Untitled record

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) 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) are administered in amounts effective to provide a sustained virological response (SVR) or other desired level of effectiveness in a subject. The subject is not administered ribavirin for the duration of the administration of the at least two DAAs. In other words, the methods preclude administration of ribavirin to the subject during the treatment regimen. The subject is also not administered interferon 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 comprise 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 injection in a subject are provided. The methods include 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, and (c) a cytochrome P-450 inhibitor to the subject for a period not exceeding twelve weeks or for another period such as

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-4 set out herein (for example, the treatment regimen may last for no more than eight weeks). Preferably, Therapeutic Agent 1, the polymerase inhibitor (s) and the cytochrome P-450 inhibitor are administered in amounts effective to provide high rates of SVR or other measure of effectiveness in the subject. As non-limiting examples

Drug 1 and the cytochrome P-450 are and are administered once a day, and the polymerase inhibitor (s) can be administered once a day or twice a day, and the treatment regimen is preferably twelve weeks (the treatment regimen can also be, for example , last 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 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 achieve SVR or other levels of effectiveness in at least about 50% of the population, preferably at least about 70%^sTo lead 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, NS3A 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 can be co-formulated into the therapeutic inhibitor

4/223 • · • ··· • · «• ·« • · therapeutic therapeutic the therapeutic active ingredient 1 (described below) and the HCV polymerase inhibitor is the therapeutic active ingredient 2 and / or the therapeutic active ingredient 3 (also described below). As an 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 150 mg to about 250 mg, and the therapeutic agent 2 is administered in a total daily dose from about 300 mg to about 1800 mg is administered or is administered at least twice daily at doses from 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 the and the

4th The therapeutic agent 1 can be administered in a total daily dose of about 100 mg to about 250 mg, and the 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 can be used in any effective manner of the

NS5A inhibitor is an example, can

Active ingredient 1 active ingredient

5/223 • · ·· ·· · ·· · ·

Dosage schedules and / or frequencies are administered for

For example, they can each be administered daily. Everyone

DAA can be administered either separately or in combination • · • ···

<td>become,</td><td>and</td><td>everyone</td><td>DAA</td><td>can at least once a day,</td><td>at least</td>

<td>twice</td><td>at the</td><td>Day</td><td>or</td><td>at least three times a day</td><td>administered</td>

<td>become.</td><td>In</td><td colspan="2">some</td><td>preferred embodiments</td><td>will the</td>

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 for a period of no more than twelve weeks, wherein the subject has neither interferon nor ribavirin for that period is administered. In some aspects, the at least two DAAs 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, which is co-administered or co-formulated with ritonavir, and (ii) Compound 2 or a pharmaceutically acceptable salt from that.

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

6/223 ·· ·· ·· · ·· ·· or a pharmaceutically acceptable salt thereof which is co-administered or co-formulated with ritonavir (ii) or a pharmaceutically acceptable salt thereof, and (iii) compound 4 or a pharmaceutically acceptable one Salt from it.

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 Teleprevir and VX-222, a combination of PSI-7977 and TMC-435 and a combination of Danprevir 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 injection 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, and (c) a cytochrome P450 inhibitor to the subject and for a period not exceeding twelve weeks, wherein the therapeutic agent 1, the at least one polymerase inhibitor and the cytochrome 450 inhibitor are administered in amounts effective to result in SVR in the subject.

In yet another aspect, the present technology provides a method of treating a population of

7/223 • ft ft «&gt; · ·» · · »ft ·&gt; · · ·· ftft ···· ftft ·· ···· ·· • · ·· • ft · · ···

Subjects having 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 that is effective to provide SVR in at least 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). 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 involves administering the at least two DAAs to a subject infected with HCV. Treatment does not include administering interferon or ribavirin. 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. 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 naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a null responder, a partial responder, or a relapser), or

8/223 _ ·· ·· * ········· ·· • · · · - y · - · · • · · · 9 · 9 · 9Ο • · · β »« · «· .

·» ·· ·· · ·. ..

may be a non-candidate for interferon treatment.

In another aspect, the present technology provides a combination of Compound 1 (or a pharmaceutically acceptable salt thereof) and Compound 2 (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 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 the treatment can also - for example last for no more than eight weeks (for example the duration is 8 weeks; or the weeks)

Duration is 7, 6, 5, 4 or 3 not the administration of or any other

Ritonavir for example compound 2

Treatment includes interferon or ribavirin. CYP3A4 inhibitor (for example

Cobicistat) is administered with Compound 1 (or a salt 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 daily). As yet another example, Compound 1 (or the salt thereof) coformulated with ritonavir (or another CYP3A4 inhibitor, cobicistat) is administered once daily (or the salt thereof). As a non-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 may be administered; and twice a day

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-93 be 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 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 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, treatment lasts for 9 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 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 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, 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 being treated 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 another example, treatment lasts for 11 weeks and the treated subject 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, it lasts

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-10 treatment 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 again In 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 yet another example, the 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, the treatment lasts for 8 weeks, and the subject being treated is a non-responder (e.g. a null responder) infected with HCV genotype 1.

In another aspect, the present technology features a combination of Compound I (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 does not include administration of interferon or ribavirin. Ritonavir or another CYP3A4 inhibitor (e.g. cobicistat) is administered with compound 1 (or the salt thereof) to improve the pharmacokinetics of the latter. Connection 1

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-11 (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 daily along with ritonavir or another CYP3A4 inhibitor (e.g. cobicistat) and Compound 3 (or the salt thereof) can be administered twice daily. 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 daily). As in turn one are compound 1 (or that another CYP3A4 inhibitor,

Compound 3 (or the salt thereof) is co-formulated in a single composition and administered concurrently (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., or may not be a candidate. 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 For example, the treatment lasts for 10 weeks and the treated subject is a naive patient infected with HCV genotype 1. In yet another example, treatment lasts for 9 weeks and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, it lasts

Salt thereof) for example ritonavir (or cobicistat), and a null responder), interferon treatment for one lasts for example

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-12·· ··

Treatment 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, lasts treatment for 11 weeks 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, 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 being 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 being 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, 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, 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 yet another example, treatment lasts for 9 weeks and the subject being treated is a

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-13Non-responders (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 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 doesn't include that

Administration of interferon or ribavirin. 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 a day, along with ritonavir or another CYP3A4 inhibitor (e.g. cobicistat), and Compound 4 (or the salt thereof) can be administered twice a day. 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 a day). As yet another example are compound 1 (or the salt thereof), ritonavir (or another CYP3A4 inhibitor, for example cobicistat), and / 223 • ·

-14 Compound 4 (or the salt thereof) co-formulated in a single composition 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 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 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, 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, treatment lasts for 8 weeks and the subject treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment continues for 12 weeks, and that

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-15 treated subject is a non-responder (e.g. null responder) infected with HCV genotype 1. In another example, treatment lasts for 11 weeks and the 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 subject treated 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 treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks, and the subject being 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 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 does not include administration of interferon or ribavirin. Ritonavir or another CYP3A4 inhibitor (e.g. cobicistat) is administered with compound 1 (or its salt) 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 a CYP3A416 / 223

-16• · • · · · · · • · · · · · • · · · · · · ·· · · · · · · · · ·

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 administered twice a day. As another example, Compound 1 (or the salt thereof), Compound 4 (or the salt thereof) and ritonavir (or another CYP3A4 inhibitor, e.g., cobicistat) are co-formulated in a single composition and simultaneously (e.g., 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 (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 no 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 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, treatment lasts for 9 weeks and the subject treated 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 HCV17 / 223

-17Genotype 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, 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 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 being treated is a non-responder (e.g., a null responder) infected with

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-18• ··· • · • · · · · · • · · · · · • · · · · · • ·· ·· ·· · ·· · ·· ·* ·· · ·· ··

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:

<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>

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

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

PSI-7977 and PSI-938,

BMS-790052 and BMS-650032, GS-5885 and GS-9451,

GS-5885, GS-9190 and GS-9451, BI-201335 and BI-27127, Telaprevir and VX-222, PSI-7977 and TMC-435 and 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 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 does not include administration of interferon or ribavirin. 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

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-19• ·· ·· · · · ·· · ·· ·· ·· · ·· ··

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, or no candidate for interferon treatment.

In yet another aspect, the present technology provides 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>PSI-7977 and BMS-790052</td>

<td>a</td><td>combination</td><td>out</td><td>PSI-7977 and BMS-650032,</td>

<td>a</td><td>combination</td><td>out</td><td>PSI-7977, BMS-790052 and BMS-650032,</td>

<td>a</td><td>combination</td><td>out</td><td>INX-189 and BMS-790052</td>

<td>a</td><td>combination</td><td>out</td><td>INX-189 and BMS-650032 or</td>

<td>a</td><td>combination</td><td>out</td><td>INX-189, BMS-790052 and BMS-650032.</td>

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 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 does not include administration of interferon or ribavirin. Treatment may include administration of ritonavir or another CYP3A4 inhibitor (for example, 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, 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 become / 223

-20 ·· ·· ···· ···· ···· • · · · · · · · · · · · · ···· • · · · · · · · · · · · ft · · ·· · ·· ·· ·· · ·· ·· 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 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 involves 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, 10, 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 does not include the administration of either inerferon or ribavirin. 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 and will be co-formulated into a single composition

21/223

-21 ···· ···· ···· ·· • · · · • · · ··· • · · 9 · ·· ·· ·· · ·· ·· simultaneously (for example administered 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

Treatment can be a combination of PSI-7977 and GS-5885 CYP3A4 inhibitor.

