasvir, and BMS791325 for use in treating HCV infection. Treatment involves administering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is no more than sixteen weeks (for example, the duration is 16 weeks; or the duration is 14, 12 or 10 weeks). The duration of the treatment regimen can also be less than 10 weeks. Treatment includes giving ribavirin, but not interferon. Treatment may include administration of ritonavir or another CYP3A4 inhibitor (e.g. cobicistat) if any of the DAAs require pharmacokinetic enhancement. The two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and the other DAA can be administered twice a day. As another example, the two DAAs are administered once a day. As yet another example, the two DAAs are co-formulated in a single composition and are administered simultaneously (e.g., once a day). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the

31/229

-31-!

» • · · * &lt; • · · * · • « · · · · » 9 9 9 9 9 « ···

HCV genotype 2 or 3 infected. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a null responder), or no candidate for interferon treatment. In one example, treatment continues for 16 weeks and the subject treated is a naive patient infected with HCV genotype 1. In another example, treatment lasts for 15 weeks and the treated subject is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 14 weeks and the treated subject is a naive patient, infected with HCV genotype 1. In yet another example, treatment lasts for 13 weeks and the subject treated is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 12 weeks and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 12 weeks and the subject being treated is a naive patient , infected with HCV genotype 2. In another example, treatment lasts for 11 weeks and the subject treated is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 10 weeks and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 9 weeks and the subject being treated is a naive patient , infected with HCV genotype 2. In yet another example, treatment lasts for 8 weeks and the subject treated is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 16 weeks and the treated subject is a naive patient infected with HCV genotype 3. In another example, treatment lasts for 15 weeks and the treated subject is a naive patient infected with HCV genotype 3. In yet another example, treatment lasts for 14 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 13 weeks and the treated subject is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 12 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 16 weeks and the treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In another example, the treatment lasts for 15 weeks, and that treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 14 weeks and the subject treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 13 weeks, and the subject being treated is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 12 weeks and the subject treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.

In yet another aspect, the present technology features a combination of PSI-7977 and GS-5885 for use in treating HCV infection. Treatment involves administering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is no more than sixteen weeks (for example, the duration is 16 weeks; or the duration is 14, 12 or 10 weeks). The duration of the treatment regimen can also be less than 10 weeks. Treatment includes giving ribavirin, but not interferon. Treatment may include administration of ritonavir or another CYP3A4 inhibitor (for example, cobicistat) if any of the DAAs require pharmacokinetic enhancement. The two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and the other DAA can be administered twice a day. As another / 229: -33-:

• · and are simultaneously daily). As a not

For example, the two DAAs are administered once a day. As yet another example, the two DAAs are co-formulated administered in a single composition (e.g., once limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype Ia or Ib. As another non-limiting example, the Patient with HCV genotype 2 or 3 infected. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a

Null Responder), or no candidate for one

Interferon treatment. In one example, treatment lasts for 16 weeks and the treated subject is a naive patient infected with HCV genotype 1. In another example, treatment lasts for 15 weeks and the treated subject is a naive patient infected with HCV Genotype 1. In yet another example, treatment continues for 14 weeks and the subject treated is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 13 weeks and the treated subject is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 12 weeks and the treated subject is a naive patient, infected with HCV genotype 1. In yet another example, treatment continues for 12 weeks and the subject treated is a naive patient infected with HCV genotype 2. In another example, treatment lasts for 11 weeks and the treated subject is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 10 weeks and the treated subject is a naive patient, infected with HCV genotype 2. In yet another example, treatment continues for 9 weeks and the subject treated is a naive patient infected with HCV genotype 2. In yet another example, treatment continues for 8 weeks and the subject treated is a naive patient infected with HCV genotype 2. In again a / 229

<img file="AT514003A2_D0013.tif" />

• · · • · · · the

HCV, for another example, continues treatment for 16 weeks and treated subject is a naive patient infected with genotype 3. In another example, treatment continues

Weeks on and the treated subject is a naive patient infected with HCV genotype 3. In yet another example, treatment lasts for 14 weeks and the treated subject is a naive patient infected with HCV genotype 3. In yet another example For example, treatment continues for 13 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, treatment lasts for 12 weeks and the treated subject is a naive patient infected with HCV genotype 3. In yet another example, treatment lasts for 16 weeks and the treated subject is a non-responder (for example a null responder) infected with HCV genotype 1. In another example, treatment lasts for 15 weeks and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 14 weeks and the treated The subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 13 weeks and the treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks, and that treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1.

In yet another aspect, the present technology features a combination of TMC-435 and daclatasvir for use in the treatment of HCV infection. Treatment involves administering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (for example, the duration is 12 weeks; or the duration is 11, 10, 9, 8, 7, 6, 5, 4 or 3 weeks). Preferably the duration of the treatment regimen is twelve weeks. The duration of the treatment can also last for example for no more than eight weeks (for example the duration is / 229

3ε: 8 weeks; or the duration is 7, 6, 5, 4 or 3 weeks). Treatment includes administering ribavirin, but does not include administering interferon. Treatment may include administration of ritonavir or another CYP3A4 inhibitor (e.g. cobicistat) if any of the DAAs require pharmacokinetic enhancement. The two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and the other DAA can be administered twice a day. As another example, the two DAAs are administered once a day. As yet another example, the two DAAs are co-formulated in a single composition and are administered simultaneously (e.g., once a day). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a null responder), or no candidate for interferon treatment. In one example, treatment lasts for 12 weeks and the treated subject is a naive patient infected with HCV genotype 1. In another example, treatment lasts for 11 weeks and the treated subject is a naive patient infected with HCV Genotype 1. In yet another example, treatment continues for 10 weeks and the subject treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks and the treated subject is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks and the treated subject is a naive patient, infected with HCV genotype 1. In yet another example, treatment continues for 12 weeks and the subject treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 11 weeks, / 229: -35 • · · • · · and the treated subject is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 10 weeks , and the treated subject is a naive patient infected with HCV genotype 2. In yet another example, treatment lasts for 9 weeks and the treated subject is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 8 weeks and the treated subject is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 12 weeks and the treated subject is a naive patient, infected with HCV genotype 3. In another example, treatment lasts for 11 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 10 weeks and the treated subject is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 9 weeks and the treated subject is a naive patient, infected with HCV genotype 3. In yet another example, treatment lasts for 8 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, treatment lasts for 12 weeks and the subject treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In another example, treatment lasts for 11 weeks and the treated The subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 10 weeks and the treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks, and that treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 8 weeks and the subject treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.

In another aspect, the present invention provides / 229 ft · · · · where the • Q * “7 · · · · • Often / · ftft · • · · · · · · · · ftft ftft · ft ·· ·· ·

Methods of treating HCV infection,

Methods comprise administering at least two direct acting antiviral agents (DAAs) and ribavirin to a subject in need thereof, and the treatment does not include administering interferon to the subject. The treatment can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. The treatment is preferably 12 weeks. Treatment can also last 8 weeks. For example, the subject being treated may be an HCV treatment naive patient. The subject can also be an experienced patient, or an interferon non-responder (e.g. a null responder). Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In one embodiment of this aspect of the invention, the at least two DAAs comprise (i) Compound 1 or a pharmaceutically acceptable salt thereof, and (ii) Compound 2 or a pharmaceutically acceptable salt thereof, and the method further comprises administering ritonavir to the subject. Ritonavir improves the pharmacokinetics or drug availability of compound 1. The treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks.

The treatment is preferably 12 weeks. The treatment can also last 8 weeks. For example, the subject being treated may be a treatment-naïve patient. The subject can also be an experienced patient, or an interferon non-responder (e.g. a null responder). Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In another embodiment of this aspect of the invention, the at least two DAAs comprise (i) Compound 1 or a pharmaceutically acceptable salt thereof, and (ii)

38/229 :-33-:

·· ·· ·· ·· ··· or a null responder) or a null responder)

Compound 4 or a pharmaceutically acceptable salt thereof, and the method further comprises administering ritonavir to the subject to improve the pharmacokinetics or drug availability of Compound 1. The treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. The treatment is preferably 12 weeks. The treatment can also last for 8 weeks. For example, the subject being treated may be a treatment-naive patient. The subject can also be a treatment-experienced patient, interferon non-responder (e.g. a

Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In another embodiment of this aspect of this invention, the at least two DAAs comprise (i) Compound 1 or a pharmaceutically acceptable salt thereof, (ii) Compound 2 or a pharmaceutically acceptable salt thereof, and (iii) Compound 4 or a pharmaceutically acceptable salt thereof, and the method further comprises administering ritonavir to the subject to improve the pharmacokinetics or drug availability of compound 1. The treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. The treatment is preferably 12 weeks. The treatment can also last for 8 weeks. For example, the subject being treated may be a treatment-naive patient. The subject may also be a treatment-experienced patient, interferon non-responder (e.g., preferably the subject being treated is infected with HCV genotype 1, e.g., HCV genotype Ia. As another non-limiting example, the subject being treated is infected with HCV Genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise an HCV and an HCV polymerase inhibitor. The

Protease inhibitor / 229: -δδ-:

• · ·

Treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. The treatment is preferably 12 weeks. Treatment can also last 8 weeks. For example, the subject being treated may be a treatment-naive patient. The subject can also be an experienced patient, or an interferon non-responder (e.g. a null responder). Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise an HCV protease inhibitor and a non-nucleoside or non-nucleotide HCV polymerase inhibitor. The treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. The treatment is preferably 12 weeks. Treatment can also last 8 weeks. For example, the subject being treated may be a treatment-naive patient.

also an experienced patient

Interferon non-responders (for example a

The subject can be, or a null responder).

Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise an HCV protease inhibitor and a nucleoside or nucleotide HCV polymerase inhibitor. The treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably that lasts

Treatment 12 weeks. Treatment can also last 8 weeks. For example, the subject being treated may be a treatment-naive patient. The subject can also be an experienced patient, or an interferon non-responder (e.g. a null responder). Preferably the subject being treated is / 229

-4α infected with HCV genotype 1, for example HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise an HCV protease inhibitor and an HCV NS5A inhibitor. The treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. The treatment is preferably 12 weeks. Treatment can also last 8 weeks. For example, the subject being treated may be a treatment-naive patient.

even a patient experienced in treatment interferon non-responder (for example a

The subject can be, or a null responder).

Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise an HCV polymerase inhibitor and an HCV NS5A inhibitor. The treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. The treatment is preferably 12 weeks. Treatment can also last 8 weeks. The treated subject can, for example, be a treatment-naive patient as well as a treatment-experienced patient

Interferon non-responders (for example a null responder).

Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise an HCV non-nucleoside or non-nucleotide polymerase inhibitor and an HCV NS5A inhibitor. The treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably that lasts

The subject can be, or a

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<img file="AT514003A2_D0014.tif" />

• · · · ·

Treatment 12 weeks. Treatment can also last 8 weeks. For example, the subject being treated may be a treatment-naive patient. The subject can also be an experienced patient, or an interferon non-responder (e.g. a null responder). Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise an HCV nucleoside or nucleotide polymerase inhibitor and an HCVNS5A inhibitor. The treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Treatment preferably lasts for 12 weeks. Treatment can also last 8 weeks. For example, the subject being treated may be a treatment-naive patient. The subject can also be a patient experienced in treatment or an interferon non-responder (e.g. a null responder). Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise PSI-7977 and TMC-435. The treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. The treatment is preferably 12 weeks. Treatment can also last 8 weeks. For example, the subject being treated may be a treatment-naive patient. The subject can also be an experienced patient, or an interferon non-responder (e.g. a null responder). Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs TMC-435 and / 229

Daclatasvir. For example, the treatment can last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably that lasts

Treatment 12 weeks. Treatment can also last 8 weeks. For example, the subject being treated may be a treatment-naive patient. The subject can also be an experienced patient, or an interferon non-responder (e.g. a null responder). Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise PSI-7977 and Daclatasvir. The treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably that lasts

Treatment 12 weeks. Treatment can also last 8 weeks. For example, the subject being treated may be a treatment-naive patient. The subject can also be an experienced patient, or an interferon non-responder (e.g. a null responder). Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise PSI-7977 and GS5885. The treatment can last for example and without limitation for no more than 12 weeks, such as 8, 9,

10, 11 or 12 weeks. Treatment preferably lasts 12

Weeks. Treatment can also last 8 weeks. For example, the subject being treated may be a treatment-naive patient. The subject can also be a treatment-experienced patient, or an interferon non-responder (e.g. a

Null responder). Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

without / 229: -ss-:

9 9 99

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise mericitabine and danoprevir. The treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably that lasts

Treatment 12 weeks. Treatment can also last 8 weeks. For example, the subject being treated may be a treatment-naive patient. The subject can also be an experienced patient, or an interferon non-responder (e.g. a null responder). Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise BMS-790052 and BMS-650032. The treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably that lasts

Treatment 12 weeks. Treatment can also last 8 weeks. For example, the subject being treated may be a treatment-naive patient. The subject can also be an experienced patient, or an interferon non-responder (e.g. a null responder). Preferably the subject being treated is infected with HCV genotype 1, for example HCV genotype Ib. As a non-limiting example, the subject treated is infected with HCV genotype la. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise INX-189, Daclatasvir and BMS-791325. The treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. The treatment is preferably 12 weeks. Treatment can also last 8 weeks. The treated treatment-naive patient

Subject can be. The subject

Example one can also be one

Be a treatment-experienced patient, or an Interferon-Non44 / 229

<img file="AT514003A2_D0015.tif" />

• ··· • · · · • ·· ···

Responder (for example a null responder). Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype la. As a non-limiting example, the subject being treated is infected with HCV genotype 3.

In yet another aspect, the present invention features methods of treating a treatment-naive subject with HCV genotype 1 infection, wherein the method comprises administering PSI-7977 and ribavirin to the patient, and the treatment does not include administering interferon to the Subject a. The treatment may, for example and without limitation, last for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. The treatment is preferably 12 weeks. Treatment can also last 8 weeks. Preferably the subject being treated is infected with genotype la. More preferably the treated subject is a naive patient infected with genotype 1. The treated subject can also be a treatment experienced patient or an interferon non-responder (e.g. a null responder) and / or it is infected with HCV genotype 3 . In one example the treatment lasts 12 weeks and the subject treated is a naive patient infected with genotype 1. In another example the treatment lasts 11 weeks and the subject treated is a naive patient infected with genotype 1. In yet another For example, the treatment lasts 10 weeks and the treated subject is a naive patient infected with genotype 1. In yet another example, treatment lasts 9 weeks and the subject being treated is a naive patient infected with genotype 1. In yet another example, treatment lasts 8 weeks and the subject treated is a naive patient infected with genotype 1. The present invention also features PSI-7977 or a pharmaceutically acceptable salt thereof for use in any treatment described in this aspect of the invention.

In yet another aspect, the present invention features methods of treating HCV infection, wherein the methods comprise administering at least two DAAs and / 229: 45-:

···· ···· ···· ···· • · · · • · · ··· • · · · «« ·· ·· · ·· ···

Comprise ribavirin to a subject in need thereof for a duration sufficient to produce a sustained virologic response. Treatment does not include administration of interferon. Any DAA combination described herein can be used. The duration can for example be no more than 8 weeks or preferably no more than 12 weeks.

A treatment regimen of the present technology is generally a complete treatment regimen, that is, no subsequent interferon-containing regimen is intended. Thus, a treatment or use described herein generally does not include a subsequent interferon-containing treatment.

Other features, objects, and advantages of the present invention will be apparent from the detailed description that follows. It should be understood, however, that the detailed description, while showing preferred embodiments of the invention, is provided for purposes of illustration, not limitation. Various changes and modifications within the scope of the invention will become apparent to those skilled in the art from the detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a 3-D surface map illustrating deviations from expected inhibitory effects of various concentrations of Compound 1 and Compound 2 in a genotype Ib HCV replicon assay.

Figure 2 is a contour map showing concentrations at which Compound 1 and Compound 2 exhibited synergistic, additive, or antagonistic interactions in the genotype Ib HCV replicon assay.

Figure 3 is a 3-D surface map illustrating deviations from expected inhibitory effects of various concentrations of Compound 1 and Compound 4 in a genotype Ib HCV replicon assay.

Figure 4 is a contour map showing concentrations at / 229 • ···

<img file="AT514003A2_D0016.tif" />

which compound 1 and compound 4 showed synergistic, additive, or antagonistic interactions in the genotype lb HCV replicon assay.

Figure 5A is a bar graph showing the percentage of cells containing HCV genotype la replicon constructs, which after 3 weeks of exposure to therapeutic agent 1, therapeutic agent 2, therapeutic agent 4 or a combination of some or all of these therapeutic agents in the presence of G418 survived.

Figure 5B is another bar graph showing the percentage of surviving la-H77 replicon cells that have grown in the presence of G418 and two or three DAA combinations for approximately three weeks.

FIG. 5C shows the effect of compound 1, compound 4 and a combination thereof in long-term HCV RNA reduction assays in IA-H77 replicon cell lines.

Figure 5D shows the effect of compound 1, compound 4 and a combination thereof in long-term HCV RNA reduction assays in Ib-Conl replicon cell lines.

FIG. 6A shows the predicted median value and 90% confidence interval of the SVR percentage for different treatment durations of a 2-DAA regimen without ribavirin; the 2 DAAs include compound 1 (in combination with ritonavir, i.e. compound 1 / r) and compound 2.

Figure 6B illustrates the predicted median and 90% confidence interval of the SVR percentage for various treatment durations of a 2-DAA regimen without ribavirin; the 2 DAAs include compound 1 (in combination with ritonavir, i.e. compound 1 / r) and compound 4.

FIG. 6C shows the predicted median value and 90% confidence interval of the SVR percentage for different treatment durations of a 3-DAA regimen without ribavirin; the 3 DAAs include: (i) Compound 1 (in combination with ritonavir, i.e. Compound 1 / r), (ii) Compound 2, and (iii) Compound 4.

Figure 7 shows the predicted exposure-response model / 229

<img file="AT514003A2_D0017.tif" />

versus the observed percentage of subjects with HCV RNA less than LOD over time in a clinical study described in Example 1.

Figure 8 demonstrates the predicted exposure response model versus the percentage of subjects observed with SVR12 in the clinical study described in Example 2A.

FIG. 9 shows the predicted median value and 90% confidence interval of SVR rates for different treatment durations of a 2-DAA regimen containing BMS-790052 and BMS-650032.

FIG. 10 shows the predicted median value of SVR rates for different treatment durations of a 3-DAA regimen containing compound 1 / r, compound 4 and PSI-7977.

FIG. 11 shows the predicted median value and 90% confidence interval of the SVR percentage for various treatment durations of a 1-DAA regimen containing PSI-7977 and ribavirin.

FIG. 12 shows the predicted median value and 90% confidence interval of the SVR percentage for different treatment durations of a 2-DAA regimen containing daclatasvir (BMS-790052) 60 mg QD and PSI-7977 400 mg QD.

FIG. 13 shows the predicted median value and 90% confidence interval of the SVR percentage for different treatment durations of a 2-DAA regimen containing TMC-435 150 mg QD and PSI-7977 400 mg QD.

FIG. 14 illustrates the predicted median value and 90% confidence interval of the SVR percentage for various treatment durations of a 2-DAA regimen containing danoprevir 100 mg BID and mercitabine 750 mg BID.

FIG. 15 shows the predicted median value and 90% confidence interval of the SVR percentage for different treatment durations of a 2-DAA regimen containing GS-9190 (tegobuvir) 30 mg BID + GS-9451 200 mg QD + GS-5885 90 mg QD.

FIG. 16 shows the predicted median value and 90% confidence interval of the SVR percentage for different treatment durations of the following DAA combo regimes: (1) GS-9451/229

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200 mg QD + GS-7977 (PSI-7977) 400 mg QD; (2) GS-5885 90 mg QD + GS-7977 (PSI-7977) 400 mg QD and (3) GS-9451 200 mg QD + GS-5885 90 mg QD + GS-7977 (PSI-7977) 400 mg QD .

FIG. 17 shows the predicted median value and 90% confidence interval of the SVR percentage for different treatment durations of a 2-DAA regimen containing TMC-435 150 mg QD and daclatasvir (BMS-790052) 60 mg QD.

DETAILED DESCRIPTION OF THE INVENTION

The present methods can include administering Therapeutic Agent 1 to a subject. Therapeutic agent 1 is compound 1

<img file="AT514003A2_D0018.tif" />

or a pharmaceutically acceptable salt thereof. Compound 1 is also known as (2R, 6S, 13aS, 14aR, 16aS, Z) -N (cyclopropylsulfonyl) -6- (5-methylpyrazine-2-carboxamido) -5,16dioxo-2- (phenanthridin-6-yloxy) 1,2,3,5,6,7,8,9,10,11,13a, 14,14a, 15,16,16ahexadecahydrocyclopropa [e] pyrrolo [1,2-a]

[1,4] diazacyclopentadecine-14a-carboxamide. Compound 1 is a potent HCV protease inhibitor. The synthesis and formulation of Compound 1 are described in US Patent Application Publication No. 2010/0144608, US Provisional Application Serial No. 61 / 339,964, filed March 10, 2010 and US Patent Application Publication No. 2011/0312973, filed March 8, 2011. All of these applications are herein incorporated by the / 229 · · · · · · · · ····· &amp; · · · · ·· · '·· · ·· · ··

Reference included in its entirety. Therapeutic agent 1 includes various salts of Compound 1. Therapeutic agent 1 can be administered in any suitable amount, such as in doses from about 0.01 to about 50 mg / kg body weight, alternatively from about 0.1 to about 25 mg / kg body weight. As non-limiting examples, the therapeutic agent 1 can be administered in a total daily dose of from about 50 mg to about 250 mg, preferably from about 100 mg to about 250 mg, and this includes, but is not limited to: for example about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, and suitable amounts in between.

Ritonavir or another inhibitor of cytochrome P-450 is preferably co-administered with therapeutic agent 1 to improve the pharmacokinetics of compound 1.

The present methods can include administering Therapeutic Agent 2 to a subject. The therapeutic agent 2 is compound 2 or a salt thereof.

Connection 2

Compound 2 is also known as N- (6- (3-tert-butyl-5 (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2methoxyphenyl) naphthaien-2-yi) methanesulfonamide. As described in, for example, International Publication No. WO2009 / 039127, therapeutic agent 2 includes various salts of compound 2 such as sodium salts, potassium salts and choline salts. Therapeutic agent 2 also includes crystalline forms of Compound 2 and their salts such as derivative, hydrate, and solvent-free crystalline forms of Compound 2 and their salts. Compositions comprising the therapeutic agent 2 can be prepared as described in, for example, international publication no.

/ 229 · · · · · · ·

-50- · · · · · ··· ® · · · ·· «t ··

WO2009 / 039127, which is incorporated herein by reference.

The therapeutic agent 2 can be administered as a free acid, a salt or a special crystalline form of the compound 2. In some embodiments, therapeutic agent 2 is administered as a sodium salt. The therapeutic agent 2 can be administered in any suitable amount, such as, for example, in doses from about 5 mg / kg to about 30 mg / kg. As non-limiting examples, the therapeutic agent 2 can be used in a total daily dose of about 300 mg to about 1800 mg, or about 400 mg to about 1600 mg, or from about 600 mg to about 1800 mg, or from about 800 mg to about 1600 mg, or any amount in between. In some embodiments, the total daily dosage amount for Therapeutic Agent 2 is approximately 600 mg. In some embodiments, the total daily dosage amount for Therapeutic Agent 2 is approximately 800 mg. In some embodiments, the total daily dosage amount for therapeutic agent 2 is approximately 1200 mg. In some embodiments, the total daily dosage amount for therapeutic agent 2 is approximately

1600 mg.

The present methods can include administering Therapeutic Agent 3 or a salt thereof to a subject. The therapeutic agent 3 is compound 3 or a salt thereof.

Connection 3

Compound 3 is also known as (E) -N- (4- (3-tert-butyl-5 (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2methoxystyryl) phenyl) methanesulfonamide. As described in, for example, International Publication No.

WO2009 / 039127, the therapeutic agent includes 3 different salts of the compound 3, such as sodium salts, potassium salts and choline salts. The

51/229 sii

<img file="AT514003A2_D0019.tif" />

• · · ·· ·

<img file="AT514003A2_D0020.tif" />

Therapeutic agent 3 also includes crystalline forms of Compound 3 and its salts such as solvate, hydrate and solvent-free crystalline forms of Compound 3 and its salts. Compositions comprising the therapeutic agent 3 can be prepared as described in, for example, international publication no. WO2009 / 039127, which is incorporated herein by reference.

The therapeutic agent 3 can be administered as a free acid, a salt or a special crystalline form of the compound 3. In some embodiments, Compound 3 is administered as a potassium salt. The therapeutic agent 3 can be administered in any suitable amount, such as, for example, in doses from about 0.5 mg / kg to about 15 mg / kg or from about 1 mg / kg to about 10 mg / kg. As non-limiting examples, the therapeutic agent 3 can be administered in a total daily dose of from about 100 mg to about 600 mg. In some embodiments, the total daily dosage amount for therapeutic agent 3 is approximately 300 mg. In some embodiments, the total daily dosage amount for therapeutic agent 3 is approximately 320 mg. In some embodiments, the total daily dosage amount for therapeutic agent 3 is approximately 400 mg. In some embodiments, the total daily dosage amount for therapeutic agent 3 is approximately 600 mg.

The present methods can include administering the therapeutic agent 4, or a salt thereof, to a subject. The therapeutic agent 4 is compound 4 or a salt thereof.

Connection 4

Compound 4 is also known as dimethyl (2S, 2'S) -1,1 '((2S, 2'S) - (4,4' - ((2S, 5S) -1- (4-tert-butylphenyl) pyrrolidine-2, 5diyl) bis (4,1phenylene) bis (azandiyl) bis (oxomethylene) bis (pyrrolidine-2,152 / 229 • · · · ·· diyl) bis (3-methyl-1-oxobutane-2,1-diyl) dicarbamate. Compound 4 can be prepared as described in, for example, US Publication No. 2010/0317568, which is incorporated herein by reference.

Therapeutic agent 4 can be administered as a free acid or a salt form. Therapeutic agent 4 can be administered in any suitable amount, such as in doses from about 0.1 mg / kg to about 200 mg / kg body weight, or from about 0.25 mg / kg to about 100 mg / kg, or from about 0.3 mg / kg to about 30 mg / kg. As non-limiting examples, the therapeutic agent 4 can be administered in a total daily dose of from about 5 mg to about 300 mg, or from about 25 mg to about 200 mg, or from about 25 mg to about 50 mg, or in any amount in between. In some embodiments, the total daily dosage amount for therapeutic agent 4 is approximately 25 mg.

The at least two DAAs can be administered together with ribavirin or a prodrug thereof in the same or in separate pharmaceutical compositions. Ribavirin can include any suitable form or formulation of ribavirin. Exemplary formulations of ribavirin include COPEGUS®, REBETOL®, and RIBASPHERE®. An exemplary prodrug of ribavirin is taribavirin, which has the chemical name 1-ß-D-ribofuranosyl-1,2,4-triazole-3carboxamidine. Ribavirin and taribavirin can be administered according to ribavirin and taribavirin administration, which is well known in the art. In some embodiments, COPEGUS® or REBETOL® is administered in a daily dosage amount of from about 500 mg to about 1500 mg in one dose or in divided doses. In some embodiments, a daily dosage amount is. In some embodiments

REBETOL® administered in a daily dose of approximately 1000 mg. In some embodiments, COPEGUS® or REBETOL® is administered in a daily dosage amount of approximately 1200 mg. In some embodiments, REBETOL® is used in a

COPEGUS® or REBETOL® administered in approximately 800 mg.

/ 229

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• · ·· ··· administered daily dose of approximately 1400 mg. Suitable doses of ribavirin depend on the weight of the individual and are, for example, about 1000-1200 mg. Suitable total daily dosages of ribavirin include, but are not limited to, about 1400 mg per day, about 1400 mg per day, alternatively about alternatively about 400 mg to 800 mg to 400 mg to about 1200 mg, alternatively about 800 mg up to about 1200 mg.

The current standard of care (SOC) for the treatment of HCV includes a treatment route of interferon, for example pegylated interferon (for example pegylated interferon-alpha-2a or pegylated interferon-alpha-2b, such as PEGASYS from Roche, or PEG- INTRON from Schering-Plow) and the antiviral drug ribavirin (for example COPEGUS from Roche, REBETOL from Schering-Plow, or RIBASPHERE from Three Rivers Pharmaceuticals). Treatment often lasts for 24-48 weeks, depending on the hepatitis C virus genotype. Other interferons include, but are not limited to, interferon alpha-2a (e.g., Roferon-A from Roche), intereron-alpha-2b (e.g., Intron-A from Schering-Plow), and interferon-alpha-con-1 (consensus interferon) ( for example Infergen by Valeant). Less than 50% of patients with chronic HCV infection with genotype 1 virus respond to this therapy. Furthermore, interferon therapy has many side effects that make patient compliance more difficult and lead to early interruption of treatment.

Interferon / ribavirin-based treatment can be physically demanding and in some cases can result in temporary disability. A significant proportion of patients will experience a range of side effects ranging from "flu-like syndrome (most commonly experienced for a few days after the weekly injection of interferon) to severe side effects including anemia, cardiovascular events, and psychiatric problems such as Example suicide or suicidal ideation. The latter are exacerbated by / 229

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the general physiological stress experienced by the patient, side effects,

Ribavirin also possesses a number of features including anemia, high pill load (for example, 5-6 pills a day split BID), and restriction of use due to teratogenicity in women of childbearing age.

The present methods provide effective treatment of HCV infection without the use of interferon and for a shorter period of time, such as a treatment duration of no more than twelve weeks, alternatively no more than eleven weeks, alternatively no more than ten weeks, alternatively no more than nine weeks, alternatively no more than eight weeks, alternatively no more than seven weeks, alternatively no more than six weeks, alternatively no more than five weeks, alternatively no more than four weeks or alternatively no more than three weeks.

In some embodiments, the present technology provides methods of treating HCV infection in a subject that comprise administering at least two DAAs with ribavirin in the absence of interferon for a period of no more than twelve weeks, alternatively no more than eight weeks . In other words, the present methods exclude interferon, that is, the subject does not receive interferon for the duration of treatment. The at least two DAAs can be co-administered or they can be administered independently (with the same or different dosage frequencies) and can be administered once a day, alternatively twice a day, alternatively three times a day.