Treatment involves 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, 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 doesn't include that

Administering either interferon or ribavirin. Which include giving ritonavir or a (e.g. cobicistat) if any of the DAAs are in need of pharmacokinetic augmentation. 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 / 223

-22·· ···· ··«· ···· ·· • ·» ·· ·· · ·· · • · *· ·* · · · ··

For 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, 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 does not include administering interferon or ribavirin. 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 another example, the two are / 223

-23DAAs co-f 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 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 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 does not include administering either interferon or ribavirin. Treatment may include administration of ritonavir or another CYP3A4 inhibitor (for example, cobicistat) if any of the DAAs require pharmacokinetic enhancement. Two DAAs can be given at the same time or one after the other. 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, patient / 223

-24 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 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 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 continues for 10 weeks and the subject treated is a naive patient infected with / 223

-25HCV genotype 3. In yet another example, the treatment lasts for 9 weeks and the subject treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 8 weeks, and that treated subject 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 another example, the treatment lasts for 9 weeks and the treated subject is a non-responder (e.g. a null responder) infected with HCV genotype 1. In 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 features a combination of PSI-7977 and TMC-435 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 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 does not include administering either interferon or ribavirin. 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 / 223

<img file="AT514002A2_D0001.tif" />

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 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 being treated 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 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 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, / 223 lasts

<img file="AT514002A2_D0002.tif" />

···· ···· ···· ·· • · · · • ·

<img file="AT514002A2_D0003.tif" />

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, 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 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, 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 yet another aspect, the present technology features 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. The / 223 • ·

<img file="AT514002A2_D0004.tif" />

Treatment does not include administration of either interferon or ribavirin. 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 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 not a candidate for interferon treatment. In one example, treatment continues for 16 weeks and the subject being 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 being treated 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 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 HCV29 / 223 • ·

<img file="AT514002A2_D0005.tif" />

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, the treatment lasts for 8 weeks and the treated subject 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 continues 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 treated subject is a naive patient infected with HCV genotype 3. In yet another example, treatment lasts for 16 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 15 weeks and the subject being treated is a non-responder (e.g. a null responder) infected with HCV geno type 1. In yet another example, treatment lasts for 14 weeks, and that treated subject is a non-responder (eg 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 (eg a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a non-responder (eg a null responder) infected with HCV genotype 1.

In yet another aspect, the present technology offers a combination of INX-189, Daclatasvir and BMS30 / 223 •

-30 • • • • • • 1 • • • • • • • des (to

791325 for use in the treatment of HCV infection. Treatment involves administering the DAA combination to a subject infected with HCV. The Dauei treatment regimen is no more than sixteen weeks

Example is the duration 16 weeks; or the duration is 14, 12 or

Weeks). The duration of the treatment regimen can also be less than 10 weeks. Treatment doesn't include that

Administering either interferon or ribavirin. The

Treatment can include administering

Include ritonavir or another CYP3A4 inhibitor (for example, cobicistat) if any of the DAAs are required. The two are administered.

pharmacokinetic enhancement DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once daily and the other DAA can be administered twice daily. 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 one example, treatment lasts 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

31/223

-31·· ·· • · · « • · · « » · · · » · · · ·· ·· ¹ · · · · · · · · · · ···. · · · • · · «·· ·· 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 that 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, 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 subject being treated is a naive patient infected with HCV genotype 3. In another example, treatment lasts for 15 weeks and the subject being treated is a naive patient, infected with HCV genotype 3. In yet another example, treatment continues for 14 weeks and the subject 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, treatment lasts for 16 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 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 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 13 weeks and that / 223

-32···· ···· _{Mte ee}¹ · · &lt; ·· ·· • ··· • · « • · «

Treatment does not include interferon or ribavirin treated subject is a non-responder (for example, a null responder) infected with HCV genotype 1. In yet another example, treatment lasts for 12 weeks and the 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 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. The administering of a. The treatment

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 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 may be infected with 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 non-responder (e.g., a no-candidate either can and become daily at the same time). As a not

Patient, an interferon null responder), or for a

Interferon treatment. In one example, treatment lasts for 16 weeks and the subject being treated is a naive patient infected with HCV genotype 1. In another example, treatment lasts for 15 weeks and the treated / 223

-33&gt; ··· ···· I, • · ·

».-·· ·· · · ·· ·· ·· ·

The 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, treatment lasts for 13 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 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, 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, 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 being treated is a naive patient , infected with HCV genotype 3. In yet another example, treatment lasts for 16 weeks and the subject treated is a non-responder (e.g. a null responder) infected with HCV genotype 1. In another example, the treatment lasts for 15 weeks, / 223

-34 • · • · &lt;·· ·· * ·· ···· · «» ··· • · «• · I and the treated subject is a non-responder (for example 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, 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 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 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 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). The

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 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 / 223 ···· ···· ····

-35Patient 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, treatment lasts for 9 weeks and the subject treated 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 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 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 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 / 223

-36·..··.···:········ ·· :: : ·. .· . · · ·. :: · * · ·· ·· ··

...........

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

In another aspect, the present invention features methods of treating HCV infection, wherein the methods include, and the treatment does not include, administering at least two direct acting antiviral agents (DAAs) to a subject in need thereof

Administration of either interferon or ribavirin to the subject. Treatment can, for example, and without

Restriction lasts 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 an HCV 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 Ia. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

/ 223

I «···

-37 • ·· • · ··· • · · • · · • Φ ·&gt; »· ··

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-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 Ia. 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) 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 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 Ia. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In another embodiment of this aspect of this

38/223

In the 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 includes 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 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 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 protease inhibitor and an 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. 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 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 protease inhibitor and a non-nucleoside or non-nucleotide HCV polymerase inhibitor. The treatment can, for example and without limitation, for no more than 12 weeks / 223

-39 • ft

The subject can be, or an ongoing, 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-responder (for example a null responder). Preferably the treated subject is infected with HCV genotype 1, for example 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 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 treated subject is infected with HCV genotype 1, for example 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 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. The treated subject can, for example, be a treatment-naive patient as well as a treatment-experienced patient

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

The subject can be, or a / 223

-40 The subject can be, or one 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. For example, the subject being treated may be a treatment-naive patient.

also an experienced patient

Interferon non-responder (for example a null responder). Preferably the treated subject is infected with HCV genotype 1, for example 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 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

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 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 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. The subject being treated can also be a treatment 41/223, for example

-41 • Be a 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 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 PSI-7977 and TMC-435. 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 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 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 TMC-435 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 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 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 the / 223 ·· ·· ···· ···· ···· ·· ··· · · ··

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 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 PSI-7977 and GS5885. 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 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 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. 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 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 BMS-790052 and BMS-650032. The treatment can be for example and without / 223

-43 Restriction lasts 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

For example, the subject can be a. The subject may be a patient experienced in treatment, or an Interferon NonResponder (e.g. a null responder). Preferably the treated subject is infected with HCV genotype 1, for example HCV genotype Ia. 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 to the patient an effective amount of PSI-7977, and treatment does not include administration of either Interferon or ribavirin to the subject. 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 subject being treated is a naive patient infected with genotype 1.

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-44• · · · · · ···· ···· ·· ··· • · · ·· ·· · ·· · • · ·· · · · ·· ··

The subject being treated may also be a treatment-experienced patient or an interferon non-responder (e.g., a null responder) and / or infected with HCV genotype 3. In one example, treatment lasts 12 weeks and the subject being treated is a naive patient infected with genotype

1. In another example, the treatment lasts 11 weeks and the treated subject is a naive patient infected with genotype 1. In yet another example, the treatment lasts 10 weeks and the treated subject is a naive patient infected with genotype 1. In yet another example the treatment lasts 9 weeks and the treated subject is a naive patient infected with genotype 1. In yet another example, the treatment is 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 included in this aspect of the Invention is described.

In yet another aspect, the present invention features methods of treating HCV infection, wherein the methods comprise administering at least two DAAs to a subject in need thereof for a duration sufficient to cause a sustained virological response achieve. Treatment does not include the administration of interferon or ribavirin. 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. Preferably, any treatment or use described herein does not include a subsequent ribavirin-containing treatment.

Other Features, Objects, and Advantages of the Present / 223

Invention will be apparent from the following detailed description. It should be understood, however, that the detailed description, while showing preferred embodiments of the invention, is presented 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

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

Figure 4 is a contour map showing concentrations at which Compound 1 and Compound 4 exhibited synergistic, additive, or antagonistic interactions in the genotype Ib HCV replicon assay.

FIG. 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.

/ 223 _r · · · · · · ·· - 4 ο ^— · · · · · · · · · · • · · · ·· ··· • ·· ·· ·· · ·· · ·· ·· ·· · ·· ··

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.

FIG. 5D shows the effect of compound 1, compound 4 and a combination thereof in long-term HCV RNA reduction assays in lb-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 versus the percentage of subjects observed with HCV RNA less than LOD over time in a clinical study.

Figure 8 demonstrates the predicted exposure-response model versus the percentage of subjects observed with SVR12 in another clinical study.

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.

Figure 11 shows the predicted median value and 90% confidence interval of the SVR percentage for various / 223 • · · ·· · · · ·· · ·· ·· ·· · ·· ··

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 Daclatasvis (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 different 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 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 + GS5885 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 1/223

-48• · · · · · • · · · · · • · · · · · • ·· · · · · · · · · ·· ·· ·· · ·· ··

<img file="AT514002A2_D0006.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 incorporated herein by reference in their 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 amount 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 the therapeutic / 223

-49I ·· »··· ···· ···· ·· • · · · · · · ··· · · · · · • · · · · · ·« ·· ··

Active ingredient 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.

<img file="AT514002A2_D0007.tif" />

Connection 2

Compound 2 is also known as N- (6- (3-tert-butyl-5 (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2methoxyphenyl) naphthalen-2-yl) 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 solvate, 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. WO2009 / 039127, which is incorporated herein by reference.

The therapeutic agent 2 can be administered as a free acid, a salt or a specific 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, therapeutic agent 2 can be used in a total daily / 223

50• 4 ·« ► · · ·

B «·» »· · ·» · · * «·· · * • · ·« 4 · · ·· 4 4 4 4 • · · 9 • · · 44 »• · · · 4 • · 4 4 4 4

4 ·· ··

Dose amounts of from about 300 mg to about 1800 mg, or about 400 mg to about 1600 mg, or from about 600 mg to about 1600 mg, or any amounts 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.

<img file="AT514002A2_D0008.tif" />

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 compound 3, such as sodium salts, potassium salts and choline salts. 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 their salts. Compositions comprising the therapeutic agent 3 can be prepared as

51/223

<img file="AT514002A2_D0009.tif" />

• · • · described in for

Example of the 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 amount 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 (azanediyl) bis (oxomethylene) bis (pyrrolidine-2,152 / 223

-52f · φ · 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 amount 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 any amount in between. In some embodiments, the total daily dosage amount for therapeutic agent 4 is approximately 25 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-Alfacon-1 (Consensus

Interferon) (for example Intergen from 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,

Make patient compliance more difficult and lead to treatment interruption.

The interferon / ribavirin-based treatment may physically affect the early / 223

-53 ·· ♦ · is experienced. Side effects, at least independently, can be demanding and in some cases can lead to temporary disability. A significant proportion of patients will experience a range of side effects, ranging from a "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 for example, suicide or suicidal ideation. The latter are exacerbated by the general physiological stress that ribavirin possesses also a number of patients including anemia, high pill load (for

Example 5-6 pills a day Split BID) and the limitation of use due to teratogenicity in women of childbearing age.

The present methods provide effective treatment of HCV infection without the use of interferon or ribavirin 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 comprising administering at least two DAAs in the absence of interferon and ribavirin for a duration of no more than twelve weeks, alternatively no more than eight weeks. In other words, the present methods exclude interferon and ribavirin, or the subject does not receive interferon or ribavirin for the duration of treatment. The two DAAs can be co-administered or can be administered (at the same or different dosage frequencies) and can be administered once a day, alternatively twice a day, alternatively three times a day.

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-54···· · · · · _Λ• · · · · · · ··· ···· ·· ··· • ·· ·· ·· · ·· · «· ·· ·· · ·♦ ··

In some embodiments, include

Treatment method involves 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. Preferably, in the methods, at least two DAAs 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. 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 preferred is the virus at the end of therapy and for at least 16 weeks after the end of the / 223 • · • · • · ··· * ··· ·· ··

Therapy (SVR16) not detectable; 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 predictive of a high rate of SVR24. Similarly, a high rate of SVR less than 12 weeks after treatment (e.g., SVR4 or SVR8) can be predictive of a high rate of SVR12. A high rate of EOT (for 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 / or the duration of the treatment regimen of the two or more DAAs are effective to produce an RVR in a subject, or an EVR in a subject, or a cEVR in a subject, or an eRVR in a subject, or to provide an absence of detectable EOT in a subject. In some embodiments, the present methods include treating a population of subjects who have HCV infection (e.g., treatment-naive subjects), and the methods include administering at least two DAAs to the subjects for a period of no more than 12 weeks, or for any other duration disclosed herein wherein the at least two DAAs are administered to the subjects in amounts that are effective, to provide an SVR (for example SVR after 8 weeks after treatment, or SVR after 24 weeks after treatment) in at least 70% of the population, alternatively in at least 75% of the population, alternatively in at least 80% of the population, alternatively in at least 85% of the population, alternatively in at least 90% of the population, alternatively in at least 95% of the population, alternatively in at least 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 to the / 223

56 Subjects for a period of no more than 12 weeks or for any other period disclosed herein wherein the at least two DAAs are administered to the subjects in amounts effective to provide an SVR (e.g., SVR after 8 weeks after treatment, or SVR after 24 weeks after treatment) in at least about 50% of the population, alternatively in at least 55% of the population, alternatively in at least 60% of the population, alternatively in at least 65% of the population. In other embodiments, the amount of DAAs 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 population, alternatively in at least about 70% of the population, alternatively in at least about 75% of the population, alternatively in at least 80% of the population, alternatively in at least 85% of the population, alternatively in at least 90% of the population , alternatively in at least 95% of the population, alternatively in approximately 100% of the

Population.

To the

For example, the present methods involve administering to a subject at least two DAAs in amounts and for periods effective to provide an SVR (e.g., SVR at 8 weeks post treatment or SVR at 24 weeks post treatment). 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 at least about 55%^sPopulation, population, population, the population, in at least about 60^! preferably preferably preferably at least in at least about that of at least about 75^! treated such methods described herein

65%

70% of those by patients, more preferably in at least

80^! of the population and highest / 223

<img file="AT514002A2_D0010.tif" />

preferably in at least about 90% of the patients treated. In some embodiments, treatment of the present technology provides an RVR or undetectable level of HCV RNA in the bloodstream at (4) weeks of treatment (preferably 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 nucleotide polymerase inhibitor or a 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-7977 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 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 include 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-790052/223

<img file="AT514002A2_D0011.tif" />

·· ·· · ·· · · · · · ·· ·· (daclatasvir). In another example, the

Combination of two or more DAAs INX-189 and BMS-790052 (Daclatasvir) one. 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 TMC-435 and daclatasvir.

It was unexpected to be interferon-free and

Ribavirin-free treatment using a combination of two or more DAAs and for a duration of no more than 12 weeks can produce a 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 unexpected that interferon-free and ribavirin-free treatment using a combination of two or more DAAs and for a duration of no more than 12 weeks could achieve a significant SVR in interferon non-responders (e.g. null responders), for example, such treatment can achieve SVR in at least about 50% of patients in the interferon non-responder population, preferably at least about 60% of the patients in the interferon non-responder population, more preferably at least about 65% of the patients in the interferon non-responder population.

Accordingly, in one aspect, the present

Technology describes a method of treating HCV infection comprising administering to patients in need thereof an effective amount of a combination of two or more DAAs. Treatment lasts 8 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dose rates. The treated patient can / 223 in · · * · ·

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; or a patient unable to take interferon. The patient can 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 can be co-formulated in different or formulated in different. Each DAA can be selected from protease inhibitors, HCV polymerase inhibitors, or 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, that of an individual

Compositions of HCVHCV NS5A times, and formulation or from one

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 / 223 • · · • · · · · • · · · • · · · · • ·· ·· 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 (e.g., 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 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).

61/223

J- - · · · · · · · -pl · - · · · · ···

Compound 1 can be co-formulated with ritonavir. In yet another example of this aspect of the technology, 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 R712 8. 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 nd BMS650032 (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 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 excludes / 223

2-0 · · -f²r:

• · · · »· · ·· &lt;· • · · ·« ·· ·· two or more DAAs 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 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, rather than a combination of two or more DAAs. 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 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 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. Other DAAs can also be included in a treatment regimen according to this aspect of the technology. In each aspect, embodiment, and example of this application, 250 mg BID can be used for Compound 2 in place of 400 mg BID; it has unexpectedly been 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 so that 250 mg of compound 2 (or the salt) in the / 223

463-ί improved formulation are bioequivalent to 400 mg

Compound 2 (or the salt) in the original formulation.

In another aspect, the present technology provides a method of treating HCV comprising administering to a patient in need of an effective amount of a combination of two or more DAAs. Treatment lasts 7 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or a different dosage frequency. 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, an interferon non-responder (e.g., a null responder), or an incapable patient is to take interferon. The patient can 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 DAA can be around the same time or at different times

Times are administered and can be a single

Formulation co-formulated, 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 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 nucleotide 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 / 223 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 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 of at least one polymerase inhibitor and at least one NS5A inhibitor (for example, a combination of at least one HCV NS5A at least one

combination

HCV non-nucleoside 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-inhibitor and one or from

<td colspan="3">Polynucleoside polymerase inhibitor).</td><td>In</td><td>one</td><td>example</td><td>is</td>

<td>combination</td><td>from two or</td><td>more</td><td>DAAs</td><td>a</td><td colspan="2">combination</td>

<td>Connection 1</td><td>(or a salt</td><td>from that)</td><td>and</td><td colspan="2">Connection 2</td><td>(or</td>

<td>Salt thereof).</td><td>Connection 1</td><td>(or</td><td>a</td><td>salt</td><td>from that)</td><td>can</td>

from being 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 or co-administered with ritonavir. In yet another example, the combination of two or more is / 223

<img file="AT514002A2_D0012.tif" />

···· · · ··

DAAs 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 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 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 includes or / 223

-566:-:

···· · · · I have more DAAs 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 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 includes the combination of two or more DAAs INX189, Daclatasvir and BMS-791325. In yet another

Example includes the combination of two or more DAAs PSI7977 and GS-5885. 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 to a patient in need thereof an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs. 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

Administer 100 or 150 mg of Compound 1 together with 100 mg of ritonavir once a day, and 400 mg of Compound 2 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, / 223 • · - · Ό / «“ · · «• · · ·

<td></td><td> • •</td><td> • · · ·</td><td> • · ·</td><td> • •</td><td></td>

<td>and 400</td><td>mg of compound 3 twice</td><td>Every day.</td><td>Other</td><td>DAAs</td><td>can also</td>

<td>in a</td><td>Treatment regimen according to</td><td>this</td><td>aspect</td><td>the</td><td>technology</td>

<td colspan="2">be included.</td><td></td><td></td><td></td><td></td>

<td>In</td><td>yet another</td><td>aspect</td><td>offers</td><td>the</td><td>present</td>