In some embodiments, include

Method of treatment the daily administration of two or more DAAs, wherein a first DAA can be administered once a day, twice a day, or three times a day and a second DAA can be administered once a day, twice a day or three times a day. In some embodiments, a third DAA can be administered once a day, twice a day, or three times a day. The DAAs can be co-administered or administered at different times or frequencies.

/ 229 ···· ···· ···&lt;

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···· • · ·

Preferably, in the methods, at least two DAAs and ribavirin are administered in amounts effective to provide a desired level of effectiveness in the subject. Preferably the treatment has reduced side effects compared to interferon containing treatments.

Various metrics can be used to express the effectiveness of the present methods of HCV treatment. One such measure is rapid virological response (RVR), which means that HCV is undetectable in the subject after 4 weeks of treatment, for example after 4 weeks of administration of two or more of the DAAs and ribavirin. Another measure is the early virological response (EVR), which means that the subject has a&gt; 21ogi₀-Showing reduction in viral load after 12 weeks of treatment. Another measure is the complete EVR (cEVR), which means that the HCV is undetectable in the subject's serum after 12 weeks of treatment. Another requirement is the extended RVR (eRVR), which means achieving RVR and cEVR, ie HCV is undetectable in weeks 4 and 12. Another requirement is the presence or absence of detectable virus at the end of therapy (EOT). Another requirement is SVR, which as used herein means that the virus is undetectable at the end of therapy and for at least 8 weeks after the end of therapy (SVR8); preferably the virus is undetectable at the end of therapy and for at least 12 weeks after the end of therapy (SVR12); more preferably the virus is undetectable at the end of therapy and for at least 16 weeks after the end of therapy (SVR16); and most preferably the virus is undetectable at the end of therapy and for at least 24 weeks after the end of therapy (SVR24). SVR24 is often viewed as a functional definition of healing; and a high rate of SVR less than 24 weeks after treatment (e.g., SVR8 or SVR12) may be prognostic for a high rate of SVR24. Similarly, a high rate of SVR less than 12 weeks after treatment (for example, SVR4 or SVR8) can be prognostic for / 229

-sc- ::

• · · · · I · · · · · · ·· ·· ·· · · · · · ·

A high rate of EOT (for one to be a high rate of SVR12

Example at week 8 or week 12) may also indicate a significant rate of SVR12 or SVR24.

In some embodiments, the amounts of the two or more DAAs and ribavirin and / or the duration of the treatment regimen are the two or more DAAs and ribavirin

<td>effective,</td><td>an RVR in one</td><td>Subject,</td><td>or</td><td>a</td><td>EVR</td><td>in</td><td>one</td>

<td>Subject,</td><td>or a cEVR in one</td><td>Subject,</td><td>or</td><td>a</td><td>eRVR</td><td>in</td><td>one</td>

<td>Subject,</td><td>or an absence</td><td colspan="3">of detectable</td><td>EOT</td><td>in</td><td>one</td>

Deliver subject. In some embodiments, the present methods include subjects who are a treatment-naive treating a population of

Have HCV infection (e.g. subjects) and the procedures include

Administer at least two DAAs and ribavirin to the

Subjects for a period not exceeding 12 weeks, or for any other period disclosed herein, wherein the at least two DAAs and ribavirin are administered to the subjects in amounts effective to provide an SVR (e.g., SVR according to 8 weeks after treatment, or SVR after 24 weeks after treatment) in at least about 70% of the population, population, population, population,

Population, alternatively alternatively alternatively alternatively alternatively in in in in in at least approximately at least approximately

5^£80%

85%

90%

95% of the of the of the at least about at least about at least about

Population, alternatively approximately 100% of the population. In some embodiments, the present methods include treating a population of IFN-experienced subjects (e.g., interferon non-responders) who have HCV infection, and the methods include administering at least two DAAs and ribavirin to the subjects for one Periods of no more than 12 weeks or for any other period disclosed herein wherein the at least two DAAs and ribavirin are administered to the subjects in amounts, effective to deliver an SVR (for example, SVR at 8 weeks after treatment, or SVR at 24 weeks after treatment) in at least approximately 50% of the population, / 229 • ···

.. .. ·· · .....

alternatively in at least about 55% of the population, alternatively in at least about 60% of the population, alternatively in at least about 65% of the population. In other embodiments, the amount of DAAs and ribavirin and the duration of treatment are effective to control one or more of an SVR (e.g., SVR after 8 weeks after treatment or SVR after 24 weeks after treatment), an RVR, an EVR, a cEVR, an eRVR, or an absence of detectable virus in EOT, in at least about 50% of the population, alternatively in at least about 55%, in at least about 60% of the population, alternatively in at least about 65% of the

<td>Population,</td><td>alternatively</td><td>in</td><td>at least</td><td>approximately</td><td> 70%</td><td>the</td>

<td>Population,</td><td>alternatively</td><td>in</td><td>at least</td><td>approximately</td><td> 75%</td><td>the</td>

<td>Population,</td><td>alternatively</td><td>in</td><td>at least</td><td>approximately</td><td> 80%</td><td>the</td>

<td>Population,</td><td>alternatively</td><td>in</td><td>at least</td><td>approximately</td><td> 85%</td><td>the</td>

<td>Population,</td><td>alternatively</td><td>in</td><td>at least</td><td>approximately</td><td> 90%</td><td>the</td>

<td>Population,</td><td>alternatively</td><td>in</td><td>at least</td><td>approximately</td><td> 95%</td><td>the</td>

<td>Population,</td><td>alternatively</td><td>in</td><td>about 100%</td><td colspan="2">of the population</td><td>to</td>

deliver. For example, the present methods involve administering at least two DAAs and ribavirin in amounts and for a duration effective to produce an SVR (e.g., SVR at 8 weeks post treatment or SVR at 24 weeks post treatment) in a subject to deliver. In some embodiments, the present technology provides an SVR (e.g., SVR at 8 weeks post treatment or SVR at 24 weeks post treatment) in at least about 50% of the population, alternatively in at least about 55% of the population

<td>Population,</td><td>in</td><td>at least</td><td>approximately</td><td> 60%</td><td>the</td><td>Population,</td>

<td>preferably</td><td>in</td><td>at least</td><td>approximately</td><td> 65%</td><td>the</td><td>Population,</td>

<td>preferably</td><td>in</td><td>at least</td><td>approximately</td><td> 70%</td><td>the</td><td>Population,</td>

preferably at least about 75% of the patients treated by such methods described herein, more preferably in at least 80% of the population, and most preferably in at least about 90% of the patients treated. In some embodiments, treatment of the present technology provides RVR or an undetectable level of HCV RNA in the bloodstream at (4) weeks of treatment (preferably / 229 ·· ·· · «

I · ···· · ·· · · · · • · ⁵^ :: : &lt; .·* .

in addition to an SVR).

A DAA of the present technology includes, but is not limited to, a protease inhibitor, an HCV polymerase inhibitor, an HCV NS5A inhibitor, an HCV NS3B inhibitor, an HCV NS4A inhibitor, an HCV NS5B inhibitor, an HCV entry inhibitor, a cyclophilin inhibitor, a CD81 inhibitor, or an internal ribosome entry site inhibitor. The HCV polymerase inhibitor can be a nucleoside or non-nucleoside polymerase inhibitor. The HCV polymerase inhibitor can be a nucleotide polymerase inhibitor or a non-nucleotide polymerase inhibitor.

In yet another example of this aspect of the technology, the combination of two or more DAAs includes PSI7977 and PSI-938. In yet another example, the combination of two or more DAAs includes PSI-7 977 and TMC-435. In yet another example, the combination of two or more DAAs includes BMS-790052 and BMS-650032. In yet another example, the combination of two or more DAAs includes GS-5885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs includes BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs includes GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes danoprevir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir). In yet another example, the combination of two or more DAAs includes PSI-7977, BMS-650032 (asunaprevir), and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes INX-189 and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and BMS-650032 (asunaprevir). In yet another example, the / 229 _ _ · · · · · · ·

Y 9 9 9 9 9 9 999

9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 9 99 9 9 9 9 9 999

Combination of two or more DAAs INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir) a. In yet another example, the combination of two or more DAAs includes TMC-435 and daclatasvir.

It was unexpected to be interferon-free and

Ribavirin-free treatment using a combination of two or more DAAs, along with ribavirin and for a duration of no more than 12 weeks, can achieve significant SVR. In some cases such treatment can achieve SVR in at least about 75% of patients, and in some cases such treatment can achieve SVR in at least about 85% of patients, and in certain cases such treatment can achieve SVR in at least about 90% of patients achieve. It was also surprising that such treatment could achieve significant virus suppression even after 4 weeks of treatment. In some embodiments, interferon-free treatment using a combination of two or more DAAs, along with ribavirin and for a duration of no more than 12 weeks, could achieve significant SVR in interferon non-responders, for example, such treatment may achieve SVR in at least approximately 50% of patients in the interferon non-responder population more preferably at least about 65% of the patients in the interferon non-responder population.

Accordingly, the present technology offers all in one

Aspect of a method of treating HCV infection which comprises administering to a patient in need thereof an effective amount of a combination of two or more DAAs, along with an effective amount of ribavirin. The treatment lasts 8 weeks and does not include the administration of any interferon. The DAAs and ribavirin can be administered at the same or different dose frequencies. The treated patient may be a treatment-naïve patient, a treatment-experienced patient, including, but not limited to, a relapser, a partial interferon responder, or an interferon non60 / 229 «» ·· ·· «· ···· · ··· ····

-so ::: &lt;. · * &lt;^:··.

,, ** ·» · ·· ···

B. a null responder), or a patient who can

Responder (e.g. incapable of, for example

Taking interferon. The patient and be infected without restriction with HCV genotype 1, such as, for example, HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3. Treatment according to this aspect of the technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time, or at different times, and can be co-formulated in a single formulation or in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCVNS5A inhibitors. For example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (for example a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV protease inhibitor and at least one Nucleoside nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least

Nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). As another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NS5A inhibitor. As yet another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NS5A inhibitor. As another example, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (for example a combination of at least two nucleoside polymerase inhibitors, or a combination of at least one nucleotide polymerase inhibitor and one or one of a nucleoside at least one or or

Nucleotide non-nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). As another example

61/229

The combination of two or more DAAs can be a combination of at least two HCV protease inhibitors. As another example, the combination of two or more DAAs can be a combination of at least two HCV NS5A inhibitors. As another example, the combination of two or more can be at least one

Being HCV

DAAs a combination of

Polymerase inhibitor and at least one NS5A inhibitor (for example a combination of at least one HCV NS5A inhibitor and at least one non-nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 can be co-formulated with ritonavir. In yet another example of this aspect of the technology, the combination of two includes or / 229

-62 • · more DAAs PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs includes PSI7977 and TMC-435. In yet another example, the combination of two or more DAAs includes BMS-790052 and BMS-650032. In yet another example, the combination of two or more DAAs includes GS-5885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs includes BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs includes GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes danoprevir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir). In yet another example, the combination of two or more DAAs includes PSI-7977, BMS-650032 (asunaprevir), and BMS790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and

BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and

BMS-650032 (asunaprevir). In yet another example, the combination of two or more DAAs includes INX-189, BMS650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes mericitabine and danoprevir. In yet another example, the combination of two or more DAAs includes INX-189, Daclatasvir, and BMS-791325. In yet another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In yet another example, the combination of two or more DAAs includes TMC-435 and daclatasvir. In yet another example, the combination of two or more DAAs includes PSI-7,977, Compound 1 (with ritonavir) and Compound 4. In yet another example, the method comprises administering an effective amount / 229 • · • ·

-63 ······· ·· · ·· «· ·· · ·· ··· of PSI-7977 as the sole DAA instead of a combination of two or more DAAs together with an effective amount of ribavirin a patient who needs it. In yet another example, the method comprises administering 100 or 200 mg of Compound 1 along with 100 mg of ritonavir once a day, and 25 mg of Compound 4 once a day. In yet another example, the method involves administering 150 mg or 250 mg of Compound 1 along with 100 mg of ritonavir once daily, and 400 mg of Compound 2 twice daily. In another example, the method involves administering 150 mg of Compound 1 along with 100 mg of ritonavir once daily and 400 mg of Compound 3 once daily. In another example, the method involves administering 150 mg of Compound 1 along with 100 mg of ritonavir once daily, and 400 mg of Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg of compound 1 along with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily, and 400 mg of compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg of Compound 1 along with 100 mg of ritonavir once daily, 25 mg of Compound 4 once daily, and 400 mg of Compound 3 twice daily. Ribavirin can be given based on patient weight, and in many cases, 1000 to 1200 mg, divided into twice a day. Other DAAs can also be included in a treatment regimen according to this aspect of the technology. In any aspect, embodiment, and example of this application, 250 mg BID can be used for Compound 2 in place of 400 mg BID; It was unexpectedly discovered that by increasing the amount of the binder (e.g. copovidone) in a solid formulation of Compound 2 (or a pharmaceutically acceptable salt thereof) the bioavailability of Compound 2 (or the salt) can be significantly improved, such that 250 mg of compound 2 (or the salt) in the improved formulation are bioequivalent to 400 mg of compound 2 (or the salt) in the original formulation.

/ 229 • · • · • ·

-64• · · ·

In another aspect, the present technology provides a method of treating HCV comprising administering to a patient in need an effective amount of a combination of two or more DAAs along with an effective amount of ribavirin. The treatment lasts 7 weeks and does not include the administration of any interferon. The DAAs and ribavirin can be administered at the same or a different dosage frequency. The patient being treated may be a treatment-naive patient, a treatment-experienced patient including, but not limited to, a relapser, a partial interferon responder, an interferon non-responder (e.g., a null responder), or a patient who is not in is able to take interferon. For example and without limitation, the patient may be infected with HCV genotype 1, such as HCV genotype la or HCV genotype lb; or with HCV genotype 2 or

3. Treatment according to this aspect of the technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times and can be co-formulated in a single formulation or in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. For example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (for example a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV protease inhibitor and at least a nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside inhibitor). As another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCVNS5A inhibitor. As yet another example, the combination of two or more DAAs can be a combination of / 229

-65 be at least one HCV protease inhibitor, at least one HCV polymerase inhibitor and at least one HCV NS5A inhibitor. As another example, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (for example, a combination of at least two nucleoside or nucleotide polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside Polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). As another example, the combination of two or more DAAs can be a combination of at least two HCV NS5A inhibitors. As another example, the combination of two or more DAAs can be a combination of at least one HCV polymerase inhibitor and at least one NS5A inhibitor (for example, a combination of at least one HCV NS5A inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV -NS5A inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) can be coformulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 or one a salt thereof) can coIn in turn another

Salt from it. Compound 1 (or be formulated with ritonavir.

Example is the combination of two or more DAAs one (or a salt thereof) and (or one

Combination of compound 1

Compound 4 (or a salt thereof). Compound 1 (salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), / 229

-66 Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be coformulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs includes PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs includes PSI-7977 and TMC-435. In yet another example, the combination of two or more DAAs includes TMC-435 and daclatasvir. In yet another example, the combination of two or more DAAs includes BMS-7 90052 and BMS-650032. In yet another example, the combination of two or more DAAs includes GS-5885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs includes BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs includes GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes danoprevir (with ritonavir) and R7128. In yet another example, the combination includes two or more

DAAs PSI-7977 and BMS-790052 (daclatasvir). In yet another example, the combination includes two or more

DAAs PSI-7977 and BMS-650032 (asunaprevir). In yet another example, the combination includes two or more

DAAs

PSI-7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-18 9 and BMS-7 90052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and BMS-650032 (asunaprevir). In yet another example, the combination of two or more DAAs includes INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more / 229 • ·

<td></td><td> -67-</td><td> • • •</td><td> • · · • · · • · ·</td><td> • · • · • ·</td><td> • · • · · · • ·</td>

<td>DAAs mericitabine</td><td>and danoprevir</td><td>• • 4 a</td><td>• · · ·&gt; · · . In</td><td>• · • · · still</td><td>• · · • · · · · another</td>

<td>Example closes</td><td>the combination</td><td>out</td><td>two</td><td>or</td><td>more DAAs INX-</td>

<td>189, daclatasvir</td><td>and BMS-791325</td><td>a</td><td>. In</td><td>still</td><td>another</td>

<td>Example closes</td><td>the combination</td><td>out</td><td>two</td><td>or</td><td>more DAAs PSI</td>

<td>7977 and GS-5885</td><td colspan="2">a. In one more</td><td colspan="3">another example closes</td>

-6Ί the combination of two or more DAAs PSI-7 977, compound 1 (with ritonavir) and compound 4. In yet another example, the method comprises administering to a patient in need of an effective amount of PSI-7,977 as the single DAA instead of a combination of two or more DAAs along with an effective amount of ribavirin. In yet another example, the method involves administering 100 or 200 mg of Compound 1 along with 100 mg of ritonavir once daily and 25 mg of Compound 4 once daily. In yet another example, the method involves administering 150 mg or 250 mg of Compound 1 along with 100 mg of ritonavir once daily, and 400 mg of Compound 2 twice daily. In another example, the method involves administering 150 mg of Compound 1 along with 100 mg of ritonavir once a day, and 400 mg of Compound 3 once a day. In another example, the method includes

Administration of 150 mg of Compound 1 together with 100 mg

Ritonavir once a day, and 400 mg of compound 3 twice a day. In another example, the method includes

Administration of 100 or 150 mg of compound 1 together with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily and 400 mg of compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg of compound 1 along with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily, and 400 mg of compound 3 twice daily. Ribavirin can be given based on patient weight, and in many cases 1000 to 1200 mg, divided into twice a day. Other DAAs can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology provides a method of treating HCV that includes the / 229

-68ft · · · · 4 ·· ·· ··

Nucleoside combination

Administering to a patient in need thereof an effective amount of a combination of two or more DAAs, along with an effective amount of ribavirin. The treatment lasts 6 weeks and does not include the administration of any interferon. The patient being treated may be a treatment-naive patient, a treatment-experienced patient including, but not limited to, a relapser, a partial interferon responder, an interferon non-responder (e.g., a null responder), or a patient who is not in is able to take interferon. The patient can be infected, for example and without limitation, with HCV genotype 1, such as, for example, HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3. Treatment according to this aspect of this technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. For example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (for example, a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least an HCV protease inhibitor and at least one or nucleotide polymerase inhibitor, or one of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside inhibitor). As another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NS5A inhibitor. As yet another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NS5A inhibitor. As another example, the / 229

-69• · • · • ·

Combination of at least two ·· ·· ·· '' - two or more DAAs a combination of

HCV polymerase inhibitors (for example a combination of at least two nucleoside or nucleotide polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). As another example, the combination of two or more DAAs can be a combination of at least two HCV protease inhibitors. As another example, the combination of two or more DAAs can be a combination of at least two HCV NS5A inhibitors. As another example, the combination of two or more can be

DAAs one

Combination of at least one

Being HCV

Polymerase inhibitor and at least one NS5A inhibitor (for example a combination of at least one HCV NS5A inhibitor and at least one non-nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor and at least one nucleoside or one nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, this is

Combination of two or more DAAs a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) can be coformulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be coformulated with ritonavir. In yet another example, the combination of two or more DAAs is one (or a salt thereof) and (or one in one

Combination of compound 1

Compound 4 (or a salt thereof). Compound 1 (salt thereof) can be co-formulated with ritonavir, another example is the combination of two or more DAAs a combination of Compound 1 (or a salt thereof), / 229

-70• · · · • ( » · « • · · · ·

Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be coformulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs includes PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs includes PSI-7977 and TMC-435. In yet another example, the combination of two or more DAAs includes TMC-435 and daclatasvir. In yet another example, the combination of two or more DAAs includes BMS-790052 and BMS-650032. In yet another example, the combination of two or more DAAs includes GS-5885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs includes BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs includes GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes danoprevir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7 977 and BMS-790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032

combination of

<td colspan="4">In yet another example S '</td>

<td>two or</td><td colspan="3">more DAAs PSI-7977,</td>

<td>BMS-790052</td><td>(Daclatasvir)</td><td>a</td><td>. In</td>

<td>closes the</td><td>combination</td><td>out</td><td>two</td>

<td>BMS-790052</td><td>(Daclatasvir)</td><td>a</td><td>. In</td>

<td>closes the</td><td>combination</td><td>out</td><td>two</td>

<td>BMS-650032</td><td>(Asunaprevir)</td><td>a</td><td>. In</td>

<td>closes the</td><td>combination</td><td>out</td><td>two</td>

<td>BMS-650032</td><td>(Asunaprevir)</td><td></td><td>and</td>

BMS-650032 one more or more in one more

In one more

DAAs INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes mericitabine and danoprevir

71/229

-71··· ···· • 9

999

999 a. In yet another example, the combination of two or more DAAs includes INX-189, Daclatasvir and BMS-791325. In yet another example, the combination of two or more DAAs includes PSI-7 977 and GS-5885. In yet another example, the combination of two or more DAAs includes PSI7977, Compound 1 (with ritonavir) and Compound 4. In yet another example, the method comprises administering to a patient in need of an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs along with an effective amount of ribavirin. In yet another example, the method comprises administering 100 or 200 mg of Compound 1 along with 100 mg of ritonavir once a day, and 25 mg of Compound 4 once a day. In yet another example, the method involves administering 150 mg or 250 mg of Compound 1 along with 100 mg of ritonavir once daily, and 400 mg of Compound 2 twice daily. In another example, the method involves administering 150 mg of Compound 1 along with 100 mg of ritonavir once a day, and 400 mg of Compound 3 once a day. In another example, the method involves administering 150 mg of Compound 1 along with 100 mg of ritonavir once daily, and 400 mg of Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg of compound 1 along with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily, and 400 mg of compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg of compound 1 along with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily, and 400 mg of compound 3 twice daily. Ribavirin can be given based on patient weight, and in many cases, 1000 to 1200 mg, divided into twice a day. Other DAAs can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology features a method of treating HCV that comprises administering an effective amount of a combination of the two / 229

-72 • · • ··· • · · · ·· · ······· · · · ·· ·· · · · ·· · ·· or more DAAs, along with an effective amount of ribavirin, to a patient in need of it. The treatment lasts 5 weeks and does not include the administration of any interferon. The DAAs and ribavirin can be administered at the same or different dosing frequencies. The patient being treated may be a treatment-naïve patient, a treatment-experienced patient including, but not limited to, a relapser, a partial interferon responder, an interferon non-responder (e.g., a null responder), or a patient who is not in is able to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3. Treatment according to this aspect of the technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. For example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (for example a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV protease inhibitor and at least a nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor. As another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NS5A inhibitor. As yet another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one / 229

-73·· ··· » · · · · · ·· ·· ··

Be an HCV NS5A inhibitor. As another example, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (for example, a combination of polymerase inhibitors, or one nucleoside or at least two nucleosides, a combination of at least one nucleotide polymerase inhibitor and at least one non-nucleoside inhibitor. Polymerase inhibitor, or a

combination of

Polymerase inhibitors). Combination of two two non-nucleosides, another example, the DAAs can be a combination of at least one or more at least two HCV protease inhibitors. As another example, the combination of two or more DAAs can be a combination of at least two HCV NS5A inhibitors. As another example, the combination of two or more of at least one NS5A inhibitor can be used

Being HCV

DAAs a combination of polymerase inhibitor and at least (for example a combination of at least one HCV NS5A inhibitor and at least one non-nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor and at least one nucleoside or

Nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, this is

Combination of two or more DAAs a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) can be coformulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be coformulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs / 229 *

-Ί4.

«« · «·· * ·« · »·« * ·· &lt;· • · · · · · · · · ···. «♦ · · ·« ······ · · * «·« · ** · ·· ··· a combination of compound 1 (or a salt thereof), compound 2 (or a salt thereof) and compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs includes PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs includes PSI-7977 and TMC-435. In yet another example, the combination of two or more DAAs includes TMC-435 and daclatasvir. In yet another example, the combination of two or more DAAs includes BMS-790052 and BMS-650032. In yet another example, the combination of two or more DAAs includes GS-5885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs includes BI201335 and BI-207127. In yet another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs includes GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes danoprevir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI7977 and BMS-790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir). In yet another example, the combination of two or more DAAs includes PSI-7977, BMS-650032 (asunaprevir), and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and BMS-650032 (asunaprevir). In yet another example, the combination of two or more DAAs includes INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the / 229 • ·

-75·· · · ·· · ·· ···

Combination of two or more DAAs mericitabine and danoprevir. In yet another example, the combination of two or more DAAs includes INX-189, Daclatasvir and BMS-791325. In yet another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In yet another example, the method comprises administering to a patient in need of an effective amount of PSI-7,977 as the single DAA instead of a combination of two or more DAAs along with an effective amount of ribavirin. In yet another example, the method comprises administering 100 or 200 mg of Compound 1 along with 100 mg of ritonavir once a day, and 25 mg of Compound 4 once a day. In yet another example, the method comprises administering 150 mg or 250 mg of Compound 1 along with 100 mg of ritonavir once daily and 400 mg of Compound 2 twice daily. In another example, the method involves administering 150 mg of Compound 1 along with 100 mg of ritonavir once a day, and 400 mg of Compound 3 once a day. In another example, the method comprises administering 150 mg of Compound 1 along with 100 mg of ritonavir once daily, and 400 mg of Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg of Compound 1 along with 100 mg of ritonavir once daily, 25 mg of Compound 4 once daily, and 400 mg of Compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg of Compound 1 along with 100 mg of ritonavir once daily, 25 mg of Compound 4 once daily, and 400 mg of Compound 3 twice daily. Ribavirin can be given based on patient weight, and in many cases, 1000 to 1200 mg, divided into twice a day. Other DAAs can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology provides a method of treating HCV which comprises administering an effective amount of a combination of two or more DAAs along with an effective amount of / 229

-76 ······ · · * ·· ·· ·· · ·· ···

Ribavirin, to a patient in need of it. The treatment lasts 4 weeks and does not include the administration of any interferon. The DAAs can be administered at the same or a different dosage frequency. The patient being treated may be a treatment-naive patient, a treatment-experienced patient including, but not limited to, a relapser, a partial interferon responder or an interferon non-responder (e.g., a null responder), or a patient who is not in is able to take interferon. The patient can be infected, for example and without limitation, with HCV genotype 1, such as, for example, HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3. Treatment according to this aspect of this technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or in different ones

Compositions be formulated. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. For example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (for example a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV protease inhibitor and at least a nucleoside or nucleotide polymerase inhibitor or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside inhibitor). As another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCVNS5A inhibitor. As yet another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NS5A inhibitor. As another example, the combination of two / 229

-ΊΊor more DAAs be a combination of at least two HCV polymerase inhibitors (for example a combination of at least two nucleoside or nucleotide polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). As another example, the combination of two or more DAAs can be a combination of at least two HCV protease inhibitors. As another example, the combination of two or more DAAs can be a combination of at least two HCV NS5A inhibitors. As another example, the combination of two or more DAAs can be a combination of at least one HCV polymerase inhibitor and at least one NS5A inhibitor (for example, a combination of at least one HCV NS5A inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least an HCV NS5A inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Connection / 229

-781 (or a salt thereof) may be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs includes PSI7977 and PSI-938. In yet another example, the combination of two or more DAAs includes PSI-7 977 and TMC-435. In yet another example, the combination of two or more DAAs includes TMC-435 and daclatasvir. In yet another example, the combination of two or more DAAs includes BMS-790052 and BMS-650032. In yet another example, the combination of two or more DAAs includes GS-5885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs includes BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs includes GS-5885 and GS9451. In yet another example, the combination of two or more DAAs includes danoprevir (with ritonavir) and R712 8. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir). In yet another example, the combination of two or more DAAs includes PSI-7977, BMS-650032 (asunaprevir), and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and BMS-650032 (asunaprevir). In yet another example, the combination of two or more DAAs includes INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes mericitabine and danoprevir. In yet another example, the combination of two or more DAAs includes INX79 / 229

-79·· ·· ··

189, daclatasvir and BMS-791325. In yet another example, the combination of two or more DAAs includes PSI7977 and GS-5885. In yet another example, the method comprises administering to a patient in need of an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs along with an effective amount of ribavirin. In yet another example, the method comprises administering 100 or 200 mg of Compound 1 along with 100 mg of ritonavir once a day, and 25 mg of Compound 4 once a day. In yet another example, the method involves administering 150 mg or 250 mg of Compound 1 along with 100 mg of ritonavir once daily, and 400 mg of Compound 2 twice daily. In another example, the method comprises administering 150 mg of Compound 1 along with 100 mg

Ritonavir once daily and 400 mg of compound 3 once daily. In another example, the method involves administering 150 mg of Compound 1

Ritonavir once daily, and 400 mg of compound 3 daily. In another example, the method includes

Administration of 100 or 150 mg of compound 1 together with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily and 400 mg of compound 2 twice daily. In another example, the method comprises administering 100 or along with 100 mg twice

100 mg ritonavir once

150 mg of compound 1 along with daily, 25 mg of compound, compound 3 twice daily, once daily, and 400 mg of ribavirin can be administered based on patient weight, and in many cases 1000 to 1200 mg, divided into twice daily. Other DAAs can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology provides a method of treating HCV which comprises administering to a patient in need an effective amount of a combination of two or more DAAs, along with an effective amount of ribavirin. Treatment lasts 3 weeks (or even less, depending on the / 229

<img file="AT514003A2_D0021.tif" />

Condition of the patient) and does not include the administration of any interferon. The DAAs and ribavirin can be administered with the same or different dosing frequencies. The patient being treated may be a treatment-naive patient, a treatment-experienced patient including, but not limited to, a relapser, a partial interferon responder, or an interferon non-responder (e.g., a null responder), or an incapable patient is to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3. Treatment according to this aspect of the technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. For example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (for example a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV protease inhibitor and at least a nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). As another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NS5A inhibitor. As yet another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NS5A inhibitor. As another example, the combination of two or more DAAs can be a combination of

81/229

-81 (for example, at least two nucleosides a combination of at least one nucleotide polymerase inhibitor and at least two HCV polymerase inhibitors can be a combination of