Technology discloses a method of treating HCV comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs. Treatment lasts 6 weeks and does not include administration of any interferon or ribavirin. 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 an incapable patient Taking interferon. The patient can 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 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 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 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 / 223

-it:-:

···· · · ··· • ·· ·· ·· · ·· ·

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 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 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 / 223

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 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 &lt;</td>

<td>two or</td><td>more DAAs</td><td colspan="2">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>

BMS-650032 one more

In one more

In another / 223 ·· ·· ···· ···· ···· ··

<img file="AT514002A2_D0013.tif" />

• Another example includes the combination of two or more DAAs INX-189, BMS-650032 (asunaprevir) 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 includes two or more

<td>DAAs mericitabine</td><td>and</td><td>Danoprevir</td><td>a</td><td>. In</td><td>still</td><td>another</td>

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

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

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

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

the combination of two or more DAAs PSI-7 977, Compound 1 (with ritonavir) and Compound 4. In yet another example, the method includes administration to one

Patients in need of an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs. 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 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

71/223 • gi »· · · 9 99“ »/ · · · · · · · · · · · ·· · 9 &lt;

Compound 3 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 comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs. Treatment lasts 5 weeks and does not include administration of any interferon or ribavirin. The DAAs can use the same or

Dosage frequency administered can be a treatment-naïve patient different from the treated patient, a treatment-experienced patient including, but not limited to

Interferon responder, or (for example, a

Nucleoside combination a relapser, a partial interferon non-responder null responder), or a patient who is unable to take interferon. The patient can 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 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 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 polymerase inhibitor. As another example, the combination of two or more / 223 • ν θ · · · · · ·· - · / Ζ · · · · · ····

DAAs 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 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 be a combination of a polymerase inhibitor and at least one HCV 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

Combination of two or more one example, the 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 a salt thereof). Compound 1 (or a salt thereof) can be coformulated with ritonavir. In yet another / 223

-:73:-:

ft · »· 4 • ·

For 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-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 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 the two

<td>or</td><td>more DAAs</td><td>PSI-7977</td><td>and</td><td>BMS-790052</td><td>a.</td><td>In</td><td>still</td><td>one</td>

<td colspan="2">another 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</td><td colspan="3">PSI-7977 and BMS-650032</td><td>(Asunaprevir)</td><td>a.</td><td>In</td><td>still</td><td>one</td>

<td colspan="2">another example</td><td>closes</td><td>the</td><td>combination</td><td>out</td><td>two</td><td>or</td><td>more</td>

DAAs PSI-7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs INX-189 and BMS-790052/223 • · · · ············ ·· • -7 / 9 · · · · · · »/ ~&gt;“ · · · · · ···

--- · · · · (daclatasvir) a. In yet another example, the combination of two or more DAAs includes INX-18 9 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 includes two or more

DAAs INX-189 and BMS-650032 (asunaprevir). In yet another example, the combination includes two or 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-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 thereof an effective amount of PSI-7977 as the single DAA rather than a combination of two or more DAAs. In yet another example, the method comprises administering 100 or 200 mg of Compound 1, 100 mg ritonavir once daily, and 25 mg 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 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 together with compound 4/223

- • 7 R * - · · · / -&gt; ·· · • · • ·· • · 4

The patient being treated may be a treatment nucleoside combination 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. 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 comprising administering to a patient in need thereof an effective amount of a combination of at least two or more DAAs. Treatment lasts 4 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or a different dosage frequency.

A treatment-naive patient can be an 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 unable to take interferon. The patient can 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 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 one HCV- Protease inhibitor and at least one nucleotide polymerase inhibitor or at least one HCV protease inhibitor, or from at least one nucleoside or nucleotide polymerase inhibitor / 223 «4 44 · 4 444444:

-17 6:-: : .· .·

4 4 4 4 4 • 4 4 4 4 4 4

44 44 4 »444 44

4

444 » 4 » 4 4 4

44 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 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 a

Be a combination of two 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 further example, the DAAs can be a combination of

DAAs be a combination of a polymerase inhibitor and at least one HCV-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 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-nucleotide 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

Non-nucleoside compound 1 (or a salt thereof) and compound 3 (or / 223

-ΊΊ • ·· of 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 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-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).

/ 223

<img file="AT514002A2_D0014.tif" />

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

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

more DAAs INX-189, BMS-650032 (asunaprevir) 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 includes two or more

DAAs mericitabine and danoprevir. In yet another

Example includes the combination of two or more DAAs INX189, Daclatasvir and BMS-791325. In yet another

Example includes the combination of two or more DAAs PSI7977 and GS-5885. 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 includes administration to one

Patients in need of an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs. 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 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 / 223

-79 and 400 mg of compound 2 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. 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 comprising administering to a patient in need of an effective amount of a combination of two or more DAAs. Treatment lasts 3 weeks (or even less, depending on the patient's condition) and does not include the administration of any interferon or ribavirin. The DAAs can be administered at the same or a different dosage frequency. 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 a patient incapable of interferon to take. The patient can 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 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 / 223

-80• · ·

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 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 or nucleotide 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 HCV NS5A inhibitor (e.g., 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 with

81/223

-81 ritonavir be co-formulated. 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). V Getting Connected 1 (or 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) and Compound 4 (or Compound 1 (or a salt thereof) may be a salt thereof) 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 one

Salt thereof) and compound compound ritonavir.

(or a salt thereof). 1 (or a salt thereof) can be co-formulated with 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 ritonavir (or a salt thereof) can be co-formulated with 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-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 includes / 223

-82 from two or more DAAs danoprevir with ritonavir and R712 8 one. 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 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 the INX-189 and BMS-650032

In yet another example, the one or more (asunaprevir) precludes a combination

DAAs two (asunaprevir) and BMS-790052 (daclatasvir)

INX-189, BMS-650032 a. 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 INS-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 INS-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 PSI-7977, Compound 1 (with ritonavir) and Compound 4. In yet another example, the method comprises administering to a patient in need thereof an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs. 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 includes administering 150 mg / 223

-83*··* *··**··*· · · · ·

Compound 1 together with 100 mg ritonavir once daily and 400 mg 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. 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 comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs. Treatment lasts 24 weeks and does not include administration of any interferon or ritonavir. The DAAs can be administered at the same or a different dosage frequency. 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, 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 / 223

-84 or more DAAs 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

Non-nucleoside of at least one

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 (e.g., 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, 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 HCV 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 85/223

-85 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 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-4951. In yet another example / 223 ·· ·········· "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>(Asunaprevir) and</td><td>BMS-790052</td><td>(Daclatasvir)</td><td>a</td><td>. In</td>

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

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

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

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

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

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

BMS-650032 one more or more one or more one or more

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 an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs. 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 together with / 223

-87• · · · ·« • · · »· ···· «··· ·· • · · · ► · · ·· · • · · · &lt;

mg of compound 4 once twice a day. In one

100 mg ritonavir once daily, daily and 400 mg compound 2 Another example, the method involves administering 100 or 150 mg compound 1 along with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg compound 3 twice daily. 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 comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs. 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 or Ribavirin a. The DAAs can be administered at 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 the Able to take interferon. The patient can 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 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 protease inhibitor and at least one non-nucleoside88/223

-88·· ·· ······«··»·· ·· · · ·· ··· 9 9 · · ··&lt;

···· ·· · · · * ·· · · ·· · · · ·

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 from 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 a further example, the combination of two or more DAAs can be a combination of at least one HCV polymerase inhibitor and at least one HCV 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 / 223

-89 of 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 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 / 223 closes

-90 Combination of two (asunaprevir) one. In yet another example or more DAAs PSI-7977 and BMS-650032 the

<td>combination of</td><td>two or</td><td colspan="3">more DAAs PSI-7 97 7,</td>

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

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

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

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

<td>DAAs INX-189 and</td><td>BMS-650032</td><td>(Asunaprevir)</td><td>a</td><td>. In</td>

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

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

BMS-650032 one more or more one or more one or more

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 thereof an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs. 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 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 involves administering 100 or 150 mg of Compound 1 along with 100 mg of ritonavir once

91/223

91 protease inhibitor daily, 25 mg of compound 4 once daily, and 400 mg of compound 3 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 comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs. Treatment lasts for 12 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at 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, or an interferon non-responder (e.g., a null responder), or an incapable patient Taking 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 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 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 (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 polymerase inhibitor). As another / 223

-92ft

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 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 HCVNS5A inhibitor. As another example, the

Combination of two or 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 one or more 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 DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV 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

combination of

Polymerase inhibitors). Combination of two 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 another / 223

In 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-7 977 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 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

<td>combination</td><td>out</td><td>two or</td><td>more DAAs</td><td colspan="2">PSI-7977,</td><td>BMS-i</td>

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

<td colspan="2">another example</td><td>closes the</td><td>combination</td><td>out</td><td>two</td><td>or</td>

<td>DAAs INX-189</td><td>and</td><td>BMS-650032</td><td>(Daclatasvir)</td><td>a.</td><td>In</td><td>still</td>

/ 223

<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 colspan="2">DAAs INX-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><td>more</td>

<td>DAAs</td><td>INX-189,</td><td colspan="2">BMS-650032</td><td>(Asunaprevir)</td><td> 1</td><td>and</td><td colspan="2">BMS-790052</td>

(Daclatasvir) a. 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 includes the combination of two or more DAAs INX189, Daclatasvir and BMS-791325. In yet another

Example includes the combination of two or more DAAs PSI7977 and GS-5885. 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 to a patient in need thereof an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs. 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 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 includes administering 100/223

-95 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 3 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 comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs. Treatment lasts 11 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or a different dosage frequency to a treatment-naïve patient 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 who is unable to take interferon may be infected with, for example and

Restriction, 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,

Polymerase inhibitors or HCV NS5A inhibitors. For one, 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 be the patient being treated, a treatment the one without

HCV example a / 223

-96 • ·· ·· ·· · ·· ·· Φ · ·· · ·· ··

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 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 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 HCV 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 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 / 223

-97• · · · · · • 9 · · · · • · · · 9 9 • 9 9 · · · ·

99 ·· 9

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-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 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-7 90052. 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 / 223 closes

<td>combination</td><td>out</td><td>two</td><td>or</td><td>more</td>

<td>(Daclatasvir)</td><td>a</td><td>. In</td><td>still</td><td>one</td>

<td>combination</td><td>out</td><td>two</td><td>or</td><td>more</td>

<td>(Asunaprevir)</td><td>a</td><td>. In</td><td>still</td><td>one</td>

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

DAAs INX-189 and BMS-790052 another example excludes the DAAs INX-189 and BMS-650032 another example excludes the

Combination of (Asunaprevir) and other example DAAs INX-18 9 and other example DAAs INX-189,

<td>two or</td><td>more DAAs</td><td>INX-189,</td>

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

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

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

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

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

BMS-650032 one or more one or more BMS-790052 (daclatasvir) one. 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 PSI7977, Compound 1 (with ritonavir) and Compound 4. In yet another example, the method comprises administering to a patient in need thereof an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs. 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 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 a / 223 • · • · • ·

Another example, the method involves the administration of 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. 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 comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs. Treatment lasts 10 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or a different dosage frequency. 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 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 one or nucleotide polymerase inhibitor, or one of at least one HCV protease inhibitor,

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-100 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 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 protease inhibitor and at least one HCV NS5A inhibitor (e.g., a combination of at least one HCV NS5A inhibitor, at least one non-nucleoside polymerase inhibitor, or a combination of 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 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 and one and

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-101·· ·· ·· ··

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 (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 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-7 90052. 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

102 / 223 ·· ···· ···· ···· ·· ···· · · ·· • · · · · · ···· ···· ·· ·«· • · · ·· ·· · ·· · ·· ·· ·· · · · ··

-102

<td>combination</td><td>out</td><td>two</td><td>or</td><td>more</td>

<td>(Daclatasvir)</td><td>a</td><td>. In</td><td>still</td><td>one</td>

<td>combination</td><td>out</td><td>two</td><td>or</td><td>more</td>

<td>(Asunaprevir)</td><td>a</td><td>. In</td><td>still</td><td>one</td>

DAAs INX-189 and BMS-790052 another example excludes the DAAs INX-189 and BMS-650032 another example excludes the

<td>combination of</td><td>two or</td><td>more DAAs</td><td>INX</td><td> 189,</td>

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

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

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

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

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

BMS-650032 one or more one or more BMS-790052 (daclatasvir) one. 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-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 thereof an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs. 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 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 ml of ritonavir once daily, 25 mg of Compound 4 once daily, and 400 mg of Compound 2 twice daily. In one

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-103► ♦ ···· ···· ···· ·· • · · · · • · · · ··· • · · · · «·· Another example, the method includes administering 100 or 150 mg Compound 1 along with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg compound 3 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 comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs. Treatment lasts 9 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or a different dosage frequency. The patient being treated may be a treatment-naïve patient, a treatment-savvy patient, including, but not limited to, a relapser, or a partial interferon responder, or an interferon non-responder (e.g., a null responder), or a patient who unable to take interferon patient may be infected with, for example and

Restriction, 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 and at least one or nucleotide polymerase inhibitor, or one of at least one HCV protease inhibitor,

The one without

Nucleoside combination

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-104 • · • ··· • · 4 • t «» ·· ··

example

Inhibitor of 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 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 HCV NS5A inhibitor (for the combination of at least one HCV NS5A, 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 one and

105 / 223 ► · · · · · ·

-105ft of 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 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-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

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-106 (asunaprevir) one, combination of (daclatasvir) one. 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 the INX-189 and BMS-650032

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

DAAs INX-189 and BMS-650032 (asunaprevir). In yet another example, the combination includes two or 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 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 thereof an effective amount of PSI-7977 as the single DAA instead of a combination of two or more DAAs. 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 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

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-107 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. 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- and ribavirin-free treatment comprising the daily administration of two DAAs, wherein the two DAAs include an HCV polymerase inhibitor, for example PSI-7977, and an NS5A inhibitor, for example BMS-790052, 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.

Viral infection in administering a polymerase inhibitor to a subject comprising the daily HCV protease inhibitor and an HCV to the subject in the absence of

Interferon and ribavirin 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 excludes administering ritonavir to the patient. In some embodiments, the HCV polymerase inhibitor is at least one nucleoside or nucleotide or at least one non-nucleoside. 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 a patient experienced in treatment. Treatment-experienced patients include Interferon NonResponders (for example null responders) partially responders (patients whose HCV-RNA levels have decreased, but never

Polymerase inhibitor polymerase inhibitor.

108 / 223

-108 became detectable) reached undetectable levels , but technology is available to treat patients and relapsers (patients who relapsed from HCV-RNA during therapy). Procedures of the can also be used to identify the non-candidates for a

risk

Ingestion

Are interferon treatment. 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 they prevent interferon from taking, and patients who have an elevated level

Have side effects or an infection from the interferon.

In some embodiments, a cytochrome P-450 inhibitor, e.g., ritonavir, is administered in either the same or a separate pharmaceutical composition with the protease inhibitor (e.g., Compound 1 (or a pharmaceutically acceptable salt thereof)) to improve pharmacokinetics. A cytochrome P-450 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 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, sequentially or simultaneously, in the same different compositions. In

In embodiments, the cytochrome P450s are administered to improve the pharmacokinetics of at least one of the DAAs. It is unrelated to for either or in some inhibitors

109 / 223

-109 ·· ·· ·· · ·· ·· Any theory, but a cytochrome P450 inhibitor could also decrease the development of resistant strains of HCV when co-administered with a DAA, thereby providing efficacy in a shorter treatment becomes. 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 in a treatment run of no more than, or less than eight weeks in the absence of interferon and ritonavir . 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 and ritonavir, the method comprising administering at least two DAAs 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 HCV polymerase inhibitor is 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 and ribavirin, the method comprising administering an HCV protease inhibitor, preferably therapeutic agent 1, with at least one HCV NS5A inhibitor to a patient that one such

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-110Treatment 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 and ribavirin, the method comprising administering at least three DAAs to a subject for no more than eight weeks without administering interferon or ribavirin. 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), VBY708 (Virobay), VX-500 (Vertex), VX-813 (Vertex), VX-985 (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 HCV111 / 223

-111Polymerase inhibitors include: ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS791325 (BMS), Filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS9669 (Gilead), 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 or nucleotide polymerase inhibitor such as GS-6620 (Gilead), IDX-102 (Idenix), IDX-184

MK-0608

RG7128 (Idenix), INX-189 (Inhibitex), (Merck), PSI-7977 (Pharmasset), PSI-938 (Pharmasset), (Roche), TMC64912 (Medivir), ALS-2200 (Alios BioPharma / Vertex),

ALS-2158 (Alios BioPharma / Vertex) or a combination thereof. A polymerase inhibitor can also be a non-nucleoside polymerase inhibitor 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 limited to, Therapeutic Agent 4, BMS-790052 (BMS) (Gilead). Non-limiting examples of 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 these a.

Non-limiting examples of suitable ones

Cyclophilin inhibitors include alisporovir (Novartis &amp; Debiopharm), NM-811 (Novartis), SCY-635 (Scynexis) or any and GS-5885 suitable

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-112• ·

Combination of these a.

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 (Idenix, protease inhibitor), VX-813 (Vertex), SCH 900518 (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 (Intermune / Roche) (protease inhibitor) protease inhibitor), (Gilead), BMS-790052 (BMS), CTS-1027 (Gilead), PF-4878691 (Pfizer), RO5303253 (Alios BioPharma / Vertex), ALS-2158 (Alios (GlaxoSmithKline) or offers the present

GSK62336805

Ingelheim), GS-9190 (Conatus), GS-9620 (Roche), ALS-2200 BioPharma / Vertex), any combinations thereof.

In some embodiments

Technology Process for treating patients with genotype 1, such as la or lb, HCV infection. The methods include administering to such patient a combination of at least 2 DAAs for no more than 12 weeks (e.g. the duration is 12 weeks), preferably no more than 8 weeks (e.g. the duration 8 weeks), wherein the treatment is not includes administration of interferon or ribavirin. Patients with genotype 1, such as Ia or Ib, infection can be treated with a combination of at least two DAAs without interferon and without ribavirin, wherein the at least two DAAs include therapeutic agent 1 and therapeutic agent 2. The therapeutic agent 1 and the therapeutic agent 2 can in

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-113 therapeutically effective amounts can be administered to provide an SVR (for example an SVR8, SVR12, SVR16 or SVR24) after a treatment duration of not more than 12 weeks (for example the duration is 12 weeks), preferably not more than 8 weeks (for Example is the duration 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 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 1000 mg, about 1500 mg, or 1800 mg. 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, if the treatment regimen of the present technology does not provide the desired SVR after treatments for no more than 12 weeks, the patient can be treated with a ribavirin-containing regimen.

therapeutic agent are administered. The

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In some embodiments, the present technology provides methods of treating patients with genotype 2 or 3 HCV infection. The methods comprise administering to such a patient a combination of at least two DAAs 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), in which the treatment does not include administering interferon or ribavirin. Patients with genotype 2 or 3 HCV infection can be treated with a combination of at least two DAAs without interferon and without ribavirin, wherein the at least two DAAs include therapeutic agent 1 and therapeutic agent 2. The therapeutic agent 1 and the therapeutic agent 2 can be administered in therapeutically effective amounts to provide an SVR (for example an SVR8, SVR12, SVR16 or SVR24) with a treatment duration of no more than 12 weeks (for example the duration is 12 weeks ), preferably no more than 8 weeks (for example, the duration is 8 weeks). The 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, 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, 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 used in connection with the therapeutic agent 1 in each of the dosages of therapeutic agent 1, which are described above,

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-115 per day. To be administered in treatment regimen. 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. 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. Some embodiments, if the present technology does not provide the desired SVR after treatments for no more than 12 weeks, the patient may be given a ribavirin -containing regimes are treated.