Polymerase inhibitors, or a nucleoside or at least one non-nucleoside polymerase inhibitor or a

combination of

Polymerase inhibitors. Combination of at least two non-nucleosides As another example, the or more DAAs can be a combination of at least two HCV protease inhibitors. As another example, the combination of two or more DAAs can be a combination of at least two HCV NS5A inhibitors. As another example, the combination of two or more can be

DAAs one

Combination of at least one

Being HCV

Polymerase inhibitor and at least one NS5A inhibitor (for example a combination of at least one HCV NS5A inhibitor and one

Non-nucleoside one or at least one

Polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor and at least one nucleoside-nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, this is

Combination of two or more DAAs a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be coformulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be coformulated with ritonavir. In another example, the combination of two or more DAAs is a combination of

Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Connection / 229 • ·

-82 (or a salt thereof) may be co-formulated with ritonavir. In a further example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs includes PSI7977 and PSI-938. In yet another example, the combination of two or more DAAs includes PSI-7 977 and TMC-435. In yet another example, the combination of two or more DAAs includes TMC-435 and daclatasvir. In yet another example, the combination of two or more DAAs includes BMS-790052 and BMS-650032. In yet another example, the combination of two or more DAAs includes GS-5885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs includes BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs includes GS-5885 and GS9451. In yet another example, the combination of two or more DAAs includes danoprevir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir). In yet another example, the combination of two or more DAAs includes PSI-7977, BMS-650032 (asunaprevir), and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and BMS-650032 (asunaprevir). In yet another example, the combination of two or more DAAs (asunaprevir) and BMS-790052 (daclatasvir). Another example, the combination of two or more DAAs includes mericitabine and danoprevir. In yet another example, the combination of two or more DAAs includes INXINX-189, BMS-650032. In another / 229

-83φ φ φ φφφ φφφφφφφ φφ φ φφ φφ φ · φ φφ φφφ

189, daclatasvir and BMS-791325. In yet another example, the combination of two or more DAAs includes PSI7977 and GS-5885. In yet another example, the method comprises administering to a patient in need of an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs along with an effective amount of ribavirin. In yet another example, the method comprises administering 100 or 200 mg of Compound 1 along with 100 mg of ritonavir once a day, and 25 mg of Compound 4 once a day. In yet another example, the method comprises administering 150 mg or 250 mg of Compound 1 along with 100 mg of ritonavir once daily and 400 mg of Compound 2 twice daily. In another example, the method comprises administering 150 mg of Compound 1 along with 100 mg of ritonavir once daily and 400 mg of Compound 3 once daily. In another example, the method comprises administering 150 mg of Compound 1 along with 100 mg of ritonavir once daily and 400 mg of Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg of compound 1 along with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily, and 400 mg of compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg of compound 1 along with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily, and 400 mg of compound 3 twice daily. Ribavirin can be given based on patient weight, and in many cases, 1000 to 1200 mg, divided into twice a day. Other DAAs can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology provides a method of treating HCV which comprises administering to a patient in need an effective amount of a combination of two or more DAAs, along with an effective amount of ribavirin. Treatment lasts 24 weeks and does not include administration of any interferon. The DAAs and ribavirin can be found in / 229: 34-:

• · 4 »· · fl can be administered with the same or a different dosage frequency. The patient being treated may be a treatment-naïve patient, a treatment-experienced patient including, but not limited to, a relapser, a partial interferon responder, an interferon non-responder (e.g., a null responder), or a patient who is not in is able to take interferon. For example and without limitation, the patient may be infected with HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3. Treatment according to this aspect of the technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. For example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (for example a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor or a combination of at least one HCV protease inhibitor and at least one Nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside inhibitor). As another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCVNS5A inhibitor. As yet another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NS5A inhibitor. As another example, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (for example, a combination of at least two nucleoside polymerase inhibitors, or a / 229: -851 • · · • · · · • · · '¹

I · · · fl »fl • ·

Combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). As another example, the combination of two or more DAAs can be a combination of at least two HCV protease inhibitors. As another example, the combination of two or more DAAs can be a combination of at least two HCV NS5A inhibitors. As another example, the combination of two or more of at least one NS5A inhibitor can be used

Being HCV

DAAs a combination of polymerase inhibitor and at least (for example a combination of at least one HCV NS5A inhibitor and at least one non-nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor and at least one nucleoside or

Nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, this is

Combination of two or more DAAs a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt / 229

- &amp; ό- \ • · thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs includes PSI-7 977 and PSI-938. In yet another example, the combination of two or more DAAs includes PSI-7977 and TMC-435. In yet another example, the combination of two or more DAAs includes TMC-435 and daclatasvir. In yet another example, the combination of two or more DAAs includes BMS-7 90052 and BMS650032. In yet another example, the combination of two or more DAAs includes GS-5885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs includes BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs includes GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes danoprevir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052. In yet another example, the combination of two or more DAAs includes PSI7977 and BMS-650032 (asunaprevir). In yet another example, the combination of two or more DAAs includes PSI7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and BMS-790052 (daclatasvir). In still

<td>one</td><td>other</td><td>example</td><td>closes</td><td>the</td><td>combination</td><td>out</td><td>two</td><td>or</td>

<td>more</td><td>DAAs INX</td><td>-189 and</td><td colspan="2">BMS-650032</td><td>(Asunaprevir)</td><td>a.</td><td>, In</td><td>still</td>

<td>one</td><td>other</td><td>example</td><td>closes</td><td>the</td><td>combination</td><td>out</td><td>two</td><td>or</td>

more DAAs INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes mericitabine and danoprevir. In yet another example, the combination of two or more DAAs includes INX-189, Daclatasvir and BMS-791325. In yet another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In yet another example, the method comprises administering an effective / 229 · ·· · ·

Amount of PSI-7977 as the sole DAA instead of a combination of two or more DAAs along with an effective amount of ribavirin to a patient in need. In yet another example, the method comprises administering 100 or 200 mg of Compound 1 along with 100 mg of ritonavir once a day, and 25 mg of Compound 4 once a day. In yet another example, the method comprises administering 150 mg or 250 mg of Compound 1 along with 100 mg of ritonavir once daily, and 400 mg of Compound 2 twice daily. In another example, the method comprises administering 150 mg of Compound 1 along with 100 mg of ritonavir once a day, and 400 mg of Compound 3 once a day. In another example, the method includes

Administer 150 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 3 twice daily. In another example, the method includes

Administer 100 or 150 mg of compound 1 together with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily and 400 mg of compound 2 twice daily. In another

For example, the method comprises administering 100 or 150 mg of compound 1 along with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily, and 400 mg of compound 3 twice daily. Ribavirin can be given based on patient weight, and in many cases 1000 to 1200 mg, divided into twice a day. Other DAAs can also be included in a treatment regimen according to this aspect of the technology.

In another aspect, the present technology provides a method of treating HCV which comprises administering to a patient in need thereof an effective amount of a combination of two or more DAAs, along with an effective amount of ribavirin. The treatment lasts from 13 to 23 weeks (for example, the duration of treatment is selected from 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 weeks) and does not include the administration of any interferon . The DAAs and ribavirin can be administered at the same or a different dosage frequency.

/ 229 : ·. .· ·.···.

The patient being treated may be a treatment-naive patient, a treatment-experienced patient including, but not limited to, a relapser, a partial interferon responder, an interferon non-responder (e.g., a null responder), or a patient who is not in is able to take interferon. The patient can be infected, for example and without limitation, with HCV genotype 1, such as, for example, HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3. Treatment according to this aspect of the technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. For example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (for example, a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV protease inhibitor

Nucleoside combination and at least one or nucleotide polymerase inhibitor or one of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside inhibitor). As another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NS5A inhibitor. As yet another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NS5A inhibitor. As another example, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (for example, a combination of at least two nucleoside polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and / 229 • β η · · * • - »8 9- · · · ·.

I · · · · &lt;

·· ·· ·· at least one non-nucleoside polymerase inhibitor or one

combination of

Polymerase inhibitors). Combination of two two non-nucleosides, another example, the DAAs can be a combination of at least one or more at least two HCV protease inhibitors. As another example, the combination of two or more DAAs can be a combination of at least two HCV NS5A inhibitors. As another example, the combination of two or more of at least one NS5A inhibitor can be used

Being HCV

DAAs a combination of polymerase inhibitor and at least (for example a combination of at least one HCV NS5A inhibitor and at least one non-nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor and at least one nucleoside or

Nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, this is

Combination of two or more DAAs a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4/229

<img file="AT514003A2_D0022.tif" />

• · · ·· ·· (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs includes PSI-7 977 and PSI-938. In yet another example, the combination of two or more DAAs includes PSI-7977 and TMC-435. In yet another example, the combination of two or more DAAs includes TMC-435 and daclatasvir. In yet another example, the combination of two or more DAAs includes BMS-790052 and BMS650032. In yet another example, the combination of two or more DAAs includes GS-5885, GS-9190, and GS9451. In yet another example, the combination of two or more DAAs includes BI-201335 and BI-207127. In yet another example, the combination includes two or more DAAs

Telaprevir and VX-222. In another example, the combination of two or more DAAs includes GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes danoprevir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052. In yet another example, the combination of two or more DAAs includes PSI7977 and BMS-650032 (asunaprevir). In yet another example, the combination of two or more DAAs includes PSI7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and BMS-790052 (daclatasvir). In still

<td>one</td><td>other</td><td>example</td><td>closes</td><td>the</td><td>combination</td><td>out</td><td>two</td><td>or</td>

<td>more</td><td>DAAs INX</td><td>-189 and</td><td colspan="2">BMS-650032</td><td>(Asunaprevir)</td><td>a.</td><td>. In</td><td>still</td>

<td>one</td><td>other</td><td>example</td><td>closes</td><td>the</td><td>combination</td><td>out</td><td>two</td><td>or</td>

more DAAs INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes mericitabine and danoprevir. In yet another example, the combination of two or more DAAs includes INX-189, Daclatasvir and BMS-791325. In yet another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In yet another example, the method comprises administering an effective amount of PSI-7977 as the sole DAA in place of one

91/229 . · · · · · · * : .-91«- . · ·.···.

. .·· · · .....· · ·· ...

.. ·· ··

Combination of two or more DAAs, along with an effective amount of ribavirin, to a patient in need of it. In yet another example, the method involves administering 100 or 200 mg of Compound 1 along with 100 mg of ritonavir once a day, and 25 mg of Compound 4 once a day. In yet another example, the method involves administering 150 mg or 250 mg of Compound 1 along with 100 mg of ritonavir once daily, and 400 mg of Compound 2 twice daily. In another example, the method involves administering 150 mg of Compound 1 along with 100 mg of ritonavir once a day, and 400 mg of Compound 3 once a day. In another example, the method includes

Administer 150 mg of compound 1 together with 100 mg of ritonavir once a day, and 400 mg of compound 3 twice a day. In another example, the method includes

Administration of 100 or 150 mg of compound 1 together with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily and 400 mg of compound 2 twice daily. In another

For example, the method involves administering 100 or 150 mg of compound 1 along with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily, and 400 mg of compound 3 twice daily. Ribavirin can be given based on patient weight, and in many cases 1000 to 1200 mg, divided into twice a day. Other DAAs can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology provides a method of treating HCV which comprises administering to a patient in need thereof an effective amount of a combination of two or more DAAs, along with an effective amount of ribavirin. Treatment lasts for 12 weeks and does not include administration of any interferon. The DAAs and ribavirin can be administered with the same or different dosing frequencies. The treated patient may be a treatment-naïve patient, a treatment-experienced patient, including, but not limited to a relapser, a / 229:: -: 93-. ·

Protease inhibitor

I · · · · Partial Interferon Responder, or an Interferon NonResponder (for example a null responder), or a patient who is unable to take interferon. For example and without limitation, the patient may be infected with HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3. Treatment according to this aspect of this technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times and can be co-formulated in a single formulation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. For example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (e.g., a combination of at least one HCV, at least one non-nucleoside and

Polymerase inhibitor or a combination of at least one HCV protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside inhibitor). As another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCVNS5A inhibitor. As yet another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NS5A inhibitor. As another example, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (for example, a combination of at least two nucleoside polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor, or a Combination of at least two non-nucleoside polymerase inhibitors). As another example / 229 ί93:

»·· · * ·· ···· ··· &lt;• · · · • · · ··· • · · ·· ·· ·· ··· The combination of two or more DAAs can be a combination of at least two Be HCV protease inhibitors. As another example, the combination of two or more DAAs can be a combination of at least two HCV NS5A inhibitors. As another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one NS5A inhibitor (for example, a combination of at least one HCV NS5A inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside inhibitor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs includes PSI-7977 and PSI-938. In yet another / 229 ···· ···· ···· ···· • · ·:: 494 • · · * • · &lt;·· ···

Example includes the combination of two or more DAAs PSI7977 and TMC-435. In yet another example, the combination of two or more DAAs includes TMC-435 and daclatasvir. In yet another example, the combination of two or more DAAs includes BMS-790052 and BMS-650032. In yet another example, the combination of two or more DAAs includes GS5885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs includes BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs includes GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes danoprevir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7 977 and

BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes PSI-7 977 and

BMS-650032 (asunaprevir). In yet another example, the combination of two or more DAAs includes PSI-7 977, BMS650032 (asunaprevir) and BMS-790052 (daclatasvir). In still

<td>one</td><td>other</td><td>example</td><td>closes</td><td>the</td><td>combination</td><td>out</td><td>two</td><td>or</td>

<td>more</td><td>DAAs INX</td><td>-189 and</td><td colspan="2">BMS-790052</td><td>(Daclatasvir)</td><td>a.</td><td>In</td><td>still</td>

<td>one</td><td>other</td><td>example</td><td>closes</td><td>the</td><td>combination</td><td>out</td><td>two</td><td>or</td>

<td>more</td><td>DAAs INX</td><td>-189 and</td><td colspan="2">BMS-650032</td><td>(Asunaprevir)</td><td>a.</td><td>In</td><td>still</td>

<td>one</td><td>other</td><td>example</td><td>closes</td><td>the</td><td>combination</td><td>out</td><td>two</td><td>or</td>

more DAAs INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes mericitabine and danoprevir. In yet another example, the combination of two or more DAAs includes INX-189, Daclatasvir and BMS-791325. In yet another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In yet another example, the method comprises administering to a patient in need of an effective amount of PSI-7,977 as the single DAA instead of a combination of two or more DAAs along with an effective amount of ribavirin. In yet another example, the method includes / 229

U9 $ • «··· · .....

the administration of 100 or 200 mg of Compound 1 together with 100 mg of ritonavir once daily, and 25 mg of Compound 4 once daily. In yet another example, the method comprises administering 150 mg or 250 mg of Compound 1 along with 100 mg of ritonavir once daily, and 400 mg of Compound 2 twice daily. In another example, the method involves administering 150 mg of Compound 1 along with 100 mg of ritonavir once a day, and 400 mg of Compound 3 once a day. In another example, the method involves administering 150 mg of Compound 1 along with 100 mg of ritonavir once daily, and 400 mg of Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg of Compound 1 along with 100 mg of ritonavir once daily, 25 mg of Compound 4 once daily, and 400 mg of Compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg of compound 1 along with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily, and 400 mg of compound 3 twice daily. Ribavirin can be given based on patient weight, and in many cases, 1000 to 1200 mg, divided into twice a day. Other DAAs can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology provides a method of treating HCV which comprises administering to a patient in need thereof an effective amount of a combination of two or more DAAs, along with an effective amount of ribavirin. Treatment lasts 11 weeks and does not include administration of any interferon. The DAAs and ribavirin can be administered with the same or different dosing frequencies. The patient being treated may be a treatment-naïve patient, a treatment-savvy patient, including, but not limited to, a relapser, a partial interferon responder, or an interferon non-responder (e.g., a null responder), or an incapable patient is to take interferon. The patient may / 229 • · • · «be infected with, for example and without limitation, HCV genotype 1, such as, for example, HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3. Treatment according to this aspect of the technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCVNS5A inhibitors. For example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (for example a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV protease inhibitor and at least a nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor. As another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NS5A inhibitor. As yet another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NS5A inhibitor. As another example, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (for example, a combination of at least two nucleoside polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside Polymerase inhibitor or a

combination of

Polymerase inhibitors). Combination of at least two As one or more two non-nucleosides, another example, the DAAs can be a combination of at least two HCV protease inhibitors. As another / 229

............ ···· ···· : :: ' ·’. .·* : · ^: ···

For example, the combination of two or more DAAs can be a combination of at least two HCV NS5A inhibitors. As another example, the combination of two or more can be

DAAs one

Combination of at least one

Being HCV

Polymerase inhibitor and at least one NS5A inhibitor (for example a combination of at least one HCV NS5A inhibitor and ernem

Non-nucleoside, for example, the DAAs is a combination of at least

Polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor. In

Combination of two or more

Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) can be coformulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs includes PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs includes PSI-7977 and TMC-435. In another / 229

I · ···· · · · «::::. * · * ·. ···.

Another example includes the combination of two or more DAAs TMC-435 and Daclatasvir. In yet another example, the combination of two or more DAAs includes BMS-790052 and BMS650032. In yet another example, the combination of two or more DAAs includes GS-5885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs includes BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs includes GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes danoprevir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052. In yet another example, the combination of two or more DAAs includes PSI7977 and BMS-650032 (asunaprevir). In yet another example, the combination of two or more DAAs includes PSI7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and BMS-790052 (daclatasvir). In still

<td>one</td><td>other</td><td>example</td><td>closes</td><td>the</td><td>combination</td><td>out</td><td>two</td><td>or</td>

<td>more</td><td>DAAs INX</td><td>-189 and</td><td colspan="2">BMS-650032</td><td>(Asunaprevir)</td><td>a.</td><td>. In</td><td>still</td>

<td>one</td><td>other</td><td>example</td><td>closes</td><td>the</td><td>combination</td><td>out</td><td>two</td><td>or</td>

more DAAs INX-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes mericitabine and danoprevir. In yet another example, the combination of two or more DAAs includes INX-189, Daclatasvir and BMS-791325. In yet another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In yet another example, the method comprises administering to a patient in need of an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs along with an effective amount of ribavirin. In yet another example, the method comprises administering 100 or 200 mg of Compound 1 along with 100 mg of ritonavir once daily, and 25 mg of Compound 4 once / 229: :: * 29-::

"··· · ·· · • · • · · · Every day. In yet another example, the method involves administering 150 mg or 250 mg of Compound 1 along with 100 mg of ritonavir once daily, and 400 mg of Compound 2 twice daily. In another example, the method involves administering 150 mg of Compound 1 along with 100 mg of ritonavir once a day, and 400 mg of Compound 3 once a day. In another example, the method involves administering 150 mg of Compound 1 along with 100 mg of ritonavir once a day, and 400 mg of Compound 3 twice a day. In another example, the method comprises administering 100 or 150 mg of compound 1 along with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily and 400 mg of compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg of Compound 1 along with 100 mg of ritonavir once daily, 25 mg of Compound 4 once daily, and 400 mg of Compound 3 twice daily. Ribavirin can be given based on patient weight, and in many cases, 1000 to 1200 mg, divided into twice a day. Other DAAs can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology provides a method of treating HCV which comprises administering to a patient in need thereof an effective amount of a combination of two or more DAAs, along with an effective amount of ribavirin. The treatment lasts 10 weeks and does not include the administration of any interferon. The DAAs and ribavirin can be administered with the same or different dosing frequencies. The patient being treated may be a treatment-naive patient, a treatment-experienced patient including, but not limited to, a relapser, a partial interferon responder, or an interferon non-responder (e.g., a null responder), or a patient who is not in the Laqe is to take interferon. For example and without limitation, the patient may be infected with HCV genotype 1, such as HCV genotype Ia or HCV genotype

100 / 229 • · ···· ···· • · • · · ·.···.

-: loo: -:. :. ·

-.. .. .· · .....

lb; or HCV genotype 2 or 3. Treatment according to this aspect of the technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. For example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least (e.g. a combination

Protease inhibitor and at least

HCV polymerase inhibitor of at least one of one

HCV non-nucleoside polymerase inhibitor, or a combination of at least one HCV protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor) . As another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NS5A inhibitor. As yet another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NS5A inhibitor. As another example, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (for example, a combination of at least two nucleoside polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside Polymerase inhibitor, or a

combination of

Polymerase inhibitors). Combination of two two non-nucleosides, another example, the DAAs can be a combination of at least one or more at least two HCV protease inhibitors. As another example, the combination of two or more DAAs can be a combination of at least two HCV NS5A inhibitors. As

101 / 229 ···· ···« : :: : ·* ·’ ·.···.

Another example can be the combination of two or more DAAs a combination of at least one HCV protease inhibitor and at least one NS5A inhibitor (for example, a

Combination of at least one HCV NS5A inhibitor, at least one non-nucleoside polymerase inhibitor, or and at least one and at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least a nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and

Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs includes PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs includes PSI7977 and TMC-435. In yet another example, the combination of two or more DAAs includes TMC-435 and daclatasvir. In yet another example, the combination of the two includes

combination of

102 / 229 ·· ·· or more DAAs BMS-790052 and BMS-650032. In yet another example, the combination of two or more DAAs includes GS5885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs includes BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs includes GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes danoprevir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7 977 and BMS-790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032

<td>(Asunaprevir) a.</td><td colspan="5">. In yet another example, the</td>

<td>combination of</td><td>two or</td><td colspan="3">more DAAs PSI-7977,</td><td>BMS-650032</td>

<td>(Asunaprevir) and</td><td>BMS-790052</td><td>(Daclatasvir)</td><td>a</td><td>. In</td><td>another one</td>

<td>another example</td><td>closes the</td><td>combination</td><td>out</td><td>two</td><td>or more</td>

<td>DAAs INX-18 9 and</td><td>BMS-790052</td><td>(Daclatasvir)</td><td>a</td><td>. In</td><td>another one</td>

<td>another example</td><td>closes the</td><td>combination</td><td>out</td><td>two</td><td>or more</td>

<td>DAAs INX-18 9 and</td><td>BMS-650032</td><td>(Asunaprevir)</td><td>a</td><td>. In</td><td>another one</td>

<td>another example</td><td>closes the</td><td>combination</td><td>out</td><td>two</td><td>or more</td>

<td>DAAs INX-189,</td><td>BMS-650032</td><td>(Asunaprevir)</td><td></td><td>and</td><td>BMS-790052</td>

(Daclatasvir) a. In yet another example, the combination of two or more DAAs includes mericitabine and danoprevir. In yet another example, the combination of two or more DAAs includes INX-189, Daclatasvir and BMS-791325. In yet another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In yet another example, the method comprises administering to a patient in need of an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs along with an effective amount of ribavirin. In yet another example, the method involves administering 100 or 200 mg of Compound 1 along with 100 mg of ritonavir once a day, and 25 mg of Compound 4 once a day. In yet another example, the method comprises administering 150 mg or 250 mg of Compound 1 together

103 / 229

-5Q3-::

with 100 mg ritonavir once daily, and 400 mg compound 2 twice daily. In another example, the method involves administering 150 mg of Compound 1 along with 100 mg of ritonavir once a day, and 400 mg of Compound 3 once a day. In another example, the method comprises administering 150 mg of Compound 1 along with 100 mg of ritonavir once daily, and 400 mg of Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg of Compound 1 along with 100 mg of ritonavir once daily, 25 mg of Compound 4 once daily, and 400 mg of Compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg of compound 1 along with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily, and 400 mg of compound 3 twice daily. Ribavirin can be given based on patient weight, and in many cases 1000 to 1200 mg, divided into twice a day. Other DAAs can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology provides a method of treating HCV which comprises administering to a patient in need an effective amount of a combination of two or more DAAs, along with an effective amount of ribavirin. The treatment lasts 9 weeks and does not include the administration of any interferon. The DAAs and ribavirin can be administered at the same or a different dosage frequency. The patient being treated may be an interferon-liver patient, a treatment-experienced patient including, but not limited to, a relapser, a partial interferon responder, or an interferon non-responder (e.g., a null responder), or a patient who is not in is able to take interferon. The patient may be infected, for example and without limitation, with HCV genotype 1, such as, for example, HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3. Treatment according to this aspect of the technology may also be effective against other HCV104 / 229 ·· ·· ···· ·· «• ·» ft ·· ftftft * • · •. .-1.04-. . · ·. ···.

aft ·· *** * * * «·« · ·· · ·· ···

Genotypes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCVNS5A inhibitors. For example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (for example a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV protease inhibitor and at least a nucleoside nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least

Nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). As another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NS5A inhibitor. As yet another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NS5A inhibitor. As another example, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (for example a combination of at least two nucleoside polymerase inhibitors, or a combination of at least nucleotide polymerase inhibitors and or of a nucleoside at least one or or

Nucleotide non-nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). As another example, the combination of two or more DAAs can be a combination of at least two HCV protease inhibitors. As another example, the combination of two or more DAAs can be a combination of at least two HCV NS5A inhibitors. As another example, the combination of two or more DAAs can be a combination of at least one HCV105 / 229

Non-nucleoside of one or more

Be polymerase inhibitor and at least one NS5A inhibitor (for example a combination of at least one HCV NS5A inhibitor and at least one

Polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor and at least one nucleoside-nucleotide polymerase inhibitor, or a combination of at least one HCV NS5A inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, this is

Combination of two or more DAAs a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In a further example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In yet another example, the combination of two or more DAAs includes PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs includes PSI7977 and TMC-435. In yet another example, the combination of two or more DAAs includes TMC-435 and daclatasvir. In yet another example, the combination of two or more DAAs includes BMS-790052 and BMS-650032. In yet another

106 / 229 • · ·· ···· ···· ···· ···· ·· ···

Example includes the combination of two or more DAAs GS5885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs includes BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs includes telaprevir and VX-222. In another example, the combination of two or more DAAs includes GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes danoprevir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7 977 and BMS-790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir). In yet another example, the

<td>combination of</td><td>two or</td><td colspan="3">more DAAs PSI-7977,</td><td>BMS-650032</td>

<td>(Asunaprevir) and</td><td>BMS-790052</td><td>(Daclatasvir)</td><td>a</td><td>. In</td><td>another one</td>

<td>another example</td><td>closes the</td><td>combination</td><td>out</td><td>two</td><td>or more</td>

<td>DAAs INX-18 9 and</td><td>BMS-790052</td><td>(Daclatasvir)</td><td>a</td><td>. In</td><td>another one</td>

<td>another example</td><td>closes the</td><td>combination</td><td>out</td><td>two</td><td>or more</td>

<td>DAAs INX-18 9 and</td><td>BMS-650032</td><td>(Asunaprevir)</td><td>a</td><td>. In</td><td>another one</td>

<td>another example</td><td>closes the</td><td>combination</td><td>out</td><td>two</td><td>or more</td>

<td>DAAs INX-189,</td><td>BMS-650032</td><td>(Asunaprevir)</td><td></td><td>and</td><td>BMS-790052</td>

(Daclatasvir) a. In yet another example, the combination of two or more DAAs includes mericitabine and danoprevir. In yet another example, the combination of two or more DAAs includes INX-189, Daclatasvir and BMS-791325. In yet another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In yet another example, the method comprises administering to a patient in need of an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs along with an effective amount of ribavirin. In yet another example, the method comprises administering 100 or 200 mg of Compound 1 along with 100 mg of ritonavir once a day, and 25 mg of Compound 4 once a day. In yet another example, the method comprises administering 150 mg or 250 mg of Compound 1 along with 100 mg of ritonavir once daily, and 400 mg of Compound 2

107 / 229 ···; «O $ -. ·. ·. · ···· 9 9 9 9« * · «··· · · · fcsj« · «· · 9 9 999 twice a day. In another example, the method comprises administering 150 mg of Compound 1 along with 100 mg of ritonavir once a day, and 400 mg of Compound 3 once a day. In another example, the method includes

Administer 150 mg of Compound 1 together with 100 mg of ritonavir once daily, and 400 mg of Compound 3 twice daily. In another example, the method includes

Administer 100 or 150 mg of compound 1 together with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily, and 400 mg of compound 2 twice daily. In another

For example, the method comprises administering 100 or 150 mg of compound 1 along with 100 mg of ritonavir once daily, 25 mg of compound 4 once daily, and 400 mg of compound 3 twice daily. Ribavirin can be given based on patient weight, and in many cases, 1000 to 1200 mg, divided into twice a day. Other DAAs can also be included in a treatment regimen according to this aspect of the technology.

In another embodiment, the present technology provides interferon-free treatment that comprises administering two DAAs daily with ribavirin, wherein the two DAAs are an HCV polymerase inhibitor, e.g., PSI-7977, and an NS5A inhibitor, e.g., BMS-790052 , include, for a period of no more than twelve weeks (for example no more than eleven weeks), preferably no more than eight weeks.

In some embodiments, the present technology provides a method of treating hepatitis C virus infection in a subject which comprises administering an HCV protease inhibitor and an HCV polymerase inhibitor to the subject daily in the absence of interferon for a period of no more than twelve weeks, preferably no more than eight weeks. In some embodiments, ritonavir (or its equivalent) is co-administered with one or more protease inhibitors to improve the pharmacokinetics of the protease inhibitor (s). Treatment further includes administering ritonavir to the patient. In some embodiments, the HCV is polymerase inhibitor

108 / 229

-10 ^ which

Therapy has reached undetectable levels, but one technology available to treat patients is interferon treatment.

at least one nucleoside or nucleotide polymerase inhibitor or at least one non-nucleoside polymerase inhibitor. In some embodiments, both a nucleoside or nucleotide polymerase inhibitor and a non-nucleoside polymerase inhibitor can be administered.

The methods of the present technology as described herein can be used to treat a naive patient or an experienced patient. Treatment-experienced patients include interferon non-responders (for example null responders), partial responders (patients whose HCV-RNA levels fell but never became undetectable) and relapsers (patients who received HCV-RNA during the

Relapsed). Methods of FIG. 4 can also be used to identify non-candidates for patients who are not candidates for interferon treatment, including, but not limited to, one or more of the following groups: patients who are intolerant to interferon, patients who are refuse to take interferon therapy, patients with medical conditions that prevent them from taking interferon, and patients who have an elevated level of interferon

Have side effects or an infection from the interferon.