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 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), in which the treatment does not include administration of interferon or ribavirin. The combination comprises the therapeutic agent 1 and the therapeutic agent 2. In a suitable manner, the patient can be a treatment-naïve patient, a patient experienced in treatment 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

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-116 administered to anyone 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 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 mixed with the therapeutic agent 1 in the dosages that are 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 mg. In some embodiments, ritonavir can either be co-administered or administered separately with therapeutic agent. Suitable dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day. In some

Embodiments when the treatment regimen of the present technology does not achieve the desired SVR after a

Providing treatment duration of no more than 12 weeks, the patient can be treated with a ribavirin-containing regimen.

In some embodiments, the present technology provides methods of treating patients with HCV infection who are non-candidates for one

Are interferon treatment. The procedures include that

To administer to such a patient a combination of

117/223 • · · ·· · ···· · ·· &lt;

117 at least two DAAs 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 or. Patients who are not candidates for interferon treatment include limited to one or more patients who are intolerant to interferon, patients who refuse to take interferon treatment, patients with medical conditions which prevent them from taking interferon, and patients who are elevated Risk for

Have side effects or an 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 a

Interferon treatment - Patients with a combination of at least two DAAs without interferon and without ribavirin are treated 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 weeks, or the duration is 8 weeks). DAAs include at least one HCV ribavirin for one, but are not of the following groups:

the duration is 12 at least two

A protease inhibitor and at least one HCV polymerase inhibitor. Suitable protease inhibitor

The at least one HCV can be therapeutic agent 1, and the at least one HCV polymerase inhibitor can be therapeutic agent 2. Therapeutic agent 1 and therapeutic agent 2 can be administered in therapeutically effective amounts to provide an SVR (e.g., an SVR8, SVR12, SVR16, or SVR24) after a

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-118 • · · · · · · · · · · · · ··· ···· ·· · · ··· ·· ·· ·· ·· «· ·· · ·· · · Duration of treatment 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 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. In some embodiments, if the treatment regimen of the present technology does not provide the desired SVR after treatments for no more than 12 weeks, the patient can be treated with a ribavirin-containing regimen.

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 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), in which the treatment does not include administration of interferon or ribavirin. The combination comprises the therapeutic agent 1, the therapeutic agent 2 and the therapeutic agent 4. In some embodiments, the patient is infected with HCV genotype 1, such as genotype la. 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

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-119 ·· ·· · * ······· «·· ·· * ··· · · · · · · · ·» »4 ··· • · · · · ·« l • · · · · ·· · · · ·

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, 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, the therapeutic agent 1 being 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 be used 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 approximately 5 mg to approximately 350 mg, preferably approximately 5 mg to approximately 300 mg, more preferably approximately 25 mg to about 200 mg can be provided. The total daily dosage of therapeutic agent 4 may or may not be

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-: ΐ 2ί ^ • · »·· · 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, in some embodiments, the patient may be a treatment naive patient, a treatment experienced patient, or an interferon non-responder. In some embodiments, if the treatment regimen of the present technology does not provide the desired SVR after 12 weeks of treatments, the patient can be treated with a regimen containing ribavirin.

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 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), in which the treatment does not include administration of interferon or ribavirin. The combination comprises the therapeutic agent 1 and the therapeutic agent 3. 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,

121 / 223 ·· ···· ···· ····

<img file="AT514002A2_D0015.tif" />

• · · · · · · ·· ·· ·· ·

<img file="AT514002A2_D0016.tif" />

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, but is 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. 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. 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, if the treatment regimen of the present technology does not provide the desired SVR after treatments longer than 12 weeks, the patient can be treated with a ribavirin-containing regimen.

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 for no

122 / 223 in the • · ·

<img file="AT514002A2_D0017.tif" />

f more than 12 weeks (for example the duration is 12 weeks), preferably no more than 8 weeks (for example the duration is 8 weeks), wherein the treatment does not include the administration of interferon or ribavirin. The combination comprises the therapeutic agent 1 and the therapeutic agent 3. 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 can be administered in therapeutically effective amounts to provide an SVR (for example 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,

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·. .· ·.:··.

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. The therapeutic agent 1 and the therapeutic agent 3 can be in any one

Dosage of per day. In treatment regimen

Combination of therapeutic agent 1 or therapeutic agent 3 given above, are administered. 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. Some embodiments, if the present technology does not provide the desired SVR after treatments for no more than 12 weeks, the patient may be given a ribavirin -containing regimes are treated.

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 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), in which the treatment does not include administration of interferon or ribavirin. The combination comprises the therapeutic agent 1 and the therapeutic agent 3. In a suitable manner, the patient can be a treatment-naive patient, a patient experienced in treatment 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. Treatment according to this aspect

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- * L2 ^ 4 · • · · ·· ·· 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 used in

In connection with the therapeutic agent 1, the therapeutic agent 1 is 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 , approximately

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 about 1000 mg. In some embodiments, ritonavir can either be co-administered with therapeutic agent 1 or administered separately with. Suitable

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-:

Regime treated the present ·· ·· ·· ·

Dosages of ritonavir included, from about 50 mg to about 400 mg per day, preferably about 100 mg per day. In some embodiments, if the treatment regimen of the present technology does not provide the desired SVR after treatments for no more than 12 weeks, the patient may become a ribavirin-containing one.

In some embodiments

Technology Method of treating patients with HCV infection who are non-candidates for interferon treatment. The methods include administering to such patient a combination of at least two DAAs 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 is not includes administration of interferon or ribavirin. The combination comprises the therapeutic agent 1 and the therapeutic agent 3. 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 do 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. 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,

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<img file="AT514002A2_D0018.tif" />

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 mg, about 900 mg, about 950 mg, or about 1000 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 some embodiments, the present technology provides methods of treating patients with an HCV genotype 1, such as Ia or Ib, infection. The

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Be patient, duration of treatment

Methods include administering to such a patient a combination of at least two DAAs 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 is not includes administration of interferon or ribavirin. The combination comprises the therapeutic agent 1 and the therapeutic agent 4. Patients with genotype la or lb infection can be treated with a combination of at least two DAAs without interferon and without ribavirin, wherein the at least 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) in a treatment period of no more than 12 weeks, preferably no more than 8 weeks . Patients can be treatment-naive or treatment-experienced. This cannot be restricted more than 10 weeks, never more than 8 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, 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 used in combination with the

<td>as</td><td> 12</td><td>Weeks</td><td>be,</td>

<td>on</td><td>Not</td><td>more</td><td>as 11</td>

<td>more</td><td>as</td><td colspan="2">9 weeks, but</td>

<td>light</td><td>more</td><td>than 7</td><td>Weeks,</td>

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<img file="AT514002A2_D0019.tif" />

therapeutic agent 1 can be provided in a total daily dose of therapeutic agent 4 of about 25 mg to about 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 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, 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 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), in which the treatment does not include administration of interferon or ribavirin. The combination comprises the therapeutic active substance 1 and the therapeutic active substance 4. The patients can be treatment-naïve patients or treatment-experienced 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

129 / 223 :-5394 ·· ··

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 HCV genotype Ia or Ib. 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 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.

130/223 • ·· ·· ·· * · · · ·· ·· ·· · ·· ··

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 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), in which the treatment does not include administration of interferon or ribavirin. The combination comprises the therapeutic active substance 1 and the therapeutic active substance 4. The patients can be treatment-naïve patients or treatment-experienced 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 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 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,

131/223 s-iS3l • ··· 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

In embodiments, the therapeutic agent 1 and the therapeutic agent 4 are administered once a day. In some embodiments, if the treatment regimen of the present technology does not provide the desired SVR after treatments for no more than 12 weeks, the patient can be treated with a ribavirin-containing regimen.

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

Are interferon treatment. The procedures include that

Administering to such a patient a combination of at least two DAAs 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 involve the administration of interferon or Ribavirin The combination comprises the therapeutic and the therapeutic active ingredient 4. Patients who are not candidates for interferon treatment include, but are not limited to, one or more of the groups: Patients who are, Patients who refuse to take, includes drug 1 following intolerant of interferon one

Interferon treatment states that they

Patients with medical prevent from taking interferon, and

132/223 ·· ···· ···· ···· ·· • r- 1Ϊ &amp; -: &lt;. · &lt;: ··.

: :: :. ::

• · ·· ·· · ·· · ·

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. Therapeutic agent 1 and 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 partially relapse patients a HEPATITIS CYP3A4 ANTIVIRAL AGENTS for

The Interferon Non-Responder Patients Interferon Responder and Interferon See GUIDANCE FOR INDUSTRY - CHRONIC

VIRUS INFECTION: DEVELOPING DIRECT-ACTING

FOR TREATMENT (FDA, September 2010, draft the definitions of naive, partial guidance)

Responder, responder-relapsers (ie, 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 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

133/223 ·'

<img file="AT514002A2_D0020.tif" />

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. In some embodiments, if the treatment regimen of the present technology does not provide the desired SVR after treatments for no more than 12 weeks, the patient can be treated with a ribavirin-containing regimen.

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 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), in which the treatment does not include administration of interferon or ribavirin.