In some embodiments, a cytochrome P-450 inhibitor, for example ritonavir, is administered either in the same or a separate pharmaceutical composition with the protease inhibitor (for example Compound 1 (or a pharmaceutically acceptable salt thereof)) to improve pharmacokinetics. A cytochrome P450 inhibitor reduces the metabolism of some protease inhibitors, such as Compound 1, thereby improving the pharmacokinetics and bioavailability of the protease inhibitor, for example Compound 1. More preferably, Compound 1 (or a pharmaceutically acceptable salt thereof is co-formulated with ritonavir in the same dosage form. Other cytochrome P450

Risk of taking

109 / 229 ·· ·· the

Inhibitors such as cobicistat can also be administered in place of ritonavir to improve the pharmacokinetics of Compound 1 (or a pharmaceutically acceptable salt thereof).

Inhibitors of cytochrome P450, such as ritonavir, can be co-administered with the DAAs, either sequentially or simultaneously, in the same or sub-compositions. In some embodiments, cytochrome P450 inhibitors are administered to the

Improve pharmacokinetics of at least one of the DAAs. It is not affiliated with any theory, but a cytochrome P450 inhibitor could also reduce the development of resistant strains of HCV when co-administered with a DAA, thereby providing efficacy in a shorter treatment. In some embodiments, ritonavir is co-administered with therapeutic agent 1. In some embodiments, ritonavir is co-administered with therapeutic agent 1 in the same compositions.

In some embodiments, the present technology provides a method of treating HCV infection comprising administering at least one protease inhibitor and at least one HCV polymerase inhibitor with ribavirin in a course of treatment of no more than, or less than eight weeks in the absence of interferon . In some embodiments, the HCV polymerase inhibitor is Compound 1, or a pharmaceutically acceptable salt thereof.

In some embodiments, the present technology provides a method of treating HCV infection without the use of interferon, the method comprising administering at least two DAAs and ribavirin to a patient in need of such treatment, wherein the at least two DAAs include at least one protease inhibitor and at least one HCV polymerase inhibitor. In some embodiments, the at least two DAAs include therapeutic agent 1 with at least one HCV polymerase inhibitor. In some embodiments, the is

110/229 • · ·· ···

HCV polymerase inhibitor at least one non-nucleoside polymerase inhibitor. In some embodiments, the non-nucleoside polymerase inhibitor is Therapeutic Agent 2 or Therapeutic Agent 3, or a combination thereof.

In some embodiments, the present technology provides a method for treating HCV infection without the use of interferon, the method comprising administering an HCV protease inhibitor, preferably therapeutic agent 1, with at least one HCV NS5A inhibitor to a patient who has one Treatment needed includes. In some embodiments, the NS5A inhibitor is therapeutic agent 4.

In some embodiments of the present technology, there is a method of treating HCV infection without the use of interferon, the method comprising administering at least three DAAs and ribavirin to a subject for no more than eight weeks without the administration of interferon. The at least three DAAs can be at least one protease inhibitor, at least one HCV polymerase inhibitor, and at least one NS5A inhibitor. In a preferred embodiment, the at least one protease inhibitor is the therapeutic agent 1, the at least one polymerase inhibitor is the therapeutic agent 2 or the therapeutic agent 3, and the at least one NS5A inhibitor is the therapeutic agent 4.

Preferred HCV protease inhibitors include, but are not limited to, Therapeutic Agent 1, Telaprevir (Vertex), Boceprevir (Merck), BI-201335 (Boehringer Ingelheim), GS-9451 (Gilead), and BMS-650032 (BMS). Other suitable protease inhibitors include, but are not limited to, ACH-1095 (Achillion), ACH-1625 (Achillion), ACH-2684 (Achillion), AVL-181 (Avila), AVL-192 (Avila), BMS-650032 ( BMS), danoprevir (RG7227 / ITMN-191, Roche), GS-9132 (Gilead), GS-9256 (Gilead), IDX-136 (Idenix), IDX-316 (Idenix), IDX-320 (Idenix), MK -5172 (Merck), narlaprevir (Schering-Plow Corp), PHX-1766 (Phenomix), TMC-435 (Tibotec), vaniprevir (MK-7009, Merck),

111/229 (Vertex), VX-985

VBY708 (Virobay), VX-500 (Vertex), VX-813 (Vertex), or a combination thereof.

Preferred non-nucleoside HCV polymerase inhibitors for use in the present technology include, but are not limited to, Therapeutic Agent 2, Therapeutic Agent 3, GS-9190 (Gilead), BI-207127 (Boehringer Ingelheim), and VX -222 (VCH-222) (Vertex &amp; ViraChem). Preferred nucleotide HCV polymerase inhibitors include, but are not limited to, PSI-7977 (Pharmasset), and PSI-938 (Pharmasset). Other suitable and non-limiting examples of suitable HCV polymerase inhibitors include: ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS791325 (BMS), Filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS9669 (Gilead), IDX-375 (Idenix ), MK-3281 (Merck), Tegobuvir, TMC-647055 (Tibotec), VCH-759 (Vertex &amp; ViraChem), VCH-916 (ViraChem), VX-759 (Vertex), GS-6620 (Gilead), IDX- 102 (Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck), RG7128 (Roche), TMC64912 (Medivir), GSK625433 (GlaxoSmithKline), BCX4678 (BioCryst), ALS-2200 (Alios BioPharma / Vertex), ALS-2158 (Alios BioPharma / Vertex) or a combination thereof. A polymerase inhibitor can be a nucleoside polymerase inhibitor such as GS-6620 (Gilead), IDX-102 (Idenix), INX-189 (Inhibitex), MK-0608 (Pharmasset), PSI-938 (Pharmasset), RG7128 (Idenix) , IDX-184 (Merck), PSI-7977 (Roche), TMC64912 (Medivir), ALS-2200

BioPharma / Vertex) polymerase inhibitor (Alios BioPharma / Vertex), ALS-2158 (Alios thereof. A non-nucleoside or a combination can also be a

Polymerase inhibitors such as PF-00868554 (Pfizer), ANA598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), Filibuvir, GL59728 (Glaxo), GL60667 (Glaxo ), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck), Tegobuvir (Gilead), TMC-647055 (Tibotec), VCH759 (Vertex &amp; ViraChem), VCH-916 (ViraChem), VX -222 (VCH-222) (Vertex &amp; ViraChem), VX-759 (Vertex) or a combination thereof.

Preferred NS5A inhibitors include, but are not

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-U24::

·· ·· limited to therapeutic agent 4, BMS-790052 (BMS) and GS-5885 (Gilead). Non-limiting examples of suitable NS5A inhibitors include GSK62336805 (GlaxoSmithKline), ACH-2928 (Achillion), AZD2836 (Astra-Zeneca), AZD7295 (Asta-Zeneca), BMS-790052 (BMS), BMS-824393 (BMS), GS5885 (Gilead), PPI-1301 (Presidio), PPI-461 (Presidio) A-831 (Arrow Therapeutics), A-689 (Arrow Therapeutics), or one

Combination of one.

Non-limiting examples of suitable ones

Cyclophilin inhibitors include alisporovir (Novartis &amp; Debiopharm), NM-811 (Novartis), SCY-635 (Scynexis), or one

Combination of one.

Non-limiting examples of suitable HCV entry inhibitors include ITX-4520 (iTherx), ITX-5061 (iTherx), or a combination thereof.

Specific examples of other DAA agents suitable for the present methods include, but are not limited to, AP-H005, A-831 (Arrow

Therapeutics) (NS5A Inhibitor), A-689 (Arrow Therapeutics) (NS5A Inhibitor), INX08189 (Inhibitex) (Polymerase Inhibitor), ITMN-191 (NS3 / 4A Protease Inhibitor), VBY-376 (Virobay), ACH-1625 (Achillion,

IDX136 (Idenix, protease inhibitor), IDX316 900518 (Intermune / Roche) (protease inhibitor)

Protease inhibitor), (Idenix, protease inhibitor),

VX-813 (Vertex),

SCH (Schering-Plow), TMC-435 (Tibotec), ITMN-191 (Intermune,

Roche), MK-7009 (Merck), IDX-PI (Novartis), R7128 (Roche), PF868554 (Pfizer) (non-nucleoside polymerase inhibitor), PF4878691 (Pfizer), IDX-184 (Idenix), IDX-375 ( Idenix, NS5B

Polymerase inhibitor), PPI-461 (Presidio), BILB-1941 (Boehringer

Ingelheim), GS-9190 (Gilead), BMS-790052 (BMS), CTS-1027 (Conatus), GS-9620 (Gilead), PF-4878691 (Pfizer), RO5303253 (Alios BioPharma / Vertex), ALS-2158 ( Alios

GSK62336805 ^ GlaxoSmithKline) or the present (Roche), ALS-2200 BioPharma / Vertex) offers any combinations thereof.

In some embodiments

Technology Process for treating patients with genotype 1, such as la or lb, HCV infection. The proceedings

113/229

113 involve administering to such a patient a combination of at least 2 DAAs and ribavirin for no more than 12 weeks, preferably no more than 8 weeks, wherein the treatment does not include administration of interferon. Patients with genotype 1, such as Ia or Ib, infection can be treated with a combination of at least two DAAs without interferon, wherein the at least two DAAs include therapeutic agent 1 and therapeutic agent 2 with ribavirin. Therapeutic Agent 1 and Therapeutic Agent 2 with ribavirin can be administered in therapeutically effective amounts to provide an SVR (e.g., SVR8, SVR12, SVR16, or SVR24) after a treatment period of no more than 12 weeks (e.g., the duration is 12 weeks), preferably no more than 8 weeks (for example, the duration is 8 weeks). Patients can be treatment-naïve or treatment-experienced HCV patients. The duration of treatment can be no more than 12 weeks, including but not limited to no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, not more than 5 weeks, not more than 4 weeks or not more than 3 weeks, for example the duration is 12 weeks, or the duration is 8 weeks. The total daily dose of Therapeutic Agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. The therapeutic agent 2 can be combined with the therapeutic agent 1 in any of the dosages of the 1 described above, total daily dosage of therapeutic agent 2 can be, but is not limited to, for example about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about therapeutic agent. The

114/229 • · · · · · · · ········· · ·· ·· ·· · ·····

1000 mg, about 1500 mg, or 1800 mg. Conveniently, ribavirin can be co-administered with therapeutic agent 1 or therapeutic agent 2 in any of the dosages described above. Suitable total daily dosages of ribavirin may depend on the weight of the individual and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient &lt;75 kg body weight or about 1200 mg per day for a patient&gt; 75 kg body weight. In some embodiments, ritonavir can either be co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include, but are not limited to, from about 50 mg to about 400 mg per day, preferably about 100 mg per day.

In some embodiments, the present technology provides methods of treating patients with genotype 2 or 3 HCV infection. The methods include administering to such a patient a combination of at least two DAAs and ribavirin for no more than 12 weeks (e.g. the duration is 12 weeks), preferably no more than 8 weeks (e.g. the duration is 8 weeks), wherein the treatment does not include the administration of interferon. Patients with genotype 2 or 3 HCV infection can be treated with a combination of at least two DAAs without interferon, wherein the at least two DAAs include therapeutic agent 1 and therapeutic agent 2 with ribavirin. The therapeutic agent 1 and the therapeutic agent 2 can be administered in therapeutically effective amounts to provide an SVR (e.g. an SVR8, SVR12, SVR16 or SVR2 4) with a treatment duration of no more than 12 weeks, preferably no more than 8 weeks . Patients can be treatment-naive HCV patients or treatment-experienced HCV patients. The duration of treatment can be no more than 12 weeks, including but not limited to no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks

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1p ;:: .... ·. ···.

more than 7 weeks, not more than 6 weeks, not more than 5 weeks, not more than 4 weeks, or not more than 3 weeks, for example the duration is 12 weeks, or the duration is 8 weeks. The total daily dosage of Therapeutic Agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg , about 170 mg, about 180 mg, about 190, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270, about 300 mg. The therapeutic agent 2 can be administered in conjunction with the therapeutic agent 1 in any of the dosages of therapeutic agent 1 described above. The total daily dosage of Therapeutic Agent 2 can be, but is not limited to, for example, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000, about 1500 mg, or 1800 mg. Suitably, ribavirin can be co-administered with therapeutic agent 1 or therapeutic agent 2 in any combination of the appropriate dosages described above. Suitable total daily dosages of ribavirin may depend on the weight of the individual and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient &lt;75 kg body weight or about 1200 mg per day for a patient&gt; 75 kg body weight. In some embodiments, ritonavir can either be co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day.

In some embodiments, the present technology provides methods of treating patients with HCV infection. The methods include administering to such a patient a combination of at least two DAAs and ribavirin for no more than 12 weeks (for example, the

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<img file="AT514003A2_D0023.tif" />

·· ·· ··

Duration 12 weeks), preferably no more than 8 weeks (e.g. duration is 8 weeks), wherein the treatment does not include administration of interferon. The combination comprises the therapeutic agent 1 and the therapeutic agent 2 and ribavirin. Suitably, the patient can be a treatment-naive patient, a treatment-experienced patient, or an interferon non-responder. In some embodiments, the patient is infected with HCV genotype 1, such as genotype Ia. In some embodiments, the patient is infected with HCV genotype lb. In some embodiments, the patient is infected with HCV genotype 2 or 3, such as 2a or 2b. In some other embodiments, the patient is infected with HCV genotype 3a. Treatment according to this aspect of the technology can also be effective against other HCV genotypes. The duration of treatment can be for no more than 12 weeks, preferably no more than 8 weeks, including but not limited to no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, for example the duration is 12 weeks, or the duration is 8 weeks. The therapeutic agent 1 and the therapeutic agent 2 can be administered in therapeutically effective amounts to provide an SVR (e.g. an SVR8, SVR12, SVR16 or SVR24) after a treatment period of no more than 12 weeks, preferably no more than 8 weeks. The total daily dosage of Therapeutic Agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg , about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. The therapeutic agent 2 can be administered with the therapeutic agent 1 in any of the dosages described above. The entire daily

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<img file="AT514003A2_D0024.tif" />

• · · • · · · ·

Dosage of therapeutic agent 2 can be, but is not limited to, for example about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg. Suitably, ribavirin can be co-administered with therapeutic agent 1 or therapeutic agent 2 in any combination of the appropriate dosages described above. Suitable total daily dosages of ribavirin may depend on the weight of the individual and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient &lt;75 kg body weight or about 1200 mg per day for a patient&gt; 75 kg body weight.

In some embodiments, the present technology provides methods of treating patients with HCV infection who are non-candidates for interferon treatment. The methods comprise administering to such a patient a combination of at least two DAAs and ribavirin for no more than 12 weeks (e.g. the duration is 12 weeks), preferably no more than 8 weeks (e.g. the duration is 8 weeks), wherein the treatment does not include the administration of interferon. Patients who are not candidates for interferon treatment include, but are not limited to, one or more of the following groups: patients who are intolerant to interferon, patients who refuse to take interferon treatment, patients with medical conditions that prevent them prevent taking interferon and patients who are at increased risk of side effects or infection from taking interferon. A non-candidate for interferon treatment may be infected with HCV genotype 1 or 2, for example genotype la or lb. A non-candidate for interferon treatment may be infected with HCV genotype 2, for example genotype 2a or 2b. Treatment according to this aspect of the technology can also be effective against other HCV genotypes. In some embodiments, non-candidates for interferon treatment may be patients

118/229 ·· ···

-lli are being treated with a combination of at least two DAAs without interferon and with ribavirin for a treatment period of no more than 12 weeks, including but not limited to no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably not more than 8 weeks, not more than 7 weeks, not more than 6 weeks, not more than 5 weeks, not more than 4 weeks, or not more than 3 weeks, for example the duration is 12 weeks, or the duration is 8 weeks. The at least two DAAs include at least one HCV protease inhibitor and at least one HCV polymerase inhibitor. Suitably, the at least one HCV protease inhibitor can be therapeutic agent 1 and the at least one HCV polymerase inhibitor can be therapeutic agent 2. The therapeutic agent 1 and the therapeutic agent 2 can be administered in therapeutically effective amounts to provide an SVR after a treatment duration of no more than 12 weeks, preferably no more than 8 weeks. The total daily dosage of Therapeutic Agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg , about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. The therapeutic agent 2 can be administered with the therapeutic agent 1 administered at any of the dosages described above. The total daily dosage of therapeutic agent 2 can be, but is not limited to, for example, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. Conveniently, ribavirin can be co-administered with therapeutic agent 1 or therapeutic agent 2 in any of the dosages described above. Suitable total daily dosages of ribavirin can depend on the weight of the individual and include, but are not limited to, from about 800 mg to about 1200

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-1193 mg, including, for example, about 1000 mg per day for a patient &lt;75 kg body weight or about 1200 mg per day for a patient weighing 75 kg.

In another aspect, the present technology provides methods of treating patients with HCV infection. The methods comprise administering to such a patient a combination of at least two DAAs and ribavirin for no more than 12 weeks (e.g. the duration is 12 weeks), preferably no more than 8 weeks (e.g. the duration is 8 weeks), wherein the treatment does not include the administration of interferon. The combination comprises the therapeutic agent 1, the therapeutic agent 2, the therapeutic agent 4 and ribavirin. In some embodiments, the patient is infected with HCV genotype 1, such as genotype Ia. Treatment according to this aspect of the technology can also be effective against other HCV genotypes. The duration of treatment can be no more than 12 weeks, including but not limited to no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, not more than 5 weeks, not more than 4 weeks, or not more than 3 weeks, for example the duration is 12 weeks, or the duration is 8 weeks. The therapeutic agent 1, the therapeutic agent 2 and the therapeutic agent 3 can be provided in effective amounts to provide an SVR (e.g. an SVR8, SVR12, SVR16 or SVR24) after a treatment period of no more than 12 weeks, preferably no more than 8 weeks. The total daily dosage of therapeutic

Active ingredient 1 can be, but is not limited to, for

Example about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about

190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 300 mg. The therapeutic agent 2 can be administered with the therapeutic agent 1

120 / 229 _ η ο ·· · · ·· ± ·· · · · 9 · ·

9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 999, wherein the therapeutic agent 1 is administered in any of the dosages described above. The total daily dosage of Therapeutic Agent 2 can be, but is not limited to, for example, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. The therapeutic agent 4 can be provided in combination with the therapeutic agent 1 and the therapeutic agent 2, wherein the therapeutic agent 1 and the therapeutic agent 2 in any combination of the dosages for the therapeutic agent 1 and the therapeutic agent 2 described above , administered. The therapeutic agent 4 can in combination with the therapeutic agent 1 and the therapeutic agent 2 in a total daily dose of the therapeutic agent 4 of an amount of about 5 mg to about 350 mg, preferably about 5 mg to about 300 mg, more preferably about 25 mg to about 200 mg can be provided. The total daily dosage of therapeutic agent 4 can be, but is not limited to, for example, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, or about 100 mg. In some embodiments, ritonavir can either be co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day. Suitably, ribavirin can be co-administered with therapeutic agent 1, therapeutic agent 2 and therapeutic agent 4, with therapeutic agent 1, therapeutic agent 2 and therapeutic agent 4 being provided in any combination of the dosages described above. Suitable total daily dosages of ribavirin may depend on the weight of the individual and include, but are not limited to, from about 800 mg to about 1200 mg,

121 / 229 ♦ ••• ft · · ··· • · · · · · · · ······· · · · ·· · · ·· · · · including, for example, about 1000 mg per day for a patient &lt;75 kg body weight or approximately 1200 mg per day for a patient&gt; 75 kg body weight. Suitably, in some embodiments, the patient may be a treatment-naïve patient, a treatment-experienced patient, or an interferon non-responder.

In some embodiments, the present technology provides methods of treating patients with genotype 1, such as genotype Ia or Ib, HCV infection. The methods comprise administering to such a patient a combination of at least two DAAs and ribavirin for no more than 12 weeks (e.g. the duration is 12 weeks), preferably no more than 8 weeks (e.g. the duration is 8 weeks), wherein the treatment does not include the administration of interferon. The combination comprises the therapeutic agent 1, the therapeutic agent 3 and ribavirin. The duration of treatment can be no more than 12 weeks, including but not limited to no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, not more than 5 weeks, not more than 4 weeks, or not more than 3 weeks, for example the duration is 12 weeks, or the duration is 8 weeks. The total daily dosage of Therapeutic Agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg , about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. The therapeutic agent 3 can be administered in conjunction with the therapeutic agent 1, the therapeutic agent 1 being administered in any of the dosages described above. The therapeutic agent 3 can be provided in combination with the therapeutic agent 1. The total daily dosage of therapeutic agent 3 can be

122 / 229 « « · · ·······

-1 »· · ♦ '1 &amp; Δ ~~ 9 9 9 9« • 9 · · · · • · · · · * ·· «· * · ·

9

999 999 is but not limited to, for example, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg , about 620 mg, about 630 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg. Ribavirin can be co-administered with therapeutic agent 1 and therapeutic agent 3 or administered separately; and Therapeutic Agent 1 and Therapeutic Agent 3 can be administered in any of the suitable dosages of Therapeutic Agent 1 or Therapeutic Agent 3 set forth above. Suitable total daily dosages of ribavirin may depend on the weight of the individual and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient &lt;75 kg body weight or about 1200 mg per day for a patient weighing 75 kg. In some embodiments, ritonavir can either be co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day.

In some embodiments, the present technology provides methods of treating patients with genotype 2 or 3, such as genotype 2a, 2b or 3a, HCV infection. The methods include administering to such a patient a combination of at least two DAAs and ribavirin for no more than 12 weeks (e.g. the duration is 12 weeks), preferably no more than 8 weeks (e.g. the duration is 8 weeks), wherein the treatment does not include the administration of interferon. The combination comprises the therapeutic agent 1, the therapeutic one

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<img file="AT514003A2_D0025.tif" />

Active ingredient 3 and ribavirin. The duration of treatment can be no more than 12 weeks, including but not limited to no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, not more than 5 weeks, not more than 4 weeks, or not more than 3 weeks, for example the duration is 12 weeks, or the duration is 8 weeks. The therapeutic agent 1 and the therapeutic agent 3 and ribavirin can be administered in therapeutically effective amounts to provide an SVR (e.g. an SVR8, SVR12, SVR16 or SVR24) in a treatment period of no more than 12 weeks, preferably no more than 8 Weeks. The total daily dosage of Therapeutic Agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. The therapeutic agent 3 can be administered with the therapeutic agent 1, the therapeutic agent 1 being administered in any of the dosages described above. The therapeutic agent 3 can be provided in combination with the therapeutic agent 1. The total daily dosage of Therapeutic Agent 3 can be, but is not limited to, for example, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg , about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 650 mg, about 700 mg, about 750 mg, about 800

124 / 229 . .. ..................

.......... ... · therapeutic 3 can be in mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg. Ribavirin can be co-administered with therapeutic agent 1 and therapeutic agent 3 or administered separately; and the

Agent 1 and the therapeutic agent of any combination of the appropriate dosages of therapeutic agent 1 or therapeutic agent 3 set forth above. Suitable total daily dosages of ribavirin may depend on the weight of the individual and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient &lt;75 kg body weight or about 1200 mg per day for a patient over 75 kg body weight. In some embodiments, ritonavir can either be co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day.

In some embodiments, the present technology provides methods of treating patients with HCV infection. The methods comprise administering to such a patient a combination of at least two DAAs and ribavirin for no more than 12 weeks (e.g. the duration is 12 weeks), preferably no more than 8 weeks (e.g. the duration is 8 weeks), wherein the treatment does not include the administration of interferon. The combination comprises the therapeutic agent 1, the therapeutic agent 3 and ribavirin. Suitably, the patient can be a treatment-naive patient, a treatment-experienced patient, or an interferon non-responder. In some embodiments, the patient is infected with HCV genotype 1, such as genotype Ia. In some embodiments, the patient is infected with HCV genotype Ib. In some other embodiments, the patient is infected with HCV genotype 2 or 3, such as 2a or 2b. In some other embodiments, the patient is infected with HCV genotype 3a.

125 / 229 . . .··. ................

.......... ...·

Treatment according to this aspect of the technology can also be effective against other HCV genotypes. The duration of treatment can be no more than 12 weeks, including but not limited to no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, not more than 5 weeks, not more than 4 weeks, or not more than 3 weeks, for example the duration is 12 weeks, or the duration is 8 weeks. The total daily dosage of Therapeutic Agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about

150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about

260 mg, about 270 mg, or about 300 mg. The therapeutic agent 3 can be administered in conjunction with the therapeutic agent 1, the therapeutic agent 1 in any of the dosages described above, agent 3 can in FIG

Active ingredient

The therapeutic is administered to the therapeutic.

Can be combined with. The entire daily

Dosage of therapeutic agent 3 can be, but is not limited to, for example, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about

460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about

560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or ribavirin can about 1000 mg.

with the therapeutic

Active ingredient 1 and the therapeutic active ingredient 3 co-administered

126 / 229 • · ·

4265• · ·

<img file="AT514003A2_D0026.tif" />

·· · ·· ··· or administered separately; and Therapeutic Agent 1 and Therapeutic Agent 3 can be administered in any combination of the appropriate dosages of Therapeutic Agent 1 or Therapeutic Agent 3 set forth above. Suitable total daily dosages of ribavirin may depend on the weight of the individual and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient &lt;75 kg body weight or about 1200 mg per day for a patient k 75 kg body weight. In some embodiments, ritonavir can either be co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir included, from about 50 mg to about 400 mg per day, preferably about 100 mg per day.

In some embodiments, the present technology provides methods of treating patients with HCV infection who are non-candidates for interferon treatment. The methods include administering to such a patient a combination of at least two DAAs and ribavirin for no more than 12 weeks (e.g. the duration is 12 weeks), preferably no more than 8 weeks (e.g. the duration is 8 weeks), wherein the Treatment does not include administration of interferon. The combination comprises the therapeutic agent 1, the therapeutic agent 3 and ribavirin. Patients who are non-candidates for interferon treatment include, but are not limited to, one or more of the following groups: patients who are intolerant to interferon, patients who refuse to take interferon treatment, patients with medical conditions who have them stop taking interferon and patients who are at increased risk of side effects or infection from taking interferon. In some embodiments, the patient is infected with HCV genotype 1, such as genotype Ia. In some embodiments, the patient is infected with HCV genotype lb.

127 / 229 ·· ····«...

-3.-27.-:

In some other embodiments, the patient is infected with HCV genotype 2 or 3, such as 2a or 2b. In some other embodiments, the patient is infected with HCV genotype 3a. Treatment according to this aspect of the technology can also be effective against other HCV genotypes. The duration of treatment can be no more than 12 weeks, including but not limited to no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, for example the duration is 12 weeks, or the duration is 8 weeks. The total daily dosage of Therapeutic Agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. The therapeutic agent 3 can be administered with the therapeutic agent 1, the therapeutic agent 1 being administered in any of the dosages described above. The therapeutic agent 3 can be provided in combination with the therapeutic agent 1. The total daily dosage of therapeutic agent 3 can be, but is not limited to, for example, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg , about 380 mg, about

390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about

500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about

610 mg, about 620 mg, about 630 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850

128 / 229 • · * · ···· ···· · · I · * * · T 9 9 · · »mg, about 900 mg, about 950 mg, or about 1000 mg. Ribavirin can be co-administered with therapeutic agent 1 and therapeutic agent 3 or administered separately; and Therapeutic Agent 1 and Therapeutic Agent 3 can be administered in any combination of the appropriate dosages of Therapeutic Agent 1 or Therapeutic Agent 3 set forth above. Suitable total daily dosages of ribavirin may depend on the weight of the individual and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient &lt;75 kg

Body weight or approximately 1200 mg per day for a patient 75 kg body weight. In some embodiments, ritonavir can either be co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include from about 50 mg to about 400 mg per day, preferably about 100 mg per day.

In some embodiments, the present technology provides methods of treating patients with an HCV genotype 1, such as Ia or Ib, infection. The methods comprise administering to such a patient a combination of at least two DAAs and ribavirin for no more than 12 weeks (e.g. the duration is 12 weeks), preferably no more than 8 weeks (e.g. the duration is 8 weeks), wherein the treatment does not include the administration of interferon. The combination comprises the therapeutic agent 1, the therapeutic agent 4 and ribavirin. Patients with genotype la or lb infection can be treated with a combination of at least two DAAs without, wherein the at least two include therapeutic agent 1 and therapeutic agent 4 and ribavirin. The therapeutic agent 1 and the therapeutic agent 4 can be administered in therapeutically effective amounts to provide an SVR (e.g. an SVR8, SVR12, SVR16, or SVR24) in a treatment period of no more than 12 weeks, preferably

Interferon DAAs den

129 / 229 &gt;· ·· ·«·· ·«»

- · ΐ2 ^ ί-: ·. . · ·. ···.

······· · · · ·· ·· ·· · ·· ··· not more than 8 weeks, patient, or duration of treatment

Patients can be treatment-naive

Treatment-experienced patients. Which be no more than 12 weeks, including but not limited to no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 Weeks, no more than 5 weeks, no more than 4 weeks or no more than 3 weeks, for example the duration is 12 weeks, or the duration is 8 weeks. The total daily dosage of Therapeutic Agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. The therapeutic agent 4 can be administered in conjunction with the therapeutic agent 1, wherein the therapeutic agent 1 is administered in any of the dosages described above. The therapeutic agent 4 can be provided in combination with the therapeutic agent 1 in a total daily dose of therapeutic agent 4 of approximately 25 mg to approximately 200 mg. The total daily dosage of Therapeutic Agent 4 can be, but is not limited to, for example, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about

180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about

290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, or about 350 mg. In some embodiments, ritonavir can either be co-administered or separately with therapeutic agent 1

130/229 .··. ................

_Ί·_ο λ · · · · · * · ·

-1 · 30 · - ^ · · ·. · ··· can be administered. Suitable dosages of ritonavir include from about 50 mg to about 400 mg per day, preferably about 100 mg per day. In suitable embodiments, the therapeutic agent 1 and the therapeutic agent 4 are administered once a day. Conveniently, ribavirin can be co-administered with therapeutic agent 1 and therapeutic agent 4 or administered separately; and Therapeutic Agent 1 and Therapeutic Agent 4 can be administered in any combination of the appropriate dosages of Therapeutic Agent 1 and Therapeutic Agent 4 set forth above. Suitable total daily dosages of ribavirin may depend on the weight of the individual and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient &lt;75 kg body weight or about 1200 mg per day for a patient&gt; 75 kg body weight.