134/223 · »·» ···· ·&gt; «·· ···· ··: -1534-:. · &lt;·· \ • · · · · * · · ϊ •« V ·· · »· · · · ·&gt; ·· ·· · ·· ··

Interferon non-responder patients can be treated with a combination of at least two DAAs without interferon and without 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 in order 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 responder 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 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 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 used in

135/223: -a.55 ^. ·

Combination with the therapeutic agent 1 administered. The total daily dosage of therapeutic agent 4 can be, but is not limited to, for example about 15

<td>mg,</td><td>approximately</td><td> 20</td><td>mg,</td><td>approximately</td><td> 25</td><td>mg,</td><td>about 30</td><td>mg, approximately</td><td> 40</td>

<td>mg,</td><td>approximately</td><td> 50</td><td>mg,</td><td>approximately</td><td> 60</td><td>mg,</td><td>about 70</td><td>mg, approximately</td><td> 75</td>

<td>mg,</td><td>approximately</td><td> 80</td><td>mg,</td><td>approximately</td><td> 90</td><td>mg</td><td>, approximately</td><td colspan="2">100 mg, approximately</td>

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 agent 1 and therapeutic agent 4 are administered once a day. Therapeutic agent 1 and therapeutic 4 can be administered in any combination of suitable dosages as described above. In some embodiments, if the treatment regimen of the present technology does not provide the desired SVR after treatments for no more than 12 weeks, the patient can be treated with a ribavirin-containing regimen.

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 without ribavirin. The treatment lasts no more than 12 weeks (for example the duration is 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 (for example the Duration 8 weeks), alternatively no more than 7 weeks, alternatively no more than 6 weeks,

136/223 or

The

Interferon 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 or ribavirin. The DAAs can be administered at the same different dosage frequencies; the treated patient may be an HCV treatment-naive patient or a HCV treatment-experienced patient, including non-responders (e.g., null responders), interferon responders (patients whose HCV RNA levels have declined but never became undetectable when treated with interferon), or relapsers (patients who reached undetectable levels of HCV-RNA during therapy, but relapsed) or a patient unable to take 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 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 an 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. 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

137/223 '•' -J 9 9 - - - * 3 / · · · ···

For example, 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.

alternatively about 60 mg GS-5885 and about 200 mg GS-9451 daily;

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 PSI-7977 (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,

Total dosages 200 mg GS-9451

Suitable examples include about 30 mg GS-5885 and from;

138/223: -1284 • · · · • · · · 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 PSI-7977 of about 400 mg and a total daily dose of PSI-938 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. In yet another example, the combination of two or more DAAs includes at least one HCV protease inhibitor and at least one HCV polymerase inhibitor. In some embodiments, the at least one protease inhibitor is TMC-435 and the at least other polymerase inhibitor is a 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

139/223: -: s9i. ·. · And about 100 mg PSI-7977, alternatively about 150 mg TMC-435 and about 100 mg PSI-7977, and may other suitable ones

Include combinations. Embodiments ritonavir added to the

Suitably in some or a suitable equivalent of at least two DAAs comprising at least one protease inhibitor, suitably in an amount from about 100 mg to about preferably about 100 mg per day

400 mg per day, in alternatives

Embodiments are the at least one protease 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

140 / 223: -ΐδθτ approximately 1500 mg BI-207127, alternatively approximately 120 mg BI-201335 and approximately 1800 mg BI-207127, alternatively approximately 120 mg BI201335 and approximately 2100 mg BI-207127, alternatively approximately 240 mg BI-201335 and approximately 1200 BI-207127 mg, alternatively about 240 mg BI-201335 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. In yet another example, the two or more DAAs include telaprevir (VS-950, and VX-222 (non-nucleoside polymerase, some examples the telaprevir is in

Way may, in some, be a suitable equivalent

Combination of protease inhibitor inhibitor). In total daily doses provided 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 provided with telaprevir in any combination with the dosage amounts of telaprevir provided above, VX-222 can be provided in about 100 mg to about IOC daily, alternatively from about 200 mc 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 administered a total daily dose from mg to total dose

141/223 • · · · · ·· · ·· · ··· ··················································································································· and also VX-222 may be a total daily dose of approximately 100 mg; Total dose of about 200 mg, alternatively telaprevir can be a total daily dose of about 2250 mg and VX-222 can be a total daily dose of about 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 about 150 mg and VX-222 can be a total daily dose of about 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.

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

142 / 223: -ι «24

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 approximately 1800 mg and the total daily dose of R7128 is approximately 200 mg, alternatively the total daily dose of danoprevir is approximately 2000 mg and the total daily dose of R7128 is approximately 200 mg, alternatively the total daily dose of danoprevir is approximately 400 mg and the total daily dose of R7128 is approximately 400 mg, alternatively, the total daily dose of danoprevir is approximately 1000 mg and the total daily dose of R7128 is approximately 400 mg, alternatively the total daily dose of danoprevir is approximately 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

143 / 223: -183 • · · about 2000 mg and the total daily dose of R7128 is about 1000 mg, alternatively the total daily dose of danoprevir is about 1800 mg and the total daily dose of R7128 is about 1000 mg, alternatively the total daily dose of danoprevir is about 400 mg and the total daily dose of R7128 is about 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 about 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.

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 500 mg to about 1500 mg, 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) can 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

144 / 223 :-1844 .· .· ···· ·· · · · • ·· ·· ·· · ·· ·

For example, the BMS-650032 (BMS) total daily dose is approximately 1200 mg and the BMS-790052 (BMS) total daily dose is approximately 60 mg, alternatively the BMS-650032 (BMS) total daily dose is approximately 300 mg and the BMS-790052 (BMS ) total daily dose is approximately 60 mg.

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 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 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 about 5 mg to about 400 mg, alternatively from about 25 mg to about 200 mg, including but not limited to, for example, 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 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. 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

145 / 223

- $ 185 mg, about about 1200 about 1500

900 mg, about 1000 mg, about 1100 mg, mg, about 1300 mg, about 1400 mg and mg and BMS-790052 (BMS) can be a daily

Have a total 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, 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.

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</td><td>, 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> 20</td>

<td>mg,</td><td>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> 50</td>

<td>mg,</td><td>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><td> 90</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

146 / 223 · · · · · · · · · · · · · · 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, GS-9190, GS-9451 and GS-5885 are administered with ritonavir or a suitable equivalent, suitably in an amount of about 100 mg to about 400 mg per day, preferably about 100 mg per day. 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 without ribavirin, wherein the two DAAs include an HCV polymerase inhibitor, for example PSI7977 and an NS5A inhibitor, for example BMS-790052, 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 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, the 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 can be converted into

147 / 223 «a aa daaa * ··· · * ·« * a

<img file="AT514002A2_D0021.tif" />

<img file="AT514002A2_D0022.tif" />

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) can 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="AT514002A2_D0023.tif" />

O

Telaprevir

148 / 223

-148·· ···· ···· ··· • ·· • · · · • · · • · · · • · · ·

<img file="AT514002A2_D0024.tif" />

TMC-435 (TMC-435350)

<img file="AT514002A2_D0025.tif" />

Vaniprevir, MK-7009

149 / 223 • · ···· ···· ···· • ·

<img file="AT514002A2_D0026.tif" />

-149BMS-650032 (asunaprevir)

<img file="AT514002A2_D0027.tif" />

Danoprevir

<img file="AT514002A2_D0028.tif" />

, 1 os N .....

N ΐί

V ii iS

0 0 y ⁰^°

N / \

Id

MK-5172

150 / 223 ·· ·· &gt;·&lt;&lt;·&gt;,&gt;&gt;&lt;&gt;&lt; ·· •150- · ·· • · · · · · • · · · · · · • · · · · · ·

X -ψ * 'jT *'

LI, ^ 0 Ϊ ΰΗ ο ο \ V /., - 'Υ // \\ ο ο

ΑΝΑ-598 (setrobuvir)

<img file="AT514002A2_D0029.tif" />

GS-333126 (GS-9190 or Tegobuvir) ^χ-'S, - '·' ό;

«4 'D'% ο 1 .... / .Y.

ς) '

Y,) ·· ..., YY Y-Ύ DL s + · '&gt; $' M ^χ$ ϊ '^ 3 ^' 'S?

ό ο ^ —Y.

SS

GS-9451

151/223

-151-

<img file="AT514002A2_D0030.tif" />

Mericitabine (R-4048 or RG7128)

<img file="AT514002A2_D0031.tif" />

Filibuvir (PF-00868554)

152 / 223

-1524 ··· · · · · ·· • · · • · · · · · · * • · · · · • · · · · cs

AXI

,. · &lt;Κ W ^Ρ X,

J ·? N '«O

Ü c&gt;

O

PSI-7977 h '7' Ά 9 \ ir iä

I 9 ”/ ··. .Λ \ (! '' V'νΛι / '

ΑΛBMS-790052 (daclatasvir)

,.,. _M. O

X ». u Xz γ h ir * 7 ”'^N 1 ¥

..-- v ..-- 'Xv A &lt;&gt;

.HCl .HCl

CI II * S1 $ Bl

<img file="AT514002A2_D0032.tif" />

BIT-225

153 / 223

-153« « · · ·· ··

JS Vf,^f'·. i

N,

I &lt;, 'Vj' 'V

Z \ ,, F- i; 9 'si ···· ···· ···· ·· • · · • · · · · · · · · · · · · · · · · · ·

PSI-352938

<img file="AT514002A2_D0033.tif" />

GS-9256

154 / 223 • ·

-154• · · · ··· ····

<img file="AT514002A2_D0034.tif" />

Alisporivir (Debio 025) l '

<img file="AT514002A2_D0035.tif" />

TMC-647055

155 / 223

-155-

<img file="AT514002A2_D0036.tif" />

BMS-791325 is preferred

Λ 'NH

<img file="AT514002A2_D0037.tif" />

/—\

As used herein, BMS-791325 can also be.