In some embodiments, the present technology provides methods of treating patients with HCV infection. The methods comprise administering to such a patient a combination of at least two DAAs and ribavirin for no more than 12 weeks (e.g. the duration is 12 weeks), preferably no more than 8 weeks (e.g. the duration is 8 weeks), wherein the treatment does not include the administration of interferon. The combination comprises the therapeutic agent 1, the therapeutic agent 4 and ribavirin. Patients can be treatment-naïve or treatment-experienced. The treatment can be administered for a duration of no more than 12 weeks, including but not limited to no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 Weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, for example the duration is 12 weeks, or the duration is 8 weeks. The patient may have HCV genotype 1, such as HCV131 / 229 ·· ·· · ο · · *** ········· • · · · · · · · ·

-jlSW-. ·. ·. ···.

·· ·· ·· · ··*···*

Have genotype la or lb. In other embodiments, the patient can have HCV genotype Ib. In some embodiments, it is contemplated to treat other HCV genotypes. The total daily dosage of Therapeutic Agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. The therapeutic agent 4 can be administered in conjunction with the therapeutic agent 1 in any of the dosages described above. The therapeutic agent 4 can be provided alone or in combination with the therapeutic agent 1. The total daily dosage of Therapeutic Agent 4 can be, but is not limited to, for example, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, or about 350 mg. In some

In embodiments, ritonavir can either be co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day. In suitable embodiments, the therapeutic agent 1 and the therapeutic agent 4 are administered once a day. In some embodiments, therapeutic agent 1 and therapeutic agent 4 are administered with ribavirin. Appropriate total daily dosages of ribavirin may depend on the weight of the individual

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:. *: f. ·. ···.

** ·· ·· · ·· ··· depend and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient &lt;75 kg body weight or about 1200 mg per day for a patient weighing 2 75 kg.

In some embodiments, the present technology provides methods of treating patients with HCV infection. The methods comprise administering to such a patient a combination of at least two DAAs and ribavirin for no more than 12 weeks (e.g. the duration is 12 weeks), preferably no more than 8 weeks (e.g. the duration is 8 weeks), wherein the treatment does not include the administration of interferon. The combination comprises the therapeutic agent 1, the therapeutic agent 4 and ribavirin. Patients can be treatment-naïve or treatment-experienced. The treatment can be administered for a duration of no more than 12 weeks, including but not limited to no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 Weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, for example the duration is 12 weeks, or the duration is 8 weeks. The patient can have HCV genotype 2 or 3, such as HCV genotype 2a. In some embodiments, the patient can have HCV genotype 2b. In other embodiments, the patient can have HCV genotype 3a. The total daily dosage of Therapeutic Agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about

180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. The therapeutic agent 4 can be administered in conjunction with the therapeutic agent 1, wherein the therapeutic agent 1 is in any of those described above

133/229 ·· ···· ·· «. · «. i -'J ···· ····: *. V: .......

Dosages being administered. The therapeutic agent 4 can be provided in combination with the therapeutic agent 1. The total daily dosage of therapeutic agent 4 can be, but is not limited to

<td>on to</td><td>example</td><td>approximately</td><td>15 mg,</td><td>approximately</td><td> 20</td><td>mg, approximately</td><td> 25</td><td>mg,</td>

<td>approximately</td><td>30 mg,</td><td>approximately</td><td>40 mg,</td><td>approximately</td><td> 50</td><td>mg, approximately</td><td> 60</td><td>mg,</td>

<td>approximately</td><td>70 mg,</td><td>approximately</td><td>75 mg,</td><td>approximately</td><td> 80</td><td>mg, approximately</td><td> 90</td><td>mg,</td>

<td>approximately</td><td>100 mg,</td><td>approximately</td><td>110 mg</td><td colspan="2">, approximately</td><td colspan="2">120 mg, approximately</td><td> 130</td>

mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, or about 350 mg. In some embodiments, ritonavir can either be co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include from about 50 mg to about 400 mg per day, per

Day. In suitable embodiments, preferably approximately 100 mg, the therapeutic agent 1 and the therapeutic agent 4 are administered once a day. In some embodiments, therapeutic agent 1 and therapeutic agent 4 are administered with ribavirin. Suitable total daily dosages of ribavirin may depend on the weight of the individual and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient &lt;75 kg body weight or about 1200 mg per day for a patient weighing 2 75 kg.

In some embodiments, the present technology provides methods of treating patients with HCV infection who are not candidates for one

Are interferon treatment. The methods include administering to such a patient a combination of at least two DAAs and ribavirin for no more than 12 weeks (e.g. the duration is 12 weeks, preferably no more than 8 weeks (e.g. the duration is 8 weeks) wherein the

134/229 * »» · ♦ · a • · «» · MM ···· • · · t · · € '♦

Treatment does not include administration of interferon. The combination comprises the therapeutic agent 1, the therapeutic agent 4 and ribavirin. Patients who are not candidates for interferon treatment include, but are not limited to, one or more of the following groups: patients who are intolerant to interferon, patients who refuse to take interferon treatment, patients with medical conditions who receive them stop taking interferon and patients who are at increased risk of side effects or infection from taking interferon. In some embodiments, the patient is infected with HCV genotype 1, such as genotype Ia. In some embodiments, the patient is infected with HCV genotype Ib. In some other embodiments, the patient is infected with HCV genotype 2 or 3, such as 2a or 2b. In some other embodiments, the patient is infected with HCV genotype 3a. Treatment according to this aspect of the technology can also be effective against other HCV genotypes. The therapeutic agent 1 and the therapeutic agent 4 can be administered in therapeutically effective amounts to provide an SVR (e.g. an SVR8, SVR12, SVR16 or SVR24) after treatment for no more than 12 weeks, preferably no more than 8 weeks. The Interferon-NonResponder patients partly include Interferon-Responders and Interferon-Rückfail-patients. See GUIDANCE FOR INDUSTRY CHRONIC HEPATITIS CYP3A4 VIRUS INFECTION: DEVELOPING DIRECTACTING ANTIVIRAL AGENTS FOR TREATMENT (FDA, September 2010, draft guidance) for definitions of naive, partial responder, responder-relapser (i.e. relapse), and null-responder patients. The interferon non-responder patients also include null-responder patients. The treatment can be administered for a duration of no more than 12 weeks, including but not limited to no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 Weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, for example that is

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-135 Duration 12 weeks, or the duration is 8 weeks. The total daily dosage of Therapeutic Agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. The therapeutic agent 4 can be administered with the therapeutic agent 1, wherein the therapeutic agent 1 is administered in any of the dosages described above. The therapeutic agent 4 can be provided in combination with the therapeutic agent 1. The total daily dosage of Therapeutic Agent 4 can be, but is not limited to, for example, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, or about 350 mg. In some embodiments, ritonavir can either be co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day. In suitable embodiments, the therapeutic agent 1 and the therapeutic agent 4 are administered once a day. Suitably, ribavirin can be co-administered with therapeutic agent 1 and therapeutic agent 4 or administered separately, with therapeutic agent 1 and therapeutic agent 4 being administered in any combination of the appropriate dosages given above

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-136 • · • · · become. Suitable total daily dosages of ribavirin may depend on the weight of the individual and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient &lt;75 kg body weight or about 1200 mg per day for a patient weighing 75 kg.

In some embodiments, the present technology provides methods of treating patients with HCV infection who are interferon non-responders (e.g., null responders). The methods comprise administering to such a patient a combination of at least two DAAs and ribavirin for no more than 12 weeks (e.g. the duration is 12 weeks), preferably no more than 8 weeks (e.g. the duration is 8 weeks), wherein the treatment does not include the administration of interferon. Interferon non-responder patients can be treated with a combination of at least two DAAs without interferon with ribavirin, wherein the two DAAs include therapeutic agent 1 and therapeutic agent 4. The therapeutic agent 1 and the therapeutic agent 4 can be administered in therapeutically effective amounts to provide an SVR (for example an SVR8, SVR12, SVR16, or SVR24) after a treatment period of no more than 12 weeks, preferably no more than 8 weeks . The Interferon NonResponder patients include interferon responders and interferon relapse patients. The interferon non-responder patient can have HCV genotype 1, such as la. The interferon non-responder patient may have HCV genotype lb. The interferon non-responder patient can have HCV genotype 2 or 3, such as genotype 2a. In some embodiments, the patient can have HCV genotype 2b. In other embodiments, the patient can have HCV genotype 3a. In some embodiments, it is contemplated to treat other HCV genotypes. The treatment can be administered for a duration of no more than 12 weeks, including but not limited to no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more

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-137 as 8 weeks, not more than 7 weeks, not more than 6 weeks, not more than 5 weeks, not more than 4 weeks, or not more than 3 weeks, for example the duration is 12 weeks, or the duration is 8 weeks . The total daily dosage of Therapeutic Agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about

150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about

260 mg, approximately 270 therapeutic active ingredient active ingredient 1 administered

300 mg. The therapeutic therapeutic mg, mg,

Active ingredient 1 administered.

mg, or about 4 can be with what the

Active ingredient 1 is administered in any of the dosages described above. The therapeutic agent 4 can be administered in combination with the therapeutic agent 1. The total daily dosage of therapeutic agent 4 can be, but is not limited to, for example, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40, about 50 mg, about 60 mg, about 70 mg, about 75 about 80 mg, about 90 mg, about 100 mg, about

110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about

220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about

330 mg, about 340 mg, or about 350 mg. In some embodiments, ritonavir can either be co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day. In suitable embodiments, therapeutic and therapeutic agent 4 are administered once a day. Conveniently, ribavirin can be co-administered with therapeutic agent 1 and therapeutic agent 4 or administered separately, with the

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Therapeutic Agent 1 and Therapeutic 4 can be administered in any combination of suitable dosages as described above. Suitable total daily dosages of ribavirin may depend on the weight of the individual and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient &lt;75 kg body weight or about 1200 mg per day for a patient weighing 75 kg.

Accordingly, in some embodiments, the present technology provides a method of treating HCV infection comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs with an effective amount of ribavirin. The treatment lasts no more than 12 weeks, alternatively no more than 11 weeks, alternatively no more than 10 weeks, alternatively no more than 9 weeks, preferably no more than 8 weeks, alternatively no more than 7 weeks, alternatively no more than 6 weeks , alternatively no more than 5 weeks, alternatively no more than 4 weeks, alternatively no more than 3 weeks, and it does not include the administration of any interferon. The DAAs and ribavirin can be administered at the same or different dosage frequencies. The patient being treated may be an HCV treatment-naive patient or a HCV treatment-experienced patient, including interferon non-responders, partial interferon non-responders (patients whose HCV RNA levels decreased but never became undetectable when they treated with interferon), or relapsers (patients who reached undetectable levels of HCV-RNA during therapy but relapsed), or a patient who is unable to Taking interferon. The patient may be infected with, for example and without limitation, HCV genotypes 1 or 2. In some embodiments, it is preferably genotypes Ia or Ib. In other embodiments, the HCV genotype is 2 or 3. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.

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-139• · • ·

For example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (for example, a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least an HCV protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, an HCV or nucleotide non-nucleoside or a combination of at least one protease inhibitor, at least one nucleoside polymerase inhibitor and at least one inhibitor).

As another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NS5A inhibitor. In one example, the combination of two or more DAAs includes GS-5885 (an NS5A inhibitor) and GS-9451 (a protease inhibitor or an NS3 protease inhibitor). In some examples, GS-5885 is provided in a daily dose of from about 3 mg to about 200 mg, alternatively from about 3 mg to about 100 mg, alternatively from about 30 mg to about 90 mg, including but not limited to, for example about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg. GS-9451 can be administered in combination with any of the daily dosages of GS-5885 described above. GS-9451 can be administered in a total daily dose of about 100 mg to about 500 mg, alternatively from about 200 mg to about 400 mg, including but not limited to, for example, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg.

Suitable examples include about 30 mg GS-5885 and about daily

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Total dosages of

200 mg GS-9451 one;

-140 alternatively about 60 mg GS-5885 and about 200 mg GS-9451; alternatively about 90 mg GS-5885 and about 200 mg GS-9451.

In another example, the present technology provides the at least two DAAs that include at least two HCV polymerase inhibitors. In some embodiments, the at least two HCV polymerase inhibitors comprise at least one nucleoside or nucleotide analog polymerase inhibitor. In some embodiments, the at least two HCV polymerase inhibitors comprise at least two nucleoside or nucleotide analog polymerase inhibitors.

Suitable nucleotide analog polymerase inhibitors include PSI7977 (Pharmasset) and PSI-938 (Pharmasset). Suitable daily dosages of the at least one nucleoside or nucleoside analog polymerase inhibitor include from about 100 mg to about 500 mg, alternatively from about 200 mg to about 400 mg, including, but not limited to, for example about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. For example, a suitable combination includes a total daily dose of PSI7977 of about 400 mg and a total daily dose of PSI938 of about 300 mg, alternatively a total daily dose of about 200 mg PSI-7977 and a total daily dose of about 300 mg PSI-938. Suitably ribavirin can be administered with the at least two DAAs, preferably in a dosage which depends on the weight of the individual, in a total daily dosage of about 400 mg to about 1400 mg, suitably about 1000 mg or about 1200 mg per day . For example, a suitable daily treatment with ribavirin is weight-dependent, for example 1000 mg / day for &lt;75 kg body weight and 1200 mg / day for k 75 kg body weight, divided into twice a day (BID). In yet another example, the combination of two DAAs includes at least one HCV protease inhibitor and one HCV polymerase inhibitor. In some

Embodiments, the at least one protease inhibitor is TMC435 and the at least other polymerase inhibitor is one or more at least

141/229 • ·

-141···· ·· 9 9

9 9 9 9 9 9 9 9 9

99 99 9 99 999

Nucleotide / nucleoside analog polymerase inhibitor, for example PSI-7977, or for example TMC-647055. Suitably the at least one protease inhibitor, for example TMC-435, is provided in a total daily dosage of about 25 mg to about 250 mg, alternatively from about 25 mg to about 200 mg, alternatively from about 50 mg to about 200 mg, alternatively from about 75 mg to about 150 mg, for example about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg; and the at least one polymerase inhibitor (e.g. PSI-7977) is provided in a total daily dose of about 100 mg to about 500 mg, alternatively from about 200 mg to about 400 mg, including but not limited to, for example, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about

450 mg, or about 500 mg. For example, a combination can be a total daily dosage of about 75 mg TMC-435 and about 400 mg PSI-7977, alternatively about 100 mg TMC-435 and about 400 mg PSI-7977, alternatively about 150 mg TMC-435 and about 400 mg PSI-7977, alternatively about 100 mg TMC-435 and about 400 mg PSI-7977, alternatively about 75 mg TMC-435 and about 200 mg PSI-7977, alternatively about 150 mg TMC-435 and about 200 mg PSI-7977, alternatively about 100 mg TMC-435 and about 200 mg PSI-7977, alternatively about 75 mg TMC-435 and about 100 mg PSI-7977, alternatively about 100 mg TMC-435 and about 100 mg PSI-7977, alternatively about 150 mg TMC -435 and about 100 mg PSI-7977, and may include other suitable combinations. Suitably, in some embodiments, ritonavir or a suitable equivalent can be added to the at least two DAAs comprising at least one protease inhibitor, suitably in an amount of about 100 mg to about 400 mg per day, preferably about 100 mg per day. Conveniently, ribavirin can be administered with the at least two DAAs, preferably in a dosage that depends on the weight of the individual, suitably about 1000 mg or about 1200 mg

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-142 "ft" ft per day. For example, a suitable daily treatment with ribavirin is weight-dependent, for example 1000 mg / day for &lt;75 kg body weight and 1200 mg / day for k 75 kg body weight, divided into twice a day (BID). In alternative embodiments, the at least one protease is BI-201335 (NS3 / 4A protease inhibitor) and the at least one HCV polymerase inhibitor is a non-nucleoside polymerase inhibitor, for example BI-207127. In some examples, the BI-201335 is provided in a total daily dose of about 100 mg to about 400 mg, alternatively from about 120 mg to about 240 mg, including about 100 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 275 mg , about 300 mg, about 320 mg, about 330 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, or about 400 mg; and BI-207127 can be administered in a total daily dose of from about 300 mg to about 3600 mg, preferably from about 1200 mg to about 2100 mg, including, but not limited to, for example about 300 mg, about 400 mg, about 500 mg , about 600 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 3000 mg, about 3200 mg, about 3400 mg, or about 3600 mg. Suitable examples include, but are not limited to, a combination of a total daily dose of about 120 mg BI-201335 and about 1200 mg BI-207127, alternatively about 120 mg BI-201335 and about 1500 mg BI-207127, alternatively about 120 mg BI-201335 and about 1800 mg BI-207127, alternatively about 120 mg BI201335 and about 2100 mg BI-207127, alternatively about 240 mg BI-201335 and about 1200 mg BI-207127, alternatively about

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Way may, in some, be a suitable equivalent

--14-5- · ·· ». ·. · ··“ O ····. * ···· • · ·. · Σ J · · ·· ·· in · * ». · · • 99 999

240 BI-201335 mg and about 1500 mg BI-207127, alternatively about 240 mg BI-201335 and about 1800 mg BI-207127, alternatively about 240 mg BI-201335 and about 2100 mg BI207127. Suitably, in some embodiments, ritonavir or a suitable equivalent can be added to the at least two DAAs comprising at least one protease inhibitor, suitably in an amount of about 100 mg per day. More suitable

Embodiments, ritonavir or added to the at least two DAAs comprising at least one protease inhibitor, suitably in an amount of 100 mg to 400 mg per day, preferably about 100 mg per day. Conveniently, ribavirin can be administered with the at least two DAAs, preferably in a dosage that depends on the weight of the individual, suitably from about 400 mg to about 1400 mg per day, for example about 1000 mg or about 1200 mg per day. For example, suitable daily treatment with ribavirin is weight dependent, for example from about 400 mg to about 1400 mg, preferably 1000 mg / day at &lt;75 kg

Body weight and 1200 mg / day for&gt; 75 kg body weight, divided into twice a day (BID). In yet another example, the combination of two or more DAAs includes telaprevir (VS950, protease inhibitor) and VX-222 (non-nucleoside polymerase inhibitor). In some examples, the telaprevir is provided in total daily doses from about 1000 mg to about 2500 mg, alternatively from about 2000 mg to about 2500 mg, including but not limited to, for example, about 1000 mg, about 1200 mg, about 1300 mg, about

1500 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about

2250 mg, about 2300 mg, about 2400 mg, about 2500 mg.

VX-222 can be administered with telaprevir in any combination with the dosage amounts of telaprevir provided above, VX-222 can be administered in approximately 100 mg daily. Total dosage to be provided by, alternatively by

144 / 229 to about 1000 mg to about 200 mg to

About 800 mg, including, but not limited to, for example about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In some examples, telaprevir can be a total daily dose of about 2250 mg and VX-222 can be a total daily dose of about 100 mg, alternatively telaprevir can be a total dose of about 2250 mg and VX-222 can be a total daily dose of about 200 mg , alternatively, telaprevir can be a total daily dose of approximately 2250 mg and VX-222 can be a total daily dose of approximately 400 mg, alternatively, telaprevir can be a total daily dose of about 2250 mg and VX-222 can be a total daily dose of about 600 mg, alternatively telaprevir can be a total daily dose of about 2250 mg and VX-222 can be a total daily dose of about 800 mg, alternatively, telaprevir can be a total daily dose of approximately 1500 mg and VX-222 can be a total daily dose of approximately 200 mg, alternatively, telaprevir can be a total daily dose of about 1500 mg and VX-222 can be a total daily dose of about 400 mg, alternatively telaprevir can be a total daily dose of about 1500 mg and VX-222 can be a total daily dose of about 800 mg. Suitably, telaprevir can be administered three times a day (TID), for example three times a day at 750 mg per dose. Another suitable daily dose of telaprevir is 1125 mg twice a day (BID). Suitably, in some embodiments, ritonavir or a suitable equivalent can be added to the at least two DAAs comprising at least one protease inhibitor, suitably in an amount of about 100 mg to about 400 mg per day, preferably about 100 mg per day. Suitably ribavirin can be administered with the at least two DAAs, preferably in a dosage depending on the weight of the individual, from about 400 mg to about 1400 mg, suitably about 1000 mg or about 1200 mg per day. For example, a suitable daily treatment with ribavirin

145 / 229 • · · ·

-145 is weight-dependent, for example 1000 mg / day for &lt;75 kg body weight and 1200 mg / day for 75 kg body weight, divided into twice a day (BID).

In yet another example, the combination of two or more DAAs includes danoprevir (protease inhibitor) and R7128 (nucleoside polymerase inhibitor). In some embodiments, danoprevir can be administered in a total daily dosage of about 100 mg to about 2000 mg, alternatively from about 200 mg to 1800 mg, alternatively from about 400 mg to 1800 mg, including but not limited to, for example, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, and other amounts in between. R7128 can be administered in a total daily dose of from about 100 mg to about 2000 mg, alternatively from about 200 mg to 2000 mg, alternatively from about 1000 mg to about 2000 mg, including, but not limited to, for example 150 mg, about 200 mg , about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg. In some examples, the total daily dose of danoprevir is about 200 mg and the total daily dose of R7128 is about 200 mg, alternatively the total daily dose of danoprevir is about 400 mg and the total daily dose of R7128 is about 200 mg, alternatively the total daily dose of the Danoprevirs approximately 1000 mg and the total daily dose of R7128 is approximately 200 mg, alternatively the total daily dose of danoprevir is about 1800 mg and the total daily dose of R7128 is about 200 mg, alternatively the total daily dose of danoprevir is about 2000 mg and the total daily dose of R7128 is about 200 mg, alternatively the daily dose

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-146 total dose of danoprevir about 400 mg and the total daily dose of R7128 is about 400 mg, alternatively the total daily dose of danoprevir is about 1000 mg and the total daily dose of R7128 is about 400 mg, alternatively the total daily dose of danoprevir is about 2000 mg and the total daily dose of R7128 is approximately 400 mg, alternatively, the total daily dose of danoprevir is approximately 1800 mg and the total daily dose of R7128 is approximately 400 mg, alternatively the total daily dose of danoprevir is approximately 400 mg and the total daily dose of R7128 is approximately 1000 mg, alternatively the total daily dose of danoprevir is approximately 1000 mg and the total daily dose of R7128 is approximately 1000 mg, alternatively, the total daily dose of danoprevir is approximately 2000 mg and the total daily dose of R7128 is approximately 1000 mg, alternatively the total daily dose of danoprevir is approximately 1800 mg and the total daily dose of R7128 is approximately 1000 mg, alternatively the total daily dose of danoprevir is approximately 400 mg and the total daily dose of R7128 is approximately 2000 mg, alternatively the total daily dose of danoprevir is about 1000 mg and the total daily dose of R7128 is about 2000 mg, alternatively the total daily dose of danoprevir is about 2000 mg and the total daily dose of R7128 is about 2000 mg, alternatively the total daily dose of danoprevir is about 1800 mg and the total daily dose of R7128 is approximately 2000 mg. In suitable embodiments, danoprevir and R7128 can be administered with ritonavir, suitably in an amount of about 100 mg to 400 mg per day, preferably about 100 mg per day. Suitably ribavirin can be administered with the at least two DAAs, preferably in a dosage depending on the weight of the individual, from about 400 mg to about 1400 mg, suitably about 1000 mg or about 1200 mg per day. For example, a suitable daily treatment with ribavirin is weight-dependent, for example 1000 mg / day for &lt;75 kg body weight and 1200 mg / day for h 75 kg body weight, divided into twice a day (BID).

147 / 229

-147*··· ···· ···· ·· ··

In some other examples of the present technology, the combination of two or more DAAs can be at least one protease inhibitor and at least one NS5A inhibitor. In some examples, the at least one protease inhibitor is an NS3 protease inhibitor. In some embodiments, the at least one protease inhibitor and the at least one NS5A inhibitor comprises BMS-650032 (BMS) and BMS-790052 (BMS), respectively. In suitable embodiments, BMS-650032 can be administered in a total daily dose of from about 300 mg to about 1500 mg, alternatively from about 1500 mg, suitable daily weight dependent, to about 500 mg up to and including, but not limited to, for example 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, and about 1500 mg and BMS-790052 (BMS) may have a total daily dose of from about 10 mg to about 200 mg, alternatively from about 50 mg to about 100 mg, including, but not limited to, for example about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In suitable examples, the BMS-650032 (BMS) total daily dose is about 1200 mg and the BMS-790052 (BMS) total daily dose is about 60 mg, alternatively the BMS-650032 (BMS) total daily dose is about 300 mg and the BMS-790052 (BMS) total daily dose is approximately 60 mg. Appropriate ribavirin can be administered with the at least two DAAs, preferably in a dosage depending on the weight of the individual, from about 400 mg to about 1400 mg, suitably about 1000 mg or about 1200 mg per day. For example, treatment with ribavirin is 1000 mg / day for &lt;75 kg

Body weight and 1200 mg / day for a body weight of 75 kg, divided into twice a day (BID).

In some other examples of the present technology, the combinations of two or more DAAs can be at least one nucleoside or nucleotide polymerase inhibitor, at least

148 / 229 ·· ·· ··&lt; • 9

-148- :::: ·. / ·· ·· ·· a protease inhibitor, and at least one NS5A inhibitor. In some examples, the at least one protease inhibitor is an NS3 protease inhibitor. In some embodiments, the at least one nucleoside or nucleotide polymerase inhibitor is INX-189, the at least one protease inhibitor is BMS-650032 (asunaprevir), and the at least one NS5A inhibitor comprises BMS-790052 (daclatasvir). Such embodiments are particularly contemplated for treating a patient infected with HCV genotype 1, such as genotype la or lb (particularly genotype la), as well as patients infected with other HCV genotypes, such as, for example Genotypes 2 or 3. In suitable embodiments, INX-189 can be administered in a total daily dose of from about 5 mg to about 400 mg, alternatively from about 25 mg to about 200 mg, including but not limited to, for example

<td>approximately</td><td> 5</td><td>mg, about 10 mg,</td><td>approximately</td><td> 15</td><td>mg, about 20</td><td>mg,</td>

<td>approximately</td><td> 25</td><td>mg, about 30 mg,</td><td>approximately</td><td> 40</td><td>mg, about 50</td><td>mg,</td>

<td>approximately</td><td> 60</td><td>mg, about 70 mg,</td><td>approximately</td><td> 80</td><td>mg, about 90</td><td>mg,</td>

<td>approximately</td><td colspan="4">100 mg, about 110 mg, about</td><td>120 mg, approximately</td><td> 125</td>

mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. In suitable embodiments, BMS-650032 can be administered in a total daily dose of from about 300 mg to about 1500 mg, alternatively from about 500 mg to about 1500 mg, including, but not limited to, for example about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg and about 1500 mg and BMS-790052 (BMS) can have a total daily dose of about 10 mg to about 200 mg, alternatively from about 50 mg to about 100 mg, including, but not limited to, for example about 10 mg , 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125

149 / 229

-149·· ·· ·

00 mg.

In suitable daily weight-dependent, to the suitable

Total dose mg, about 150 mg, or about examples, the BMS-650032 (BMS) daily about 1200 mg and the BMS-790052 (BMS) total daily dose is about 60 mg, alternatively the BMS-650032 (BMS) total daily dose is about 300 mg and the BMS-790052 (BMS) total daily dose is approximately 60 mg. Appropriate ribavirin can be administered with the at least two DAAs, preferably in a dosage depending on the weight of the individual, from about 400 mg to about 1400 mg, suitably about 1000 mg or about 1200 mg per day. For example, there is a treatment with ribavirin

Example 1000 mg / day for &lt;75 kg

Body weight and 1200 mg / day with a body weight of 75 kg, divided into twice a day (BID).

As yet another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NS5A inhibitor. In one example, the combination of two or more DAAs includes GS-5885 (an NS5A inhibitor), GS-9190 (tegobuvir, a non-nucleoside polymerase inhibitor), and GS-9451 (a protease inhibitor or an NS3 protease inhibitor). In some examples, GS-5885 is provided in a daily dose of from about 3 mg to about 200 mg, alternatively from about 3 mg to about 100 mg, alternatively from about 30 mg to about 90 mg, including but not limited to, for example approximately

<td>3 mg, about 5 mg,</td><td>approximately</td><td> 10</td><td>mg,</td><td>approximately</td><td> 15</td><td>mg,</td><td>approximately</td>

<td>mg, about 25 mg,</td><td>approximately</td><td> 30</td><td>mg,</td><td>approximately</td><td> 40</td><td>mg,</td><td>approximately</td>

<td>mg, about 60 mg,</td><td>approximately</td><td> 70</td><td>mg,</td><td>approximately</td><td> 80</td><td>mg,</td><td>approximately</td>

mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg, and GS- 9190 is provided in a daily dose of from about 10 mg to about 100 mg, alternatively from about 30 mg to about 90 mg, including, but not limited to, for example about 10 mg, about 20 mg, about 30 mg, about 40 mg , about 50 mg, about 60 mg, about 70

150 / 229

-150 * · · 1 ·· ·· mg, about 80 mg, about 90 mg, or about 100 mg; and GS-9451 can be administered in a daily dose of about 100 mg to about 500 mg, alternatively from about 200 mg to about 400 mg, including but not limited to about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg. Suitable examples include daily amounts of about 30 mg GS-5885, about 60 mg GS-9190, and about 200 mg GS-9451; alternatively, about 60 mg GS-5885, about 60 mg GS-9190, and about 200 mg GS-9451; alternatively about 90 mg GS-5885, about 60 mg GS-9190, and about 200 mg GS-9451. In some embodiments, the GS-9190, GS-9451 and GS-5885 are administered with ritonavir or a suitable equivalent, suitably in an amount from about 100 mg to about 400 mg per day, preferably about 100 mg per day. Appropriate ribavirin can be administered with the at least two DAAs, preferably in a dosage depending on the weight of the individual, from about 400 mg to about 1400 mg, suitably about 1000 mg or about 1200 mg per day. For example, a suitable daily treatment with ribavirin is weight-dependent, for example 1000 mg / day for &lt;75 kg body weight and 1200 mg / day for h 75 kg body weight, divided into twice a day (BID). As yet another example, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NS5A inhibitor.

In another embodiment, the present technology provides interferon-free treatment comprising administering two DAAs daily with ribavirin, wherein the two DAAs are an HCV polymerase inhibitor, for example PSI-7977 and an NS5A inhibitor, for example BMS-790052 include, for a period of no more than eleven weeks, preferably no more than eight weeks. PSI-7977 and BMS-790052 are administered in an amount effective to provide SVR with a treatment duration of no more than eleven weeks, no more than ten weeks, no more than nine weeks, no more than eight

151/229

-151ft · ··· · ftft 4 * · · · · 4 • · · · ftft ¹ · · ·· ftft • · ftft ftft ft

Weeks, no more than seven weeks, no more than six weeks, no more than five weeks, no more than four weeks or no more than three weeks. Patients can be treatment-naïve or treatment-experienced. In some embodiments, patients may have HCV genotype 1, such as la or lb. In some embodiments, the patients can be genotype 2 or 3, such as 2a, 2b, or 3a. PSI-7977 may be provided in a total daily dose of about 100 mg to about 500 mg, alternatively from about 200 mg to about 400 mg, including, but not limited to, for example about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg. BMS-790052 can be administered in combination with PSI-7977 in any daily dose of PSI-7977 provided above. BMS-790052 (BMS) may have a total daily dose of from about 10 mg to about 200 mg, alternatively from about 50 mg to about 100 mg, including but not limited to about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In a suitable example, PSI-7977 is administered in a total daily dose of 400 mg and BMS-790052 is administered in a total daily dose of 60 mg.

The chemical structures of some of these HCV inhibitors, as reported by numerous sources, are provided below:

<img file="AT514003A2_D0027.tif" />

152 / 229

-152• · • · · · » · · · · » · · · &lt;

» · · · · &lt;

·· ·· ·· ·· ···· ···· ···· ···· ίί Ύ

-X. ..Ck "hk

X Ίί τ ^? ·?&gt;. '' ι - '' 'yMVMv' UU / \ HI? V

Wx rxz '* H

BMS-650032 (asunaprevir) □

<img file="AT514003A2_D0028.tif" />

Danoprevir

<img file="AT514003A2_D0029.tif" />

K1X ίΗΙΙ :: * Μ

<img file="AT514003A2_D0030.tif" />

&lt;7, Ä&gt; N ..... '

V&gt;:

1 $ i

Y • 'O «V. ···&gt; ·., Rr id

MK-5172

153 / 229

-153·· ·· ···· ···· • · · · · · • · · · · · • · · · · · • · · · · · · • · 99 9 9 · • · · · ···· ·· ···

GS-333126 (GS-9190 or Tegobuvir)

<img file="AT514003A2_D0031.tif" />

Mericitabine (R-4048 or RG7128)

<img file="AT514003A2_D0032.tif" />

Filibuvir (PF-00868554)

154 / 229

-154···· ·« • ·

BMS-790052 (daclatasvir)

<img file="AT514003A2_D0033.tif" />

BMS-791325 is preferably / \ o ... xA .X. &gt; -v NV

X x ^H ί! ,1

, .X ^SK\ ... ^ t - 'x ... Z&gt;

As used herein, BMS-791325 can also be See Publications below.

http://wwwl.easl.eu/easl201 l / program / Posters / Abstract680.htm;

and http://clinicaltrials.gov/show/NCT00664625.

For GS-5885 see publications at http: /7www.natap.org/2011/'EASL/EASL_68.htm;

155 / 229

-155·· ···· ···· ···· ···· : :: : &lt; .·' ·?··. ·· ··*’··* :

http://wwwl.easl.eu/easl201 l / program / posters / Abstractl097.htm;

and http: // clinicaltrials. go v / ct2 / show / NCTO 1353248.

Each HCV inhibitor or DAA described herein includes its suitable salt forms when used in therapeutic treatments or pharmaceutical formulations.

The following table lists non-limiting examples of the treatment regimes of the present technology. In each treatment regimen, the two or more DAAs with or without ritonavir are administered daily to an HCV patient undergoing such treatment. All treatments are interferon-free. Administration of ribavirin is included in each regimen. Each treatment regimen can also optionally include the administration of one or more other additional DAAs to the patient. The duration of each treatment regimen can, for example and without limitation, last for no more than 12 weeks, for no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, no more than 8 weeks, alternatively no more than 7 weeks Weeks, alternatively for no more than 6 weeks, alternatively for no more than 5 weeks, alternatively for no more than 4 weeks, and may depend on the patient's reaction. In any given regimen described above, for example and without limitation, the drugs can be co-formulated in a single solid dosage form, provided each has the same dosage frequency.

For example, two or more drugs used in a regimen can be co-formulated in amorphous forms or molecularly dispersed in a matrix comprising a water soluble polymer and optionally a surface 156/229

-156• · ·····.. ;

·· ·· ·· · ·· ...

active substance. As another example, therapeutic agent 1 and ritonavir (RTV) are formulated in an amorphous form or molecularly dispersed in a matrix comprising a water-soluble polymer and optionally a surfactant, and therapeutic agent 3 can be combined with amorphous compound 1 and RTV in one be combined with a single solid dosage form. As yet another example, Compound 1 and RTV are formulated in a different dosage form than that of Therapeutic Agent 3.

Table 1

Non-limiting example of interferon-free treatment regimens with two or more DAAs (without ribavirin and with or without ritonavir)

<td>regime</td><td>Used in treatment Medicinal substances</td><td>Suitable daily Total dosages</td>

<td rowspan="2"> 1</td><td>Therapeutic active ingredient 1 * +</td><td>150 to 250 mg (preferably 150, 200, 250 mg)</td>

<td>Therapeutic agent 4</td><td>5 mg to 300 mg (preferably 25 mg)</td>

<td rowspan="3"> 2</td><td>Therapeutic active ingredient 1 * +</td><td>150 to 250 mg (preferably 150, 200, 250 mg)</td>

<td>Therapeutic agent 4+</td><td>5 mg to 300 mg (preferably 25 to 200 mg)</td>

<td>Therapeutic agent 2</td><td>300 to 1800 mg (preferably. 400 mg or 800 mg)</td>

<td rowspan="3"> 3</td><td>Therapeutic active ingredient 1 * +</td><td>150-250 mg (preferably 150 mg or 250 mg)</td>

<td>Therapeutic agent 3+</td><td>50 mg-1000 mg (preferably 400 mg)</td>

<td>Therapeutic agent 4</td><td>5 mg-300 mg (preferably 25 mg-200 mg, more preferably 25 mg)</td>

<td rowspan="2"> 4</td><td>Therapeutic active ingredient 1 * +</td><td>150-250 mg (150 mg, 200 mg or 250 mg)</td>

<td>Therapeutic agent 2</td><td>300-1800 mg (preferably 200 mg, 800 mg)</td>

<td> 5</td><td>Therapeutic active ingredient 1 * +</td><td>50 mg to 250 mg (preferably 50 mg or 250 mg)</td>

157 / 229 • · ·· »··* ·«·· ···· «...

-157-

<td>regime</td><td>Used in treatment Medicinal substances</td><td>Suitable daily Total doses</td>

<td></td><td>Therapeutic agent 3</td><td>50 mg to 1000 mg (preferably 400 mg to 800 mg)</td>

<td rowspan="2"> 6</td><td>PSI-7977 +</td><td>100 mg to 500 mg (preferably 200, 400 mg)</td>

<td>PSI-938</td><td>100 mg to 500 mg (preferably 300 mg)</td>

<td rowspan="2"> 7</td><td>BMS-790052 +</td><td>10 mg to 200 mg (preferably 60 mg)</td>

<td>BMS-650032</td><td>300 mg to 1500 mg (preferably 1200 mg)</td>

<td rowspan="3"> 8</td><td>GS-5885 +</td><td>3 mg to 200 to (preferably 30 mg to 90 mg)</td>

<td>GS-9190 +</td><td>30 mg to 90 mg (preferably 60 mg)</td>

<td>GS-9451</td><td>100 mg to 500 mg (preferably 200 mg)</td>

<td rowspan="2"> 9</td><td>GS-5885 +</td><td>3 mg to 200 mg (preferably 30 to 90 mg)</td>

<td>GS-9451</td><td>100 mg to 500 mg (preferably 200 mg)</td>

<td rowspan="2"> 10</td><td>BI-201335 +</td><td>100 mg to 400 mg (preferably 120 mg or 240 mg)</td>

<td>BI-207127</td><td>300 mg to 3600 mg (preferably 1200 mg to 2100 mg)</td>

<td rowspan="2"> 11</td><td>PSI-7977 +</td><td>100 mg to 500 mg (preferably 400 mg)</td>

<td>TMC-435</td><td>25 mg to 200 mg (preferably 75 mg to 150 mg)</td>

<td rowspan="2"> 12</td><td>Telaprevir +</td><td>1000 mg to 2500 mg (preferably 2250 mg)</td>

<td>VX-222</td><td>200 mg to 800 mg</td>

<td rowspan="2"> 13</td><td>Danoprevir * +</td><td>100 mg to 2000 mg (preferably 200 mg or 400 mg)</td>

<td>R7128</td><td>100 mg to 2000 mg (preferably 200 mg, 400 mg, 1000 mg or 2000 mg)</td>

<td rowspan="2"> 14</td><td>Danoprevirh</td><td>100 mg to 2000 mg (preferably 800 mg or 1000 mg, or 1800 mg or 2000 mg)</td>

<td>R7128</td><td>100 mg to 2000 mg (preferably 200 mg, 400 mg, 1000 mg or 2000 mg)</td>

<td rowspan="2"> 15</td><td>PSI-7977 +</td><td>100 mg to 500 mg (preferably 400 mg)</td>

<td>Daclatasvir (BMS-790052)</td><td>10-200 mg (preferably 60 mg)</td>

158 / 229

-158• ·

<td>regime</td><td>Used in treatment Medicinal substances</td><td>Suitable daily Total doses</td>

<td rowspan="2"> 16</td><td>PSI-7977 +</td><td>100 mg to 2000 mg (preferably 1800 mg or 2000 mg)</td>

<td>Asunaprevir (BMS-650032)</td><td>300-1500 mg (preferably 1200 mg)</td>

<td rowspan="3"> 17</td><td>PSI-7977 +</td><td>100 mg to 500 mg (preferably 400 mg)</td>

<td>Daclatasvir (BMS-790052)</td><td>10-200 mg (preferably 60 mg)</td>

<td>Asunaprevir (BMS-659932)</td><td>300-1500 mg (preferably 1200 mg)</td>

* Ritonavir or a suitable equivalent can be added to any of these treatments as described and can be added to any of these treatments in a total daily dosage as described in the present technology; preferably ritonavir is co-formulated with the therapeutic agent 1 or danoprevir; the dose of ritonavir is preferably 100 mg. preferably = preferred.

** In each regimen, ribavirin is preferred in one

Weight fraction of 400 mg to 1400 mg (preferably 1000 mg to 1200 mg) is used.

Additional non-limiting examples of interferon-free treatment regimens with two or more DAAs, with ribavirin and with or without ritonavir or an appropriate equivalent, include the following: (a) more therapeutic

Active ingredient 1 at a total daily dose of 5 mg to 150 mg (preferably 5 mg, 25 mg, 50 mg or 100 mg) with ritonavir or a suitable equivalent, and therapeutic active ingredient 4 at a total daily dose of 5 mg to 150 mg ( preferably 5 mg, 25 mg, 50 mg or 100 mg); (b) therapeutic agent 1 at a total daily dose of 5 mg to 200 mg (preferably 5 mg, 25 mg, 50 mg, 100 mg) with ritonavir or a suitable equivalent, therapeutic agent 4 at a total daily dose of 5 mg to 200 mg (preferably 25 mg or 100 mg), and therapeutic agent 2 at a total daily dose of 200 mg to 800 mg (preferably 400 mg or 800 mg); (c) therapeutic agent 1 at a total daily dose of 5 mg to 150 mg (preferably 5 mg, 25 mg, 50 mg or 100 mg) with

159 / 229 • ·

-159 ritonavir or a suitable equivalent, therapeutic agent 3 at a total daily dose of 100 mg to 600 mg (preferably 400 mg), and therapeutic agent 4 at a total daily dose of 5 mg to 300 mg (preferably 25 mg to 200 mg, more preferably 25 mg); (d) therapeutic agent 1 at a total daily dose of 5 mg to 150 mg (preferably 5 mg, 25 mg, 50 mg, 100 mg) with ritonavir or a suitable equivalent, and therapeutic agent 2 at a total daily dose of 200-800 mg ; (e) GS-5885 at a total daily dose of 3-200 mg (preferably 30-90 mg). GS-9190 at a total daily dose of 30-90 mg (preferably 60 mg) and GS-9451 at a total daily dose of 100-500 mg (preferably 200 mg); (f) GS-5885 at a total daily dose of 3 mg to 200 mg (preferably 30 mg, 60 mg or 90 mg) and GS-9451 at a total daily dose of 100 mg to 500 mg (preferably 200 mg); (g) BI-201335 for a total daily dose of 100 mg to 400 mg (preferably 120 mg, 240 mg) and BI-207127 for a total daily dose of 300 mg to 3600 mg (preferably 1200 or 1500 mg, 1800 mg or 2100 mg ); (h) PSI-7977 at a total daily dose of 100 mg to 500 mg (preferably 100, 200 mg) and TMC-435 at a total daily dose of 25 mg to 200 mg (preferably 75 mg, 100 mg or 150 mg); (i) Telaprevir at a total daily dose of 1000 mg to 2500 mg (preferably 1500 or 2250 mg), and VX-222 at a total daily dose of 100 mg to 800 mg (preferably 100 mg, 200 mg, 400 mg, 600 mg or 800 mg); (j) INX-189 at a total daily dose of 5 mg to 400 mg (preferably 50 mg, 100 mg or 200 mg), and daclatasvir (BMS790052) at a total daily dose of 10 mg to 200 mg (preferably 60 mg); (k) INX-189 at a total daily dose of 5 mg to 400 mg (preferably 50 mg, 100 mg or 200 mg), and asunaprevir (BMS-650032) at a total daily dose of 300 mg to 1500 mg (preferably 1200 mg) ; and (1) INX-189 at a total daily dose of 5 mg to 400 mg (preferably 50 mg, 100 mg or 200 mg), daclatasvir (BMS-790052) at a total daily dose of 10 mg to 200 mg (preferably 60 mg) and asunaprevir (BMS-650032) at a total daily dose of 300 mg to 1500 mg (preferably 1200 mg). In each of these examples

160/229 • · • · • ·

Ritonavir or its appropriate equivalent can be added to any of these treatments as described and can be added to any of these treatments at a daily total dosage as in this one Technology described to be added; preferably ritonavir is co-formulated with the therapeutic agent 1 or danoprevir; the dose of ritonavir is preferably 100 mg. In each of these examples, ritonavir or its appropriate equivalent can be added to any of these treatments as described in current technology. Preferably, ritonavir is co-formulated with therapeutic agent 1 or danoprevir. The dose of ritonavir is preferably 100 mg. In these examples, ribovirin is preferably used in an amount by weight of 400 mg to 1400 mg (preferably 1000 mg to 1200 mg)

The treatments of the present technology may be effective in treating HCV infection against HCV genotypes 1, 2, 3, 4, 5, 6, including subgenotypes such as the

Example la, lb, 2a and 3a.

In general, and depending on the patient's conditions, the total daily dose of the DAAs of the present technology (either as single or divided doses) can be administered in amounts from about 0.001 mg / kg to about 200 mg / kg, or about 0.001 mg / kg to about 30 mg / kg, or from about 0.001 mg / kg to about 30 mg / kg, or from about 0.01 mg / kg, to about 10 mg / kg (ie mg of the compound or salt per kg of body weight) and this includes any amounts or ranges in between including, but not limited to, increments of 0.001 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.05 mg / kg and multiple factors thereof (for example 0.25x, 0.5x, lx, 2x, 3x, 5x, lOx, lOOx etc.). Suitable dosages of the DAAs of the present technology include, but are not limited to, from about 25 mg to about 2000 mg, from about 25 mg to about 1500 mg, from about 25 mg to about 1600 mg, from about 25 mg to about 1000 mg , from about 25 mg to about 800 mg, from about 25 mg to about 500 mg, from about 25 mg to about 250 mg, from about 50 mg to

161/229 • ·

-161 ··· ♦ ··· ·· · · · · · «· · ··· about 2000 mg, from about 50 mg to about 1500 mg, from about 50 mg to about 1600 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 800 mg, from about 50 mg to about 500 mg, from about 50 mg to about 250 mg and include, but are not limited to, for example about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 80 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 165 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 250 mg, and any increments in between, including increments of about 1 mg, about 2 mg , about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, and multiples thereof (e.g. 0.25x, 0.5x, lx, 2x, 3x, 5x, 10x, 100x, etc.). It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration , the excretion rate, the drug combination and the severity of the disease that is being treated.

The cytochrome P-450 inhibitor can be administered in any suitable amount, such as, for example, in doses from about 0.3 mg / kg to about 2 mg / kg or from about 0.6 mg / kg to about 1.5 mg / kg . As non-limiting examples, the cytochrome P-450 inhibitor can be administered in a total daily dose amount of from about 25 mg to about 300 mg, or from about 50 mg to about 250 mg, or from about 100 mg to about 200 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a total daily dose of about 100 mg to about 400 mg, preferably about 100 mg. In some embodiments, the cytochrome

162/229

<img file="AT514003A2_D0034.tif" />

-162-

<img file="AT514003A2_D0035.tif" />

• ··· ···· · • · · · • · · · ♦ · ·· · ·· ···

P-450 inhibitor administered at a total daily dose of approximately 25 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a total daily dose of about 50 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a total daily dose of about 75 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a total daily dose of about 100 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a total daily dose amount of about 125 mg.

For example and without limitation, the one or more DAAs and ribavirin can be administered simultaneously or sequentially, and with the same or different frequencies. For example, a DAA can be administered immediately before or after the administration of another DAA. A short delay or time gap may exist between the administration of one DAA and another DAA. The frequency of administration can also vary. For example, a first DAA can be administered once a day and a second DAA can be administered twice or three times a day. For example, a first DAA can be administered once a day with or without ritonavir, and a second DAA can be administered twice a day.

The DAAs of the present technology can be co-formulated in a single dosage form. Non-limiting examples of suitable dosage forms include liquid or solid dosage forms. For example, a dosage form of Compound 1 is described as a solid dosage form in US Patent Application Publication No. 2011/0312973 filed March 8, 2011 and entitled "Solid Compositions, the entire contents of which are incorporated herein by reference. More preferably, the dosage form is a solid dosage form in which at least one of the DAAs is in an amorphous form, or most preferably is molecularly dispersed, in a matrix comprising a pharmaceutically acceptable water-soluble polymer and a pharmaceutically

163/229

-163 • · · · · · ·. •••••• · · · · ·· ·· ·· · ·· ··· compatible surfactant. The other DAAs can also be present in an amorphous form or be molecularly dispersed in the matrix, or be formulated in different forms (in a crystalline form).

The DAAs of the present technology can be formulated in various dosage forms. It will be understood that the total daily dosage of the compounds and compositions to be administered will be decided by the attending physician within the scope of sound medical judgment.

In one embodiment, a method of treating a naive subject comprises administering therapeutic agent 1 at a dose of 150 mg QD once a day, therapeutic agent 2 at a dose of 400 mg or 800 mg BID twice a day, and ritonavir at one dose of 100 mg QD once a day plus an effective amount of ribavirin (for example, 1000 mg, or 1200 mg, or in an amount based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.

In one embodiment, a method of treating a naive subject comprises administering therapeutic agent 1 at a dose of 50 mg QD, therapeutic agent 2 at a dose of 400 mg or 800 mg BID, ritonavir at a dose of 100 mg QD, and an effective one Amount of ribavirin (for example, 1000 mg, or 1200 mg, or in an amount based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.

In one embodiment, a method of treating a naive subject comprises administering therapeutic agent 1 at a dose of 250 mg QD, therapeutic agent 2 at a dose of 400 mg BID, ritonavir at a dose of 100 mg QD, and an effective amount of Ribavirin (for example, 1000 mg, or 1200 mg, or in an amount based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.

In another embodiment, a method for

164 / 229

-164Treatment of a naive subject the administration of therapeutic agent 1 at a dose of 150 mg QD, therapeutic agent 2 at a dose of 400 mg BID, ritonavir at a dose of 100 mg QD and an effective amount of ribavirin (for example, 1000 mg, or 1200 mg, or in an amount based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.

In yet another embodiment, a method of treating a peginterferon + ribavirin (P / RBV) NonResponder comprises administering therapeutic agent 1 at a dose of 150 mg QD, therapeutic agent 2 at a dose of 400 mg BID, ritonavir at a dose of 100 mg QD, and an effective amount of ribavirin (for example, 1000 mg, or 1200 mg, or in an amount based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.

In yet another embodiment, a method of treating a peginterferon + ribavirin (P / RBV) NonResponder comprises administering therapeutic agent 1 at a dose of 50 mg QD, therapeutic agent 2 at a dose of 400 mg BID, ritonavir at a dose of 100 mg QD, and an effective amount of ribavirin (for example, 1000 mg, or 1200 mg, or in an amount based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.

In one embodiment, a method of treating a naive subject comprises administering therapeutic agent 1 at a total daily dose of 150 mg QD, therapeutic agent 3 at a total daily dose of 400 mg QD, and ritonavir at a dose of 100 mg QD, and an effective amount of ribavirin (for example, 1000 mg, or 1200 mg, or in an amount based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.

In another embodiment, a method of treating a naive subject comprises administering thera165 / 229

-165 • · ·· ·· ·· · ·· ··· therapeutic agent 1 at a total daily dose of 100 mg or 200 mg QD, therapeutic agent 4 at a total daily dose of 25 mg QD, ritonavir at a dose of 100 mg QD, and an effective amount of ribavirin (for example, 1000 mg, or 1200 mg, or in an amount based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.

In yet another embodiment, a method of treating a naive subject comprises administering therapeutic agent 1 at a total daily dose of 100 mg or 150 mg QD, therapeutic agent 2 at a dose of 400 mg BID, therapeutic agent 4 at a total daily dose Dose of 25 mg QD, ritonavir at a dose of 100 mg QD, and an effective amount of ribavirin (for example 1000 mg, or 1200 mg or in an amount which is based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.

It should be understood that the embodiments described above and the following examples are given by way of illustration, not limitation. Various changes and modifications within the scope of the present invention will become apparent to those skilled in the art from the description herein.

Example 1 Use of a 2-DAA combination with ribavirin (RBV) to treat treatment-naïve patients infected with HCV genotype 1.

Previously untreated patients with HCV infection were treated with a protease inhibitor (in combination with ritonavir), a polymerase inhibitor, and ribavirin. The treatment was without interferon.

Patients included 11 treatment-naïve, non-cirrhotic HCV genotype 1 infected patients between the ages of 18 and 65. All patients had the IL28B CC genotype. All patients completed 12 weeks of therapy with compound 1 and ritonavir (compound 1 / r) dosed in

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Combination with compound 3 and ribavirin (RBV). Compound 1 (150 mg once daily (QD)) was dosed with 100 mg QD ritonavir, 400 mg QD compound 3, and weight-based amounts of RBV (1,000-1,200 mg / day twice daily) in treatment-naive patients with genotype ( GT) 1 HCV infected.

The HCV RNA levels were measured by the TaqMan assay. Five of the eleven patients had hepatitis C ribonucleic acid (HCV RNA) &lt;25 IU / ml (ie below the limit of measurement) at 2 weeks. Another 5 patients had undetectable levels of HCV RNA at 2 weeks. At 3 weeks, three of the eleven patients had HCV RNA levels less than 25 IU / ml, and eight patients had undetectable levels of HCV RNA. Ten of the eleven patients had undetectable levels of HCV RNA at 4 weeks, and one patient had HCV RNA levels less than 25 IU / ml. All eleven patients had undetectable levels of HCV RNA at 5 weeks. HCV RNA levels remained undetectable in all patients at weeks 6, 7, 8, 9, 10, 11, and 12. All patients had undetectable levels of HCV RNA at post-treatment weeks 2 and 4. At post-treatment weeks 8 and 12, a single patient had detectable HCV RNA (breakthrough) and the remaining 10 patients had no detectable level of HCV RNA. These remaining ten patients were further tested at post-treatment weeks 16 and 24, and all had undetectable levels of HCV RNA at both time points. One of the remaining ten patients showed unexpectedly detectable HCV RNA at post-treatment week 36.

Example 2A Use of a 2-DAA combination with ribavirin to treat treatment-naïve patients or non-responders infected with HCV genotype 1.

Group 1. Previously untreated patients with HCV infection were treated with a protease inhibitor (in combination with ritonavir), a polymerase inhibitor, and ribavirin. The treatment was without interferon.

Patients included 19 treatment-naïve patients between the ages of 18 and 65. One patient discontinued the study

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-167- . :: : ., • · · · · · ······· · . .

·· ·· ·· · ·· ...

at week 3. All remaining 18 patients completed 12 weeks of therapy with compound 1 / r dosed in combination with compound 2 and RBV. Compound 1 (250 mg QD) was dosed with 100 mg QD ritonavir, 400 mg BID Compound 2, and RBV in treatment-naive patients infected with GT1 HCV.

Group 2. Previously untreated patients who had HCV infection were treated with a protease inhibitor (in combination with ritonavir), a polymerase inhibitor, and ribavirin. The treatment was without interferon.

Patients included 14 treatment-naïve patients between the ages of 18 and 65. One patient discontinued the study at week 1. Therefore, there were a total of 13 patients in the study. All 13 patients completed 12 weeks of therapy with compound 1 / r dosed in combination with compound 2 and RBV. Compound 1 (150 mg QD) was dosed with 100 mg QD ritonavir, 400 mg BID Compound 2, and RBV in treatment-naive patients infected with GTl HCV.

Group 3. Peginterferon + Ribavirin (P / RBV) non-responders were treated with a protease inhibitor (in combination with ritonavir), a polymerase inhibitor and ribavirin. The treatment was without interferon.

Patients included 17 P / RBV non-responders between the ages of 18 and 65. Patients were treated with compound 1 / r dosed in combination with compound 2 and RBV for 12 weeks. Compound 1 (150 mg QD) was dosed with 100 mg QD ritonavir, 400 mg BID compound 2, and RBV in P / RBV-NonResponders infected with GT1 HCV. Four patients had breakthroughs during treatment and discontinued the study before week 7.

The baseline characteristics of the patients are shown in the table below.

Table 2

<td></td><td>Group 1</td><td>Group 2</td><td>Group 3</td>

<td>Genotype (la / lb)</td><td> 17/2</td><td> 11/3</td><td> 16/1</td>

<td>IL28B:</td><td></td><td></td><td></td>

<td>CC</td><td> 10</td><td> 5</td><td> 0</td>

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<td>CT</td><td> 7</td><td> 7</td><td> 11</td>

<td>TT</td><td> 2</td><td> 2</td><td> 5</td>

<td>indefinite</td><td> 0</td><td> 0</td><td> 1</td>

<td>middle baselines HCV RNA (log IU / ml)</td><td> 6,4 [4,1-7,2]</td><td> 6,9 [3,1-7,5]</td><td> 6,9 [6,0-7,8]</td>

Results from group 1. Ten of the nineteen patients had HCV RNA &lt;25 IU / ml at 2 weeks. Another eight had undetectable levels of HCV RNA at 2 weeks. At week 3, one patient discontinued, four of the remaining 18 patients had HCV RNA levels less than 25 IU / ml, and fourteen of the remaining 18 patients had undetectable levels of HCV RNA. At week 4, seventeen of the remaining 18 patients had undetectable levels of HCV RNA; one patient had HCV RNA &lt;25 IU / ml. At week 5, all of the remaining 18 patients had undetectable levels of HCV RNA. At week 6, seventeen of the remaining 18 patients had undetectable levels of HCV RNA, and one patient had HCV RNA &lt;25 IU / ml. At weeks 7, 8, 9, 10, 11, and 12, all of the remaining 18 patients had undetectable levels of HCV RNA (one patient was not tested at week 12). At post-treatment weeks 2, 4, 8, and 12, all of the remaining 18 patients (including the one who was not tested at week 12 during treatment) had undetectable levels of HCV RNA. At post-treatment week 24, 17 of the remaining 18 patients were tested and all of the 17 patients who were tested had undetectable levels of HCV RNA. At post-treatment week 24, all of the remaining 18 patients were tested and no detectable levels of HCV RNA were found.

A larger clinical study using the same drug combination showed approximately 85-90% SVR4 and SVR12 rates after a 12 week treatment regimen in treatment-naïve patients. Among these patients, the SVR4 and SVR12 rates (not virologic errors removed) in genotype la patients were approximately 86 and 82%, respectively. All of these SVR4 and SVR12 rates were based on observational data.

Results from group 2. Of the thirteen tested

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169 patients had six HCV RNA &lt;25 IU / ml at 2 weeks. Another six patients had undetectable levels of HCV RNA at 2 weeks. At week 3, two patients had HCV RNA levels less than 25 IU / ml and ten patients had undetectable levels of HCV RNA. Eleven of the thirteen patients had undetectable levels of HCV RNA at 4 weeks and two had HCV RNA &lt;25 IU / ml. At weeks 5, 6, 7, 8, 9, and 10, all 13 patients were tested and had undetectable levels of HCV RNA. One patient had detectable levels of HCV RNA at week 11 (the remaining 12 patients had undetectable levels of HCV RNA at week 11), but HCV RNA levels in that patient, as in all other patients, were undetectable at week 12. At post-treatment weeks 2, 4, 8, and 12, all 13 patients tested (including the one who had detectable levels of HCV RNA at week 11 during treatment) had undetectable levels of HCV RNA. At post-treatment weeks 24, twelve of the thirteen patients were tested and no detectable levels of HCV RNA were found.

Results from Group 3. Seven of the seventeen patients tested had HCV RNA &lt;25 IU / ml at 2 weeks. Another seven patients had undetectable levels of HCV RNA at 2 weeks. Three patients had detectable levels of HCV RNA at 2 weeks. At week 3, three patients had HCV RNA levels less than 25 IU / ml, twelve patients had undetectable levels of HCV RNA, and two patients had detectable levels of HCV RNA. At week 4, two patients had HCV RNA levels less than 24 IU / ml, thirteen patients had undetectable levels of HCV RNA, and two patients had detectable levels of HCV RNA. Sixteen patients were tested at 5 weeks; thirteen patients had undetectable levels of HCV RNA and three patients had detectable levels of HCV RNA. Fifteen patients were tested at 6 weeks; twelve patients had undetectable levels of HCV RNA and three patients had detectable levels of HCV RNA. All thirteen patients tested at seven weeks had undetectable levels of HCV RNA. Twelve of the thirteen patients who were tested at 8 weeks had

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-170φ φφφ φφ φφ φφ φ · Φ Φ ·· undetectable levels of HCV RNA; one patient had HCV RNA levels less than 25 IU / ml. All ten patients tested at 9 weeks had undetectable levels of HCV RNA. Twelve of the thirteen patients tested at 9 weeks had undetectable levels of HCV RNA; one patient had detectable levels of HCV RNA. Twelve of the thirteen patients tested at 10 weeks had undetectable levels of HCV RNA; one patient had detectable levels of HCV RNA. Eleven of the twelve patients tested at 11 weeks had undetectable levels of HCV RNA; one patient had HCV RNA levels less than 25 IU / ml. Ten of the twelve patients tested at week 12 of treatment had undetectable levels of HCV RNA; one patient had HCV RNA levels less than 25 IU / ml and another patient had detectable levels of HCV RNA. The one patient who had HCV RNA levels less than 25 IU / ml at week 12 of treatment had a breakthrough at post-treatment week 2. At post-treatment weeks 2 and 4, ten patients who had undetectable HCV RNA at week 12 of treatment were tested; eight of the ten patients had undetectable levels of HCV RNA; and the remaining two patients had detectable HCV RNA (breakthrough). The eight patients who had undetectable HCV RNA at post-treatment weeks 2 and 4 were further tested at post-treatment weeks 8 and 12 and no detectable HCV RNA was found.

The seventeen non-responder patients in Group 3 included 6 null responders and 11 partial responders. Three of the six null responders and five of the eleven partial responders reached SVR12.

The study also showed that the IL28B host genotype did not appear to have a significant effect on SVR12 in this study (including Groups 1, 2, and 3).

Example 2B Use of a 2-DAA combination with ribavirin to treat treatment-naïve patients infected with genotype 1, 2 or 3.

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Genotype 1

Ten previously untreated patients infected with HCV genotype 1 were treated with a 2-DAA combination with ribavirin. The treatment was interferon-free and was designed for 12 weeks. The 2-DAA combination included compound 1 / r (200/100 mg QD) and compound 4 (25 mg QD).

The weight-based dosage of ribavirin ranged from 1000 to 1200 mg divided into twice daily. At weeks 5, 6, and 7 of treatment, nine out of ten patients showed no detectable HCV RNA; and the remaining one patient had HCV RNA levels less than 25 IU / ml. At week 8 of treatment, five of the nine patients were tested and they showed no detectable HCV RNA. At weeks 9 and 10 of treatment, four of the five patients were further tested and no detectable HCV RNA was found. At week 11, two of the four patients were tested and no detectable HCV RNA was found.

Additional tests showed that all of the initial ten patients had no detectable HCV RNA at weeks 8, 9, 10, and 11 of treatment. At week 12, nine of the initial 10 patients showed undetectable HCV RNA, and one had HCV RNA levels less than 25 IU / ml. At post-treatment week 2, all of the ten patients were tested (including the one with HCV RNA levels less than 25 IU / ml at week 12 of treatment) and all ten patients showed no detectable HCV RNA. At post-treatment weeks 4, 8 and 12, all of the ten patients were tested and no detectable HCV RNA was found. Eight of the ten patients were further tested at post-treatment week 24 and no detectable HCV RNA was found.

A larger clinical study using the same drug combination showed an approximately 90% SVR4 rate and an approximately 83% SVR12 rate after a 12-week treatment regimen in treatment-naïve patients. Among these patients, the SVR4 and SVR12 rates (not virologic errors removed) in genotype la patients were approximately 92 and 95%, respectively. All of these SVR4 and SVR12 rates were based on observational data.

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Genotype 2

Ten previously untreated patients infected with HCV genotype 2 were treated with the same regimen of this example. At week 4 of treatment, all of the ten patients were tested and they showed no detectable HCV RNA. At weeks 5 and 6 of treatment, all of the ten patients were tested and no detectable HCV RNA was found. At weeks 9-11 of treatment, all of the ten patients were further tested and nine of these showed no detectable HCV RNA and one patient showed HCV RNA levels less than 25 IU / ml. At week 12 of treatment, new of the initial ten patients were tested, eight of the nine patients found no detectable HCV RNA and one showed detectable HCV RNA.

The patient who showed detectable HCV RNA at week 12 of treatment was confirmed to have a breakthrough at post-treatment week 2. Eight of the initial ten patients were also tested at post-treatment week 2 and no detectable HCV RNA was found; eight of the initial ten patients were further tested at post-treatment weeks 4, 8, and 12 and no detectable HCV RNA was found; and three of the initial ten patients were further tested at post-treatment week 24 and no detectable HCV RNA was found.

Genotype 3

Similarly, ten previously untreated patients infected with HCV genotype 3 were treated with the same regimen of this example. At week 5 of treatment, two patients had a viral relapse; seven of the remaining eight patients had no detectable HCV RNA; and one of the remaining eight patients had HCV RNA levels less than 25 IU / ml. At week 12 of treatment, and among the eight non-breakthrough patients, one patient was lost from the study, another showed detectable HCV RNA, and the remaining six found no detectable HCV RNA.

At post-treatment weeks 2, 4, and 8, two more patients appeared to have a breakthrough, and six patients had

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-173 • · ♦ · · «·· ·· · ·· ··· no detectable HCV RNA. At post-treatment weeks 12 and 24, five patients found no detectable HCV RNA.

One of the two patients who had a viral relapse at week 5 of treatment was treated with a combination of peginterferon and ribavirin (P / RBV) starting at week 12. After four weeks of P / RBV treatment, the patient was tested and no detectable HCV RNA was found.

Example 2C. Use of a 2-DAA combination with ribavirin to treat treatment-experienced patients infected with genotype 1.

Sixteen treatment-experienced patients with HCV genotype 1 infection were treated with a 2-DAA combination with ribavirin for 12 weeks. The treatment was interferon-free. The 2-DAA combination included compound 1 / r (200/100 QD) and compound 4 (25 mg QD). The weight-based dosage of ribavirin ranged from 1000 to 1200 mg divided into twice daily. These patients had previously undergone standard interferon-ribavirin therapy, but did not respond (interferon null responders).

At week 6 of treatment, all six patients showed no detectable HCV RNA. At week 8 of treatment, all six patients were tested and among them five showed no detectable HCV RNA and one had HCV RNA levels less than 25 IU / ml. At weeks 10 and 12 of treatment, all six patients were tested and no detectable HCV RNA was found.

At post-treatment weeks 2 and 4, all six patients were tested, one had a breakthrough and the remaining five patients found no detectable HCV RNA. At post-treatment weeks 8 and 12, the five non-breakthrough patients were further tested and no detectable HCV RNA was found. A larger clinical study using the same drug combination showed approximately 85% to 90% SVR4 and SVR12 rates after a 12 week treatment regimen in interferon nulls. Among these patients, the SVR4 and SVR 12 rates (non-virological

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-17 499 99 · • 9 9 »• · · · • · · 9 • ♦« · «·« «» ·· »» Ö · 9 9 ·

9

9 * *

9» ···

Errors removed) in genotype la patients about 80%. these SVR4 and SVR12 rates were based on observational data.

All

Example 2D Use of a 3-DAA combination with ribavirin to treat treatment-naïve or treatment-experienced patients infected with genotype 1.

3-DAA combination Treatment with was

Treatment-naive patients

Six previously untreated patients with HCV genotype 1 infection were treated with a 3-DAA combination with ribavirin for 8 weeks. The treatment was interferon free. The 3-DAA combination included compound 1 / r (150/100 mg

QD), Compound 2 (400 mg BID), and Compound 4 (25 mg QD).

The weight-based dosage of ribavirin ranged from 1000 to 1200 mg divided into twice daily. At week 8 of treatment, all six patients had no detectable HCV RNA. At post-treatment weeks 2, 4, 8, 12, and 24, all six patients had no detectable HCV RNA.

Nine previously untreated patients with HCV genotype 1 infection were treated with ribavirin for 12 weeks

Interferon-free. The 3-DAA combination included compound 1 / r (150/100 mg QD or 100/100 QD), compound 2 (400 mg BID), and

Compound 4 (25 mg QD). The weight-based dosage of

Ribavirin ranged from 1000 to 1200 mg divided into twice daily. At week 8 of treatment, all nine patients had no detectable HCV RNA. At week 12 of treatment, all nine patients were tested and no detectable HCV RNA was found. At post-treatment weeks 2, 4, 8, 12, and 24, all of the nine patients were further tested and they showed no detectable HCV RNA.

A larger clinical study using the same drug combination showed approximately 95% SVR4 and SVR12 rates after the 12-week treatment regimen in treatment-naive patients, and approximately 85 to 90% SVR4 and SVR12 rates after the 8-week treatment regimen in treatment-naive patients. Among these patients, the SVR4 and SVR12 rates (not

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-175 ······· · · · ·· β · · * · ·· ··· removed) in genotype la patients about 98 after the 12-week treatment regimen, and about 85-90% after the 8-week treatment regimen Treatment regimen. All of these SVR4 and SVR12 rates were based on observational data.

Treatment-experienced patients

Ten treatment-experienced patients with HCV genotype 1 infection were treated with a 3-DAA combination with ribavirin; four patients were treated for 12 weeks, one patient was treated for sixteen weeks, and the remaining five patients were treated for 24 weeks. The treatment was interferon-free. The 3-DAA combination included compound 1 / r (150/100 mg QD or 100/100 mg QD), compound 2 (400 mg BID), and compound 4 (25 mg QD). The weight-based dosage of ribavirin ranged from 1000 to 1200 mg divided into twice daily. These patients had previously undergone standard interferon / ribavirin therapy, but did not react (interferon null resonator).

At weeks 6, 8, 10 and 12 of treatment, all ten patients showed no detectable HCV RNA.

At post-treatment weeks 2, 4, 8, and 12, none of the four patients found any detectable HCV RNA in the 12-week treatment regimen; and two of the four patients were further tested at post-treatment week 24 and no detectable HCV RNA was found. At post-treatment weeks 2, 4, 8 and 12, the patient found no detectable HCV RNA in the 16-week treatment regimen. All five patients on the 24 week treatment regimen were tested at post-treatment weeks 2 and 4 and no detectable HCV RNA was found; and four of the five patients were further tested at post-treatment week 8 and no detectable HCV RNA was found; and one of the five patients was further tested at post-treatment week 12 and no detectable HCV RNA was found.

A larger clinical study using the same drug combination showed approximately 90 to 95% SVR4 and SVR12 rates after a 12 week treatment regimen in interferon nulls. Among these patients were the SVR4 and SVR12

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Rates (not removing virological errors) in genotype la patients approximately 85-90%. All of these SVR4 and SVR12 rates were based on observational data.

Example 3 Synergistic Concentrations of Compound 1 and Compound 2 in a Genotype Ib HCV Replicon Assay

Examples 3-5 are illustrative and in no way limit the scope of this disclosure. Without being supported by any theory, the unexpected synergistic effects from the combination of different classes of HCV inhibitors (for example a combination of a protease inhibitor (such as Compound 1) and a polymerase inhibitor (such as Compound 2) or a Combination of a protease inhibitor (such as compound 1) and an NS5A inhibitor (such as compound 4)) to the effectiveness of the short-lasting, Interferon-free therapies contribute to the present technology.

Materials: A replicon cell line was derived from the human hepatoma cell line Huh7. It was derived from HCV genotype Ib (Conl) and is a bicistronic subgenomic replicon, essentially similar to those described in Science 285 (5424): 110-3 (1999). The first cistron of the construct contains a firefly luciferase proter and a neomycin phosphotransferase selectable marker. Replicon cells were obtained in Dulbecco's Modified Eagle Medium (DMEM) containing 100 IU / ml penicillin, 100 mg / ml streptomycin (Invitrogen), 200 mg / ml G418, an aminoglycoside antibiotic (Invitrogen) and 10% fetal bovine serum (FBS) at 37 ° C and 5% CO2.

Replicon cell culture: replicon cells at a density of 5000 cells per notch of a 96-notch plate in 100 μΐ DMEM contain 5% FBS. The following day, Compounds 1 and 2 were diluted in dimethyl sulfoxide (DMSO) to create a 200X stick in a series of 6 twofold dilutions. The dilution series was then further diluted 100x in the medium containing 5% FBS.

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Combination Studies: Combination studies were performed to evaluate the interaction effects of Therapeutic Agent 1 and Therapeutic Agent 2 in the replicon assay described above. The purpose of these studies was to determine whether there are doses or concentrations of each compound where there is synergy or antagonism with the other compound. Three experiments with three plates in each experiment were performed on three separate days. Six concentrations of Compound 1 alone and six concentrations of Compound 2 alone were tested in each plate. In addition, 36 combinations of concentrations of the two compounds were tested for each plate. The variable analyzed was the percentage of inhibition of the luciferase signal.

The dilutions of each compound were combined with the dilutions of the other compound in a checkerboard fashion. The concentrations tested were chosen to ensure that the IC₅₀ for each compound alone is in the middle of the serial dilution range. Medium with inhibitor (s) was added to the cell culture plates which already contained 100 μl of DMEM with 5% FBS. The cells were grown in a tissue culture incubator at 37 ° C and 5% CO₂ incubated for three days. The inhibitory effects of the compounds on HCV replication were determined by measuring the activity of a luciferase reporter gene using a luciferase assay system kit (Promega) according to the manufacturer's instructions. Passive lysis buffer (30 μΐ, Promega) was added to each well and the plates were incubated for 15 minutes with shaking to lyse the cells. Luciferin solution (100 μl, Promega) was added to each well and the luciferase activity was measured using a Victor Interferon Luminometer (Perkin-Elmer) . To determine the EC50, the luciferase inhibition data were analyzed using the GraphPad Prism 4 software. Three experiments were performed with three replicates per experiment. The percent inhibition results were analyzed with regard to synergy, additivity and antagonism according to Pritchard and

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Shipman Model (Antiviral Research 14: 181-206 (1990)).

Combination Analysis: Prichard and Shipman proposed a straightforward approach to solving this drug-drug interaction problem. The method was able to calculate theoretical additive effects directly from the individual dose-response curves determined in the assay. The calculated theoretical additivity was then compared to the experimental dose-response surface, and then subtracted to reveal any areas of aberrant interaction. The following equation was used to calculate the theoretical additive effects:

Z = X + Y (1 - X) = X + Y - XY, where Z is the total inhibition produced by the combination of drugs X and Y, where X and Y represent the inhibition produced by drugs X and Y, respectively. Y was generated alone.

A difference between the actually observed level of inhibition and the predicted value was calculated for each concentration combination for each plate in each experiment to determine whether the observed combined effect was greater than the theoretical additive effect Z calculated from the equation above . For each concentration combination, the replicates (across all plates and experiments) were used to calculate a mean difference between the observed and predicted levels of inhibition, their standard errors, and their two-sided 95% confidence intervals.

The synergy or antagonism of a concentration combination was determined based on the following 2 rules: First, the 95% CI of the mean difference between the observed and predicted levels of inhibition was calculated at each concentration combination. If the lower limit of the 95% CI is greater than zero, then the drug combination is considered to have a synergistic effect; if the upper limit of the 95% CI is less than zero,

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-179.··. .··............. «...

ITT · · · ·· τ · · · * · · * * · * · * · then the drug combination would be considered an antagonistic one

Having effect; otherwise there is no significant

Antagonism or synergy in this combination of concentrations.

Second, the synergistic or antagonistic effect must have its relative mean difference, the absolute mean difference divided by its corresponding observed mean inhibition, greater than 1%. By doing this, small differences of statistical significance caused by very small variance could be excluded.

Combination of therapeutic agent 1 and. therapeutic agent 2: the inhibitory effects on replicons produced by each drug alone or in combination with the other at concentrations up to ten times above the EC₅₀ were examined in the genotype Ib (Conl) replicon using a checkerboard titration pattern (two-fold serial dilutions) in a standard three day antiviral assay. The concentrations tested were chosen to ensure that the EC₅₀Values ​​of the compounds were in the middle of the serial dilution range. For compound 1, the concentrations ranged from 0.031 nM to 1.0 nM. For compound 2, the concentrations ranged from 0.125 nM to 4.0 nM. Synergy, additivity and antagonism were assessed using the Pritchard and Shipman model.

Results: The results of the assay analysis are illustrated in FIGS. 1 and 2 and Table 2. In the 3-D surface plot of FIG. 1, deviations from the expected interactions between compound 1 and compound 2 are purely additive at concentrations associated with a horizontal plane at 0%. Synergistic interactions between compound 1 and compound 2 appear as a peak upward in the horizontal plane with a height corresponding to the percentage of additivity calculated above. Antagonistic interactions between Compound 1 and Compound 2 appear as a sagging point or trough down the horizontal plane with a negative value indicating the percentage below the calculated additivity. Synergistic interactions appear

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-180 • · · • · · · Dark gray, additive interactions appear white and antagonistic interactions appear speckled.

As illustrated in the 3D surface plot of Figure 1 and the contour plot of Figure 2, an additive or synergistic effect exists most at the concentrations for Compound 1 and Compound 2. In particular, there is a concentration region showing synergy with most Concentrations of Compound 1 and at the lower to mid-range dose concentrations of Compound 2.

Table 3 below lists the combinations of the concentrations of Compound 1 and Compound 2 with statistically significant synergistic or antagonistic effects based on the Prichard and Shipman model analysis. For each combination of combinations, Table 3 includes the mean difference in the observed and predicted break in inhibition, the standard deviation or error of the mean difference, and the upper and lower limits of the 95% confidence interval.

According to Table 2, all combinations of compound 1 and compound 2 listed in the table have statistically significant synergistic effects.

The results shown in Figures 1 and 2 and Table 2 demonstrate that the combination of therapeutic agent 1 and therapeutic agent 2 achieves additivity or synergy with most of the concentration combinations of the two agents. Taken together, these in vitro replicon results suggest that therapeutic agent 2 should produce a significant antiviral effect in patients when administered in combination with therapeutic agent 1 in patients infected with HCV.

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<img file="AT514003A2_D0036.tif" />

Table 3

<td>connection</td><td>connection</td><td>Medium</td><td>Default-</td><td>lower 95%</td><td>upper 95%</td>

<td>2, nM</td><td>1, nM</td><td>Difference in</td><td>error of</td><td>Trust</td><td>Trust</td>

<td></td><td></td><td>Break of the</td><td>middle</td><td>border</td><td>border</td>

<td></td><td></td><td>Inhibition:</td><td>difference</td><td></td><td></td>

<td></td><td></td><td>observed -</td><td></td><td></td><td></td>

<td></td><td></td><td>predicted</td><td></td><td></td><td></td>

<td> .125</td><td> .12500</td><td> 0.06176</td><td> 0.023352</td><td> 0.007912</td><td> 0.11561</td>

<td> .125</td><td> .25000</td><td> 0.05321</td><td> 0.022199</td><td> 0.002024</td><td> 0.10440</td>

<td> .125</td><td> .50000</td><td> 0.01176</td><td> 0.002680</td><td> 0.005583</td><td> 0.01794</td>

<td> .250</td><td>, 25000c</td><td> 0.06626</td><td> 0.020630</td><td> 0.018692</td><td> 0.11384</td>

<td> .250</td><td> .50000</td><td> 0.01061</td><td> 0.002677</td><td> 0.004438</td><td> 0.01679</td>

<td> .500</td><td> .06250</td><td> 0.04373</td><td> 0.014897</td><td> 0.009375</td><td> 0.07808</td>

<td> .500</td><td> .12500</td><td> 0.10416</td><td> 0.026757</td><td> 0.042454</td><td> 0.16586</td>

<td> .500</td><td> .25000</td><td> 0.09327</td><td> 0.019859</td><td> 0.047471</td><td> 0.13906</td>

<td> .500</td><td> .50000</td><td> 0.01422</td><td> 0.003333</td><td> 0.006535</td><td> 0.02191</td>

<td> 1.00</td><td> .06250</td><td> 0.06696</td><td> 0.020488</td><td> 0.019715</td><td> 0.11421</td>

<td> 1.00</td><td> .12500</td><td> 0.14103</td><td> 0.021289</td><td> 0.091939</td><td> 0.19013</td>

<td> 1.00</td><td> .25000</td><td> 0.11027</td><td> 0.016762</td><td> 0.071617</td><td> 0.14892</td>

<td> 1.00</td><td> .50000</td><td> 0.01365</td><td> 0.002312</td><td> 0.008315</td><td> 0.01898</td>

<td> 2.00</td><td> .06250</td><td> 0.05974</td><td> 0.007690</td><td> 0.042004</td><td> 0.07747</td>

<td> 2.00</td><td> .12500</td><td> 0.10032</td><td> 0.011820</td><td> 0.073066</td><td> 0.12758</td>

<td> 2.00</td><td> .25000</td><td> 0.07117</td><td> 0.009428</td><td> 0.049428</td><td> 0.09291</td>

<td> 4.00</td><td> .03125</td><td> 0.03235</td><td> 0.003950</td><td> 0.023236</td><td> 0.04145</td>

<td> 4.00</td><td> .06250</td><td> 0.05141</td><td> 0.004313</td><td> 0.041470</td><td> 0.06136</td>

<td> 4.00</td><td> .12500</td><td> 0.06572</td><td> 0.004692</td><td> 0.054901</td><td> 0.07654</td>

<td> 4.00</td><td> .25000</td><td> 0.03452</td><td> 0.004775</td><td> 0.023509</td><td> 0.04553</td>

<td>Example 4</td><td colspan="2">Synergistic</td><td colspan="2">Concentrations of</td><td>connection</td>

<td>connection</td><td colspan="4">4 in genotype lb HCV replicon assay</td><td></td>

Materials: The replicon cell line was derived from the human hepatoma cell line Huh7. It was derived from HCV genotype Ib (Conl) and is a bicistronic subgenomic replicon, essentially similar to those described in Science 285 (5424): 110-3 (1999). The first cistron of the construct contains a firefly luciferase reporter and a neomycin phosphotransferase selectable marker. Replicon182/229 • · · · ·

-182 cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) containing 100 IU / ml penicillin, 100 mg / ml streptomycin (Invitrogen), 200 mg / ml G418 (Invitrogen) and 10% fetal bovine serum (FBS) at 37 ° C and 5 % CO₂.

Replicon cell culture: replicon cells were sown at a density of 5000 cells per notch of a 96-notch plate in 100 μΐ DMEM containing 5% FBS. The following day, the compounds were diluted in dimethyl sulfoxide (DMSO) to create a 200X stick in a series of 6 twofold dilutions. The dilution series were then further diluted 100-fold in the medium containing 5% FBS.

Combination Studies: Combination studies were performed to evaluate the interaction effects of Therapeutic Agent 1 and Therapeutic Agent 4 in the replicon assay described above. The purpose of these studies was to determine the doses or concentrations of each compound where synergism or antagonism with the other compound is shown. Three experiments with three plates in each experiment were performed on three separate days. Six concentrations of Compound 1 alone and six concentrations of Compound 2 alone were tested in each plate. In addition, 36 combinations of concentrations of the two compounds were tested for each plate. The variable analyzed was the percentage of inhibition of the luciferase signal.

The dilutions of each compound were combined with the dilutions of the other compound in a checkerboard pattern. The concentrations tested were chosen to ensure that the EC₅₀ for each compound alone is in the middle of the serial dilution range. Medium with inhibitor (s) was added to the cell culture plates which already contained 100 μl DMEM with 5% FBS. The cells were grown in a tissue culture incubator at 37 ° C and 5% CO₂ incubated for three days. The inhibitory effects of the compounds on HCV replication were determined by measuring the activity of a luciferase reporter gene and using a luciferase assay system kit (Promega) according to the manufacturer's instructions.

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-183······· ·· · • · ·· * · · · · · · ·

Passive lysis buffer (30 ml, Promega) was added to each well and the plates were incubated for 15 minutes with shaking to lyse the cells. Luciferin solution (100 μl, Promega) was added to each well and the luciferase activity was measured using a Victor Interferon Luminometer (Perkin-Elmer). To the EC₅₀ To determine, the luciferase inhibition data were analyzed using the GraphPad Prism 4 software. Three experiments were performed with three replicates per experiment. The percentage inhibition results were analyzed with regard to synergy, additivity and antagonism according to the Pritchard and Shipman model (Antiviral Research 14: 181-206 (1990)).

Combination analysis: The Prichard and Shipman approach to calculating the theoretical additive effects (described in Example 3) was used for this example.

The difference between the actual observed percentage of inhibition and the predetermined value was calculated for each concentration combination for each plate in each experiment in order to determine whether the observed combined effect was greater than the theoretical additive effect Z calculated from the Prichard and Shipman equation has been. For each concentration combination, the replicates (across all plates and experiments) were used to calculate a mean difference between the observed and predicted proportions of inhibition, their standard deviation, and their bilateral 95% confidence interval.

Synergy or antagonism for a concentration combination was determined based on the same rules set out in Example 3.

Combination of therapeutic agent 1 and therapeutic agent 4: The inhibitory effects in the replicon, produced by each drug alone or in combination with the other at concentrations up to ten times above the EC₅₀were examined in the genotype Ib (Conl) replicon using a checkerboard titration pattern (two-fold serial dilutions) in the standard three day antiviral assay. The concentrations tested were chosen to ensure that the EC₅₀-Values ​​of the connections in the middle of the

184/229 • · · · ·

-184 • • • • • • • • • • • • serial dilution range. For compound 4 the concentrations ranged from 0.000 nM to 0.0063 nM and for compound 1 the concentrations ranged from 0.023 nM to 0.75 nM. Synergy, additivity and antagonism were assessed using the Pritchard and Shipman model.

Results: The results of the assay analysis are shown in FIGS. 3 and 4 and Table 3. In the 3-D surface diagram of FIG. 3, the deviations from the expected interactions between compound 1 and compound 4 are purely additive at concentrations associated with a horizontal plane at 0%. Synergistic interactions between Compound 1 and Compound 4 appear as a peak upward in the horizontal plane with a height corresponding to the percentage above the calculated additivity. Antagonistic interactions between Compound 1 and Compound 4 appear as a sagging point or indentation down the horizontal plane with a negative value indicating the percentage below the calculated additivity. Synergistic interactions appear shaded in dark gray, additive interactions appear white, and antagonistic interactions appear speckled.

As shown in the 3-D surface plot of Figure 3 and the contour plot of Figure 4, an additive or synergistic effect exists at most at the concentrations for Compound 1 and Compound 4. In particular, there is a concentration range which shows synergy at the lower dose concentrations of compound 4 and the mid-range dose concentrations of compound 1.

Table 4 below lists combinations of concentrations of Compound 1 and Compound 4 with statistically significant synergistic or antagonistic effects based on the Prichard and Shipman model analysis. For each combination of concentrations, Table 4 includes the mean difference in the observed and predicted portion of inhibition, the standard deviation or error of the mean difference, and the upper and lower limits of the 95% confidence interval.

According to Table 4, most of the combinations of

185/229 • · • · · ·

-185• · · · ·· · · ······· ·· · ·· ·· ·· · ·· ···

Compound 1 and Compound 4, which are listed in the table, have statistically significant synergistic effects. A small amount of antagonism was seen with the lowest Compound 1 concentrations.

The results, which are presented in FIGS. 3 and 4 and Table 4, show that the combination of therapeutic agent 4 and therapeutic agent 1 achieves additivity at most with the concentration combinations of the two active agents and synergy achieved with certain concentration combinations, in particular at low concentrations of therapeutic agent 4 and mid-range concentrations of therapeutic agent 1. Taken together, these in vitro replicon results suggest that therapeutic agent 4 should produce a significant antiviral effect in patients when administered in combination with therapeutic agent 1 in patients infected with HCV.

Table 4

<td>connection 4, nM</td><td>connection 1, nM</td><td>Medium Difference in Break of the Inhibition: observed - predicted</td><td>Standard error of the middle difference</td><td>lower 95% Trust border</td><td>upper 95% Trust border</td>

<td> 0.000197</td><td> 0.375000</td><td> 0.09895</td><td> 0.033975</td><td> 0.02060</td><td> 0.17729</td>

<td> 0.000394</td><td> 0.187500</td><td> 0.16900</td><td> 0.038934</td><td> 0.07922</td><td> 0.25878</td>

<td> 0.000394</td><td> 0.375000</td><td> 0.11401</td><td> 0.027710</td><td> 0.05011</td><td> 0.17791</td>

<td> 0.000788</td><td> 0.187500</td><td> 0.15349</td><td> 0.038860</td><td> 0.06388</td><td> 0.24310</td>

<td> 0.000788</td><td> 0.375000</td><td> 0.09992</td><td> 0.027266</td><td> 0.03704</td><td> 0.16279</td>

<td> 0.001575</td><td> 0.023438</td><td> -0.08326</td><td> 0.027126</td><td> -0.14582</td><td> -0.02071</td>

<td> 0.001575</td><td> 0.046875</td><td> -0.11894</td><td> 0.026099</td><td> -0.17913</td><td> -0.05876</td>

<td> 0.001575</td><td> 0.187500</td><td> 0.07958</td><td> 0.020080</td><td> 0.03328</td><td> 0.12588</td>

<td> 0.003150</td><td> 0.023438</td><td> -0.10156</td><td> 0.018406</td><td> -0.14401</td><td> -0.05912</td>

<td> 0.003150</td><td> 0.046875</td><td> -0.08091</td><td> 0.014615</td><td> -0.11462</td><td> -0.04721</td>

Example 5. Reduction of HCV infected cells with combinations of therapeutic agents 1, 2 and 4

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999 The replicon also has a neomycin and the frequency of resistant replicon colonies selected by therapeutic agent 1, therapeutic agent 2, therapeutic agent 4 or various combinations of these agents, the stable subgenomic replicon cell line was derived from the HCV genotype la (H77 ; Genbank accession number AF011751) was used. The replicon construct was bicistronic and the cell line was generated by introducing the constructs into cell lines containing the

Hepatoma cell line Huh-7, a firefly luciferase reporter

Phosphotransferase (Neo) selectable marker. The two coding regions, separated by the FMDV 2a protease, comprise the first cistron of the bicistronic replicon construct, the second cistron containing the HCV NS3-NS5B coding region with the addition of adaptive mutations E1202G, K1691R, K2040R and S2204I. This HCV replicon cell line was maintained in Dulbecco's modified Eagles medium (DMEM; Invitrogen) containing 10% (v / v) fetal bovine serum, 100 IU / ml penicillin, 100 pg / ml streptomycin, and 200 pg / ml G418 (all from Invitrogen) . la-H77 replicon cells (105-106) were placed in 150 mm cell culture plates and in the presence of G418 (400 pg / ml) and

Compound 1, Compound 2, and / or Compound 4 are placed at concentrations that are either 10-fold (10X) or 100-fold (100X) above the EC₅₀Value for the HCV genotype la replicon cell line grown. The EC₅₀Values ​​for Compound 1, Compound 2 and Compound 4 used for this experiment were 0.9, 7.7 and 0.01 nM, respectively. After three weeks of treatment, the majority of replicon cells were freed of replicon RNA and therefore unable to survive in the G418-containing medium, since the replicon RNA included the neomarker that confers G418 resistance. The cells containing resistant replicon variants survived and formed colonies, and these colonies were stained with 1% crystal purple in 10% protocol SafeFix II reagent (Fisher Scientific), and counted. As shown in Figure 5A, the combination of Compound 4 plus either Compound 1 or Compound 2 performed at either 10-fold or 100-fold above their corresponding EC₅₀-Value too

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-is: - ::

significantly fewer colonies than either Compound 1, Compound 2, or Compound 4 alone at 10-fold or 100-fold above their corresponding EC₅₀-Value.

Figure 5B illustrates the percentage of colonies that survived two vs. three DAA combinations. In colony survival assays, Ia-H77 replicon cells were grown in the presence of a DAA combination and G418 for approximately three weeks, after which time the cells containing resistant replicon variants had colonized. The cells were stained with crystal purple and counted. Triple Combination is either a combination of Compounds 1, 2 and 4 at concentrations 5 times (5X) above their respective EC₅₀Values ​​or a combination of compounds 1, 2 and 4 at concentrations 10 times (10X) above their corresponding EC₅₀Values.

FIGS. 5C and 5D show the effect of a combination of compounds 1 and 4 in long-term HCV-RNA reduction assays in genotype 1 replicon cell lines. In long-term replicon RNA reduction assays, 106 replicon cells were placed in the absence of G418. The inhibitors at concentrations either 10-fold (10X) or 100-fold (100X) above their respective EC₅₀Values ​​were added and cells were grown to approximately 95% confluence (4 days). With each run, 106 cells were removed and frozen and an additional 106 cells were added to another flask with fresh medium and inhibitors. The RNA was extracted from 106 cells and the HCV-RNA was measured in a real-time RT-PCR assay. Figures 5C and 5D show that in both Ia and Ib replicon cells, the combination of compounds 1 and 4, each at 10-fold above EC50, is more effective in clearing cells of replicon than at 100-fold above EC50 of either inhibitor alone.

Predominantly resistant variants selected from compound 1, 2 or 4 in genotype 1 replicons were also determined. For compound 1, the predominant resistance variants in IA-H77 replicons include R155K, D168A and D168V with fold resistance of 26, 48 and 128, respectively; and the prevailing resistance variants

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-188h «······ · · · ♦ · ·· ·· · ·· ··· in lb-Conl replicons include R155K, A156T and D168V with fold resistance of 48, 9 and 190, respectively. For compound 2, the predominant resistance variants in la-H77 replicons include C316Y, M414T, Y448C and S556G with fold resistance of 1600, 36,

980 or 15 a; and the predominant variants of resistance in Ib Conl replicons include C316Y, M414T and D559G with fold resistance of 1400, 26 and 100, respectively. For compound 4, the predominant resistance variants in la-H77 replicons include M28T, M28V, Q30R, Y93C and Y93H with fold resistance of 9000, 60, 800,

1700 and 41,000, respectively; and the predominant variants of resistance in Ib Conl replicons include Y93H with 55 fold resistance. These experiments also showed that in genotype la a number of variants selected by compounds 2 or 4 transmitted higher levels of resistance than those selected by compound 1, and that in genotype lb a variant (C316Y) selected by compound 2 transmitted a higher level Levels of resistance conferred than those selected by either Compound 1 or Compound 4.

The above examples show that the combination of two different classes of DAAs (e.g. a combination of an HCV protease inhibitor and an HCV polymerase inhibitor, or a combination of an HCV protease inhibitor and HCVNS5A inhibitor, or a combination of an HCV polymerase inhibitor and an HCV NS5A inhibitor) can lead to an improved resistance barrier in patients , relative to a single DAA alone, while the combination of three different classes of DAAs (for example, a combination of an HCV protease inhibitor, an HCV polymerase inhibitor, and an HCV NS5A inhibitor) can lead to an even more significant resistance barrier. It is expected that an improvement in the resistance barrier achieved by the co-administration of multiple DAAs from different classes or with a different mechanism of action will correlate with improved efficacy in patients.

Example 6. Creation of a clinical model for interferon-free DAA combination therapies

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-18 9:« · · ·· ··

This example describes a new clinical model for estimating optimal doses and durations of interferon-free HCV therapies using a combination of different DAAs. This model reasonably predicted the efficacy of numerous DAA combinations in interferon-free, short-term therapies.

A mechanistic model was used to develop the relationship between DAA exposures and antiviral efficacy in HCV infected subjects. This model was used to conduct clinical studies simulations of clinical outcomes after administration of different DAA combination regimens (e.g. specific DAA combinations and different doses of DAAs) and duration of therapy.

Numerous DAAs have been extensively documented in order to select mutants after a short duration of monotherapy (e.g. less than 1 week). The viral dynamic model of this example included single and double mutants. Specifically, the model included two single mutants and one double mutant for each of the two DAA combination regimens. Thus, a 2-DAA combination regimen (e.g., a combination of a protease inhibitor and an NS5A inhibitor) included 2 single mutants and one double mutant. A 3-DAA combination (for example, a combination of a protease inhibitor, a polymerase inhibitor, and an NS5A inhibitor, such as a combination of a protease inhibitor, a non-nucleoside polymerase inhibitor (NNPI), and an NS5A inhibitor) included 3 singles and two double mutants.

The model has 3 components: hepatocytes (uninfected or target cell), infected cell and viral dynamics. The differential equations that describe the dynamics of the 3 components are as follows:

(1) Hepatocytes (uninfected or target cell) dynamics dT / dt = s - de * T- (1-η) * β * Τ * (νΐ, WT + VLPoly + VLProt + VLNS5A + VLNS5AProt + VLPolyProt)

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-i9Ci- ::: ·. . * • · · · · · · · • · · · · · * (2) Infected cell dynamics (a) Infected with wild-type virus d IWT / dt = (1-η) * β * T * VLWT - δ * IWT (b) infected with polymerase mutant virus d IPoly / dt = (1-η) * β * T * VLPoly - ö * IPoly (c) infected with protease mutant virus d IProt / dt = (1-η ) * β * T * VLProt - δ * IProt (d) Infected with NS5A mutant virus d INS5A / dt = (1 -η) * β * T * VLNS5A - δ * INS5A (e) Infected with protease NS5A double mutant virus d INS5AProt / dt = (1-η) * β * T * VLNS5AProt - δ * INS5AProt (f) Infected with protease polymerase double mutant virus d IPolyProt / dt = (lq) * ß * T * VLPolyProt - δ * IPolyProt (3) Viral dynamics (a) Wild-type virus d VLWT / dt = (l-3 * ß) * p * (l-Effl) * IWT + μ * (p * (l-Eff2) * Fitl * IPoly + p * (l-Eff3) * Fit2 * IProt + p * (lEff4) * Fit3 * INS5A) - c * VLWT (b)

Polymerase mutant virus

191/229 d VLPoly / dt = (1- μ -φ) * p * (l-Eff2) * Fit 1 »IPoly + μ * p * (l-Effl)» IWT + φ * p * (1 -E £ ß) * Fit4 * IPolyProt - c * VLPoly «» w

-i9V ::

(c) Protease mutant virus d VLProt / dt = (1- μ - 2 * φ) * p * (l-Efß) * Fit2 * IProt + μ * p * (IE £ ß) * IWT + φ * (p * (lEff5) * Fit4 * IPolyProt + p * (l-Eff6) * Fit5 * INS5AProt) - c * VLProt (d) NS5A mutant virus d VLNS5A / dt = (1- μ - φ) * ρ * (1- ΕίΤ4) * Κβ * ΙΝ85Α + μ * p * (l-Effl) * IWT + φ * p * (lEff6) * Fit5 * INS5AProt - c * VLNS5A (e) NS5A and protease double mutant virus d VLNS5AProt / dt = ( 1-2 * φ) * ρ * (1-ΕΑ6) * Ρί15 * 1Ν85ΑΡΓ0ί + φ * (p * (l-Eff4) * Fit3 * INS5A + p * (lEfß) * Fit2 * IProt) - c * VLNS5AProt (f ) Poly and Protease Mutant double mutant virus d VLPolyProt / dt = (1-2 * φ) * ρ * (1-Ε1Τ5) * Ρΐί4 * ΙΡο1γΡΓθ1 + φ * (p * (l-Ef £ 2) * Fitl * IPoly + p * (lEfß ) * Fit2 * IProt) - c * VLPolyProt

The parameters used in the equations above are described in Table 5.

Table 5. Viral dynamics parameters

<td></td><td>parameter</td><td>Honor exercise</td>

<td>s</td><td></td><td>Zero order production of Hepatocytes</td>

<td>T</td><td></td><td>Number of target or uninfected Hepatocytes</td>

<td>de</td><td></td><td>Rate constant first Order for the death of hepatocytes</td>

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<img file="AT514003A2_D0037.tif" />

-192

<td>parameter</td><td>Honor exercise</td>

<td>. -f.</td><td>Rate constant for the Infection of hepatocytes by the virus</td>

<td>Z7 \</td><td>Rate constant first Okay for the death of infected Hepatocytes</td>

<td>oss,</td><td>partial reduction in Rate constant for the Infection of hepatocytes by the virus</td>

<td></td><td>Possibility of forming individual Mutants and mutation back to wild Type</td>

<td>ή</td><td>Possibility of forming duplicates Mutants and mutation back too single mutant</td>

<td> ///</td><td>Production speed of the wild type virus</td>

<td>c</td><td>Virus clearance rate</td>

<td>Effl, Eff2, Eff3, Eff4</td><td>Inhibiting the production of wild-type, Polymerase, protease or NS5A mutant</td>

<td>Eff5, Eff6</td><td>Inhibition of the production of polymerase Protease or NS5A protease double mutant</td>

<td>Fitl, Fit2, Fit3</td><td>Fitness of polymerase, protease or NS5A mutant relative to wild-type virus</td>

<td>Fit4, Fit5</td><td>Fitness of polymerase, protease or NS5A protease double mutant relative to Wild-type virus</td>

<td>IWT, Ipoly, Iprot, INS5A</td><td>Number of cells with wild-type, Polymerase, protease or NS5A Mutants are infected</td>

<td>Ipoly-Prot, INS5A-Prot</td><td>Number of cells exposed to polymerase, Protease or NS5A protease Double mutant are infected</td>

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-193r • ·

<td>parameter</td><td>Honor exercise</td>

<td>VLWT, VLPoly, VLProt, VLNS5A</td><td>Viral load for wild-type virus, Polymerase, protease or NS5A Mutant virus</td>

<td>VLPoly-Prot, VLNS5A-Prot</td><td>Viral load for polymerase, protease or NS5A protease double mutant</td>

As shown in the differential equations for the viral dynamics, the effect of DAA is included as an inhibition of the production of the viral load. For example, the effect of DAA (s) is also the production of wild-type virus against as (1-Effl) *, where Effl is the break in viral production that is inhibited. In the absence of drug Effl = 0 and in the presence of drug Effl assumes a value between 0 and 1. Effl is described using an Emax model:

Effl = Emax * Conc / (EC₅o + Conc) where Emax is the maximum inhibition, Conc is the plasma DAA concentration and EC₅₀ is the concentration that inhibits the production of the viral load by 50%. Since the fold-change in the EC₅₀ for the mutants compared to wild-type virus, based on values ​​obtained from in vitro replicon studies, the EC₅₀ estimated only for the wild-type virus.

For DAA combinations, the effect was assumed to be multiplicative and was included as follows:

(1-effl) = (l-eff_DAA1) * (l-eff_THEREA2) * (l-eff_THEREA3)

The effect of ribavirin (RBV) can also be added to the infection rate as an Emax model. In the presence of

Ribavirin decreases the infection rate by a factor (1- ° ¾ in which

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-194 »η ^— Coiicrbv / (ECso-rbv + Coiicrbv)

The model does not include a double mutant to the polymerase + NS5A inhibitors. In 3-DAA regimes, a polymerase + NS5A double mutant is often of the wild type for the protease inhibitor. Thus, this double mutant was not expected to significantly affect the clinical outcomes for a 3-DAA regime simulation. On the other hand, the model can be easily adapted to simulate a 2-DAA regimen containing a polymerase inhibitor and an NS5A inhibitor by treating the polymerase inhibitor (e.g. PSI-7977) as a protease inhibitor in the model.

The lowest available limit of detection (LOD) of viral challenge assays is 10 IU / ml. Assuming 3 virion particles per IU, that means approximately 0.5 million viruses in the body at LOD. Thus, subjects must be treated for a significant period of time after their viral load falls below the LOD in order to achieve healing. This duration depends on the potency of the compounds and the individual response to therapy.

A threshold concept was used to predict the time required for healing. For simulations, it was assumed that an HCV infected subject achieves SVR when the viral load reaches less than 1 virion in the total plasma and extracellular fluid volume (approximately 15,000 ml), i.e. measurement of a viral load of &lt;1 copy / 15,000 ml or &lt; 0.33 IU / 15000 ml. This translates to approximately 5 log IU / ml. Cf. Snoeck E et al. , CLIN PHARMACOL THER. 87 (6): 706-13 (2010) wherein, based on data from patients treated with peg-IFN and ribavirin, it was estimated that subjects achieve SVR when the predicted number of infected cells fell below 1. While such low viral loads cannot be measured experimentally, they can be simulated using the viral dynamics model.

The model can be used to predict SVR for any combination of DAAs, with or without interferon,

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-19 ^ • • • • • • • • • • • • and with or without ribavirin.

As non-limiting examples, various interferon-free treatment regimens using different combinations of Compound 1, Compound 2 and / or Compound 4 with or without ribavirin were evaluated using the model of this example. The following approach was used to include mutants in the model:

a. a single mutant per DAA

b. one double mutant per DAA combination

For a combination of two DAAs, for example a combination of Compound 1 and Compound 2, the model included one mutant resistant to Compound 1, one mutant resistant to Compound 2, and a double mutant resistant to both Compound 1 and Compound 2. Compound 1 is co-administered or co-formulated with ritonavir (or other pharmacokinetic enhancer) to improve drug exposure of the drug.

A double mutant against compound 2 and compound 4 was not included in the model. In the 3-DAA regimens, a compound 2 / compound 4 double mutant is likely wild-type for compound 1 due to the high potency and resistance profile of compound 1. thus, compound 2 / compound 4 double mutant is not expected to have the clinical results for Treatments containing compound 1 affected.

Individual mutants included in the model were based on mutants observed for the individual DAAs in phase lb and 2a studies (e.g., clinical studies M10-351, M12-116, and Mll-602). For double mutants with resistance to 2 DAA classes, it was assumed that the sensitivity (EC₅₀) from double mutants to drug is a combination of 2 single mutants. Thus, for Compound 1 and Compound 2, the individual mutants were D168V and M414T, respectively, and the double mutant was D168V-M414T. In this scenario, the D168V mutant would be less sensitive to compound 1, but would be as sensitive to compound 2 as the Wild196 / 229 • · ·

<img file="AT514003A2_D0038.tif" />

Type virus. Similarly, the M414T mutant would be less sensitive to Compound 2 but would be as sensitive to Compound 1 as the wild-type virus. The double mutant D168V-M414T would be less sensitive to both compound 1 and compound 2.

The fold change in the EC₅₀ for the mutants compared to the wild-type virus was based on values ​​obtained from in vitro replicon studies. Since the monotherapy data for compound 4 is a variety of mutants with different EC₅₀ indicated a value of 100x changes in the EC₅₀ used for compound 4 for development and simulations.

The baseline prevalence of the mutants was estimated during model fitting, while the mutation rate was based on literature values. Both the baseline prevalence and the mutation rate determined the mutant fitness.

Pharmacokinetic data and viral exposure data from 140 treatment-naïve HCV infected subjects were used to construct the model. For the development, the number of target cells at the baseline, the number of infected cells at the baseline, the death rate of the target cells and the mutation rates were based on literature values. See, for example, Snoeck et al. supra; Rong et al. SCI TRANSL MED. 2 (30): 30ra32 (2000); Neal and Pravin, ACOP 2009 (http://2009.goacop.org/sites/all/assets/webform/Lauren-Neal_ACoP_2 00 9.pdf;

Neumann et al. SCIENCE 282 (5386): 103-7 (1998); Shudo et al. ANTIVIR THER. 13 (7): 919-26 (2008); and Dahari et al. J THEOR BIOL. 247 (2): 371-81 (2007). The rate of production of the virus and the rate of infection of the virus were derived from other parameters in the model. All other parameters were estimated. The creation of an exposure antiviral response model was carried out using NONMEM 7.2.

Clinical trial simulations were performed using Trial Simulator Version 2.2.1. Fifty subjects and 50 replicates were simulated for each treatment. A subject failure rate from the study for any reason was assumed to be 8% over 24 weeks based on available literature on trials in subjects with HCV. All

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Simulations were carried out assuming 100% compliance. Covariates included in the simulations were genotype la / lb status. The simulated clinical results included: (1) the percentage of subjects below the limit of detection (LOD) of 10 IU / ml and (2) the percentage of subjects who achieved SVR.

The clinical trial simulations were performed to determine the optimal dose and duration for SVR. Over 80 scenarios were simulated to predict the percentage of subjects with SVR after administration of various 2 and 3 DAA combinations (for example 1 - Compound 2, or Compound 1 + Compound 4, or Compound 1 + Compound 2 + Compound 4), without RBV, in a range of doses for each DAA (e.g. Compound 1 / ritonavir at 250/100, 150/100 or 100/100 mg QD, Compound 4 at 5, 25 or 100 mg QD, and Compound 2 at 400 or 800 mg BID) and through a range of treatment durations (e.g., 2, 4, 6, 8, 10, 12, 16 and 24 weeks).

The optimal dose and duration were predicted based on the percentage of subjects with a viral load of less than -51og IU / ml threshold for SVR. Selected and relevant results of the simulation for the 2- and 3-DAA combinations of compounds 1, 2 and / or 4 are shown in FIGS. 6A, 6B and 6C for two different doses of compound 1. Figure 6A shows the predicted mean SVR percentage (% SVR) and the 90% confidence interval (the vertical bar at the top of each SVR percentage column) for different treatment durations using a combination of compound 1 and compound 2; Figure 6B shows the predicted mean and 90% confidence interval for different treatment durations using a combination of compound 1 and compound 4; and Figure 6C shows the predicted mean and 90% confidence intervals for different treatment durations using a combination of Compound 1, Compound 2 and Compound 4. In each simulation RBV was included and Compound 1 was used with 100 mg ritonavir and the subjects are HCV- genotype

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1, treatment-naive patients. SVR24 is lower than SVR12 in some cases due to failure; longer durations are not necessarily predicted to improve SVR, but could result in more failures resulting in lower SVR.

The model predicted that at 8-12 weeks of dosing, at least 80 to 90% subjects could achieve SVR with 2 and 3 DAA combinations. The model also predicted that durations less than 8 weeks could heal a significant number of subjects. A 2-DAA regimen was predicted to cure over 40% of the subjects, and a 3-DAA regimen was predicted to cure approximately 60% of the subjects with as little as 6 weeks of dosing. Dosing for periods longer than 12 weeks was not expected to significantly increase the percentage of subjects with SVR. The addition of the third DAA was predicted to shorten the duration of treatment by 2-4 weeks, since optimal durations for the 3-DAA combination of Compound 1, Compound 2 and Compound 4 were predicted to be 8-10 weeks.

Figures 6A, 6B and 6C illustrate the predictions for DAA combinations without ribavirin. The model also predicts similar or comparable SVR percentages for these DAA combinations when used with ribavirin. In addition, the effect of interferon (e.g. pegylated interferon) can also be added by including interferon similar to a DAA but without any resistance mutants.

One of the advantages of the model is that it allows the study of various viral parameters and their effects on dose, duration and SVR. For example, while it is very difficult or impossible to determine the effect of mutant parameters experimentally, they can be examined using the model. Thus, SVR can be predicted with the model in a patient population who have different mutants.

The model was used to simulate a treatment regimen of Example 1 which included 150/100 mg Compound 1 / ritonavir QD + 400 mg Compound 3 QD + weight-dependent amounts of RBV BID for 12 weeks and the percentage of

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Subjects with HCV RNA less than LOD at 2, 4, 8, 10, and

Weeks have been summarized in FIG. 7. The mean predicted versus observed percentage of subjects with below LOD (% LOD) at respective weeks is shown in FIG. 95% confidence intervals for the predicted data (the vertical bar at the top of each corresponding LOD predicted percentage column) were also given. As shown in Figure 7, the model reasonably predicted the clinical outcome of% LOD.

The model was also used to simulate the treatment described in Example 2A. The mean predicted versus observed percentage SVR (% SVR) after 12 weeks of treatment is shown in FIG. 95% confidence intervals for the predicted data (the vertical bar at the top of each corresponding predicted SVR percentage column) were also given. As shown in Figure 8, the predicted SVR percentages were in good agreement with the observed SVR percentages. Simulations also predict that the same treatment regimen as described in Example 2A, but without ribavirin, will have similar or comparable LOD percentages for different treatment durations.

The viral dynamic exposure response model of this example provided a quantitative method to reasonably predict SVR for various combinations of antiviral compounds. Based on exposure antiviral response modeling and clinical trial simulations, it showed that (1) the addition of a 3. DAA to a 2-DAA combination can reduce the optimal duration of treatment and / or the increase in SVR; (2) 8-12 week dosing is the optimal duration of therapy for 2 and 3 DAA combinations of Compound 1 / r, Compound 2, and Compound 4; and (3) periods of less than 8 weeks of interferon-free treatment were predicted to cure a significant percentage of subjects.

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Example 7. Clinical Modeling for Interferon-Free DAA Combination Therapies Containing BMS-7090052 and BMS-659932

The model described above was also used to predict the SVR percentage of interferon-free treatment regimens containing BMS-790052 and BMS-650032 without ribavirin based on existing published clinical data including two phase 1 and one phase 2 studies of BMS790052 and a phase 1 and a phase 2a study of BMS650032. FIG. 9 shows the predicted mean SVR percentage and 90% SVR confidence interval for different treatment durations of a 2-DAA regimen containing BMS-790052 (60 mg

QD) and BMS-650032 (600 BID) in genotype 1 naive subjects. The combination of BMS-790052 (60 mg

QD) plus BMS-650032 (600 mg BID) in genotype 1 subjects would achieve improved SVR for durations of 12 weeks or more with predicted SVR rates of approximately 70% for 10 weeks of dosing. Similar regimens containing ribavirin or regimens with similar dosages of BMS-790052 and BMS-650032 with or without ribavirin are expected to achieve similar SVR rates.

Example 8. Clinical modeling for interferon-free

Therapies containing PSI-7977

Similarly, a 3-DAA regimen without interferon and ribavirin was modeled for genotype 1 patients based on existing clinical data. The 3-DAA regimen contains 200/100 mg QD Compound 1 / r, 50 mg QD Compound 4, and 400 mg QD PSI-7977. FIG. 10 shows the predicted mean SVR rates for different treatment periods of this 3-DAA combination. This 3-DAA combination was predicted to have over 60% SVR in 6 weeks and over 80% SVR over a duration of 8 weeks, 10 weeks, 12 weeks, or longer of treatment. Similar regimens but containing ribavirin or regimens with similar dosages of Compound 1 / r, Compound 4 and PSI-7977 with or without ribavirin are expected to achieve similar SVR rates.

The model can also be used to preview SVR201 / 229

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Commitments for regimens that include a single DAA or a single DAA with ribavirin. For example, the model predictions for PSI-7977 + ribavirin were obtained for various durations for the treatment of HCV genotype 1 treatment-naive patients. Figure 11 shows the predicted mean value and 90% confidence interval of the SVR percentage for various treatment durations of a regimen containing PSI-7977 (as the only DAA; 400 mg QD) and ribavirin (600 mg BID). The 90% confidence interval for the predicted SVR (the vertical bar at the top of each corresponding predicted SVR percentage column) is also given in FIG. The prediction was based on the previously published clinical data for PSI-7977. The SVR rate for PSI-7977 + ribavirin was predicted to be around 75-90% after 12 weeks of dosing and about 55-75% after 8 weeks of dosing, in genotype 1 patients. Similar SVR percentages for genotype 1 treatment-naive patients are expected for similar regimens, the similar PSI-7977 QD dosage (e.g. 200-600 QD) and weight-based amounts of ribavirin (e.g. 1000 to 1200 mg divided twice daily were) contained.

Data from two phase 1 and one phase 2 studies of daclatasvir (BMS-790052) and one phase 1 and one phase 2 study of PSI-7977 were used to estimate the pharmacokinetics and viral dynamics model parameters. The predictions for a 2-DAA combination with daclatasvir (BMS-790052) and PSI7977 in genotype 1 naive patients are shown in FIG. The model predicted that after 10-12 weeks of dosing with the combination of daclatasvir and PSI-7977 without ribavirin, at least 90% of HCV genotype 1 naive patients can achieve SVR. Similar or SVR rates are predicted when ribavirin is included in regimens.

Similarly, data from a phase la study of TMC-435 and a phase 1 and phase 2 study of PSI-7977 were used to estimate pharmacokinetics and viral dynamics model parameters. The predictions for a 2-DAA combination with the TMC-435 and PSI-7977 in genotype 1 naive patients are shown in FIG. The model says

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9 99 999 predicts that after 10-12 weeks of dosing with the combination of TMC-435 and PSI-7977 without ribavirin, at least 90% of HCV patients can achieve SVR. Similar or SVR rates are predicted when ribavirin is included in regimens.

Example 9. Clinical modeling for interferon-free DAA combination therapies containing danoprevir and mercitabine

In addition, data from a phase 1 and a phase 2 study of danoprevir and mercitabine were used to estimate pharmacokinetics and viral dynamics model parameters. Ritonavir was co-administered with danoprevir to improve the pharmacokinetics of danoprevir. The predictions for a 2-DAA combination with danoprevir and mercitabine in genotype 1 naive patients are shown in FIG. The model predicts that after 16 weeks of dosing with the combination of danoprevir and mercitabine without ribavirin, at least 90% of HCV patients can achieve SVR. Similar or SVR rates are predicted when ribavirin is included in regimens.

Example 10. Clinical modeling for interferon-free DAA combination therapies containing tegobuvir (GS-9190), GS-9451 and GS5885

Data from phase 1 and phase 2 studies of GS-9190 (tegobuvir), GS-9451 and GS-5885 were used to estimate the pharmacokinetics and viral dynamics model parameters. The predictions for the combination with GS-9190 (tegobuvir), GS-9451 and GS-5885 in genotype 1 naive patients are shown in FIG. The model predicts that after 12 weeks of dosing with the combination of GS-9190 (tegobuvir) + GS-9451 + GS-5885 + RBV approximately 70% of genotype 1 naive patients can achieve SVR, and after 2-4 weeks of treatment for over 8 0% of genotype 1 naive patients can achieve SVR. Similar or SVR rates are predicted when ribavirin is included in regimens.

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Example 11. Clinical Modeling for Interferon-Free DAA Combination Therapies Containing PSI-7977 (GS-7977)

Data from phase 1 and phase 2 studies of GS-9451 and GS7977 (PSI-7977) were used to estimate pharmacokinetics and viral dynamics model parameters. The predictions for the combination with GS-9451 and GS-7977 (PSI-7977) in

Genotype 1 naive patients are shown in FIG.

Data from phase 1 and phase 2 studies of GS-5885 and GS7977 (PSI-7977) were used to estimate pharmacokinetics and viral dynamics model parameters. The predictions for the combination with GS-5885 and GS-7977 (PSI-7977) in

Genotype 1 naive patients are shown in FIG.

Data from phase 1 and phase 2 studies of GS-9451, GS5885, and GS-7977 (PSI-7977) were used to estimate the pharmacokinetics and viral dynamics model parameters. The predictions for the combination with GS-9451, GS-5885 and GS-7977 (PSI-7977) in genotype 1 naive patients are shown in FIG.

The model predicts that after 12 weeks of dosing with the combination of GS-9451 and GS-7977 (PSI-7977) or the combination of GS-5885 and GS-7977 (PSI-7977), or the

Combination of GS-9451, GS-5885 and GS-7977 (PSI-7977) can achieve at least 90% of genotype 1 naive patients SVR. Similar or SVR rates are predicted when ribavirin is included in regimens.

Example 12. Clinical Modeling for Interferon-Free DAA Combination Therapies Containing TMC-435 and Daclatasvir (BMS-790052)

Data from a phase la study of TMC-435 and from two phase 1 and phase 2 studies of daclatasvir (BMS-790052) were used to estimate the pharmacokinetics and viral dynamics model parameters. The predictions for the combination with TMC-435 and daclatasvir in genotype 1 naive patients are shown in FIG.

The model predicts that after 12 weeks of dosing with the combination of TMC-435 and daclatasvir (BMS-790052),

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The foregoing description of the present invention has provided illustration and description, but is not intended to be exhaustive or to limit the invention to the precise details disclosed. Modifications and variations are possible in light of the above teachings or can be acquired from practice of the invention. Thus, it should be noted that the scope of the invention is defined by the claims and their equivalents.