See also publications at http: // www 1 .easl.eu / eas! 201 l / program / Posters / Abstract680.htm;

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

For GS-5885 see publications at http://www.natap.org/201 l / EASL / EASL_68.htm;

http: // www 1 .easl.eu / easl2011 / program / Posters / Abstract 1097.htm;

and http://clinicaltrials.gov/ct2/show/NCT01353248.

Any HCV inhibitor or DAA,

156 / 223 which is described herein • · ··· ····

-156* 2 1 _ · · · · • · · ·· ·· · ·· !

• · ·· ·· · · · · · includes its appropriate 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 and ribavirin-free. 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, 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 surfactant. 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.

157 / 223 ···· ···· ····

-157-

<img file="AT514002A2_D0038.tif" />

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 doses</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 rowspan="2"> 5</td><td>Therapeutic active ingredient 1 * +</td><td>50 mg to 250 mg (preferably 50 mg or 250 mg)</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> 8</td><td>GS-5885 +</td><td>3 mg to 200 to (preferably 30 mg to 90 mg)</td>

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-158• · ·· ···· ···· ···· ·· • · · · ·

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

<td rowspan="2"></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>Danoprevir!</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>

<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>

159 / 223

-159 ···· ···· • · · · «• · · · · · 9 9 · ·» ····· • · · · • · · · · · • · * * ritonavir or its appropriate 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. Pref. = preferred.

Additional non-limiting examples of interferon-free treatment regimens with two or more DAAs, without ribavirin and with or without ritonavir or an appropriate equivalent, include the following: (a) 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 ritonavir or a suitable equivalent, and therapeutic agent 4 at a total daily dose of 5 mg up 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 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, even 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)

160/223 • · • · • ·

-160·· ···· ···· ···· ·· • · · • · ··· • · · · « • · · · · ·· « ·· ·· · ·· ..

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 (BMS-790052) at a total daily dose of 10 mg to 200 mg (preferably 60 mg) ; (k) INX-189 for a daily

Total 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 any of these examples, ritonavir or a suitable equivalent to any of these can and can be added

Treatments as described for any of these

Treatments are added at a total daily dose 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.

The treatments of the present technology can be effective in treating HCV infection against HCV genotypes 1, 2, 3, 4, 5, 6, including subgenotypes such as la, lb, 2a, and 3a.

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-161 ··· ···· ···· «• · · · · · · ··« • · · a • · · · · · ;;

• · • · ·

I · · ·· ··

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 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 4 mg, about 5 mg, about 6 mg, about 15 mg, about 20 mg, about 25 mg and Multiples of this (for example 0.25 x, 0.5x, lx, 2x, 3x, 5x, lOx, lOOx, about 3 mg, about 10 mg,

162/223

-162etc.). It will be understood, however, that the specific_ee • · · · · • · · · · • · • ··· • · 4 • · 4 ·· ·· * · · · · ·· ·· «

Dose level for any particular variety of factors will depend on

Activity of the specific compound used, age, body weight, general state of health, diet, administration time, the

Patients of any including the

Gender, 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 used in a total daily dose

<td>of</td><td>approximately</td><td> 25</td><td>mg</td><td>to</td><td>about 300</td>

<td>of</td><td>approximately</td><td> 50</td><td>mg</td><td>to</td><td>about 250</td>

<td>to</td><td>approximately</td><td colspan="2"> 200</td><td>mg.</td><td>In some</td>

<td colspan="3">Cytochrome P-450</td><td colspan="3">Inhibitor in one</td>

about 100 mg to about 400 mg administered, preferably about 100 mg. P-450 inhibitor

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

In embodiments, the cytochrome P-450 inhibitor is administered in a total daily dose amount 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 P450 inhibitor is administered in a total daily dose amount of about 125 mg.

For example and without limitation, the one or more DAAs 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. There may be a short delay or a time gap between administration

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-163-

<img file="AT514002A2_D0039.tif" />

• · • ··· • * · ·· exist from 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 molecularly dispersed, in a matrix comprising a pharmaceutically acceptable water-soluble polymer and a pharmaceutically acceptable 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, and ritonavir at a dose of 100 mg, once a day; and therapeutic agent 2 at a dose of 400 mg or 800 mg twice a day. Treatment lasts for 12 weeks and at the end of treatment the subject has no detectable virus.

164 / 223

-164• ·&gt;

·· ·· · ··

In one embodiment, a method of treating a naive subject comprises administering Therapeutic Agent 1 at a dose of 50 mg, and ritonavir at a dose of 100 mg, once a day; therapeutic agent 2 at a dose of 400 mg or 800 mg twice a day. Treatment lasts for 12 weeks and 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, and ritonavir at a dose of 100 mg, once a day; and therapeutic agent 2 at a dose of 400 mg BID. Treatment lasts for 12 weeks and at the end of treatment the subject has no detectable virus.

In another embodiment, a method of treating a naive subject comprises administering Therapeutic Agent 1 at a dose of 150 mg and ritonavir at a dose of 100 mg, once a day; and therapeutic agent 2 at a dose of 400 mg BID. Treatment continues for 12 weeks and 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 and ritonavir at a dose of 100 mg once a day; and therapeutic agent 2 at a dose of 400 mg BID. Treatment lasts for 12 weeks and 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, and ritonavir at one dose of 100 mg QD for 12 weeks. At the end of treatment, the subject has no detectable virus.

In one embodiment, a method for

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-165^ ··: :

Treatment of a naive subject involves administering therapeutic agent 1 at a total daily dose of 150 mg, therapeutic agent 3 at a total daily dose of 400 mg, and ritonavir at a dose of 100 mg once a day 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 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, ritonavir at a dose of 100 mg 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, ritonavir at a dose of 100 mg QD for 12 weeks. At the end of treatment, the subject has no detectable virus.

It should be understood that the above-described embodiments and the following examples apply to

Illustration, Not for Various Changes and

Restriction

Modifications are given within the

The scope of the present invention will become apparent to those skilled in the art from this description.

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

Examples 1-3 are illustrative and in no way limit the scope of this disclosure. Without being based on 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

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-166«

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 short-acting, interferon and ribavirin -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 and a neomycin phosphotransferase

Replicon cells were obtained in Dulbecco

Luciferase reporter selectable marker, Modified Eagle's Medium (DMEM) containing 100 IU / ml penicillin,

200 mg / ml G418, single and 10% fetal

100 mg / ml streptomycin (Invitrogen), aminoglycoside antibiotic (Invitrogen)

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 BMS-650032 twofold dilutions. The dilution series was then further diluted 100x in the medium containing 5% FBS.

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 alone and six

Concentrations of compound 2 alone were in each plate

Combinations of two connections for each plate

167 / 223 examined. In addition, 36 concentrations of

-167 t

• · examined. 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% CO₂incubated 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 μL, 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 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: 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:

168/223 • ·

-168-::..:. .: : ...:: :

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, then the drug combination would be deemed to have an antagonistic effect; otherwise there is no significant antagonism or synergy with this concentration combination.

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

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-163-:: :

Compound 1 ranged from 0.031 nM to 1.0 nM.

the

For

Replicons produced by each drug alone or in combination with the other at concentrations up to ten fold 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

Concentrations in the range of

Compound 2 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 dark gray, additive interactions appear white, and antagonistic interactions appear speckled.

As illustrated in the 3D surface plot of FIG. 1 and the contour diagram of FIG. 2, there is most of an additive or synergistic effect

Concentrations for Compound 1 and Compound 2. In particular, there is a concentration region that shows synergy at most of the concentrations of Compound 1 and at the lower to mid-range dose concentrations of Compound 2.

Table 2 below lists the combinations of the concentrations of Compound 1 and Compound 2 with one

170 / 223 • · ·* ···· ········ ·· • · · · · 9 9 9

9 9 9 9 9 9999

-1704 :: :. :: . :: :

• · · · 9 9 9 9 9 9 9 statistically significant synergistic or antagonistic effects, based on the Prichard and Shipman model analysis. For each combination of combinations, Table 2 includes the mean difference in 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.

171/223 ·· ···· ···· 4··· 44

-1714 :

Table 2

<td>connection 2, 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> .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 2 connection</td><td colspan="5">Synergistic concentrations of compound 4 in genotype lb HCV replicon assay</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 selectable

Construct contains a firefly luciferase reporter and a neomycin phosphotransferase selectable marker.

172 / 223

Active ingredient 1 described

Replicon cells were kept 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% C0₂.

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 and therapeutic agent 4 in the above replicon assay. The purpose of this

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.

173 / 223 • · · · ft ··········· · · · · · · ftft • · · · · ft ···

-1T3- ::

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

Approach to calculating the theoretical

Effects (described in Example 1) 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 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.

Shipman additive

Synergy or a

Antagonism for

Concentration combination was determined based on the same rules set out in Example 1.

Combination of therapeutic agent 1 therapeutic agent 4: The inhibitory effects replicon, produced by each drug alone or in combination with the other at concentrations of up to ten times above the EC₅₀ were examined in the genotype Ib (Conl) replicon using a checkerboard titration pattern

174 / 223 and im in to

-174-δ (two-fold serial dilutions) in the standard three day antiviral assay. The concentrations tested were chosen to ensure that the EC₅₀^-Compound values ​​were in the middle of the 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

Antagonistic interactions

Compounds 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 are shaded, additive interactions, 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 3 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 3 includes the mean calculated additivities.

between connection 1 and appear dark gray and white

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-173- ::

• · · • · · · · • · · · · · · • · · · · · • · · » · · · ·

Difference in the observed and predicted portion of inhibition, the standard deviation or the error of the mean difference, and the upper and lower limits of the 95% confidence interval.

According to Table 3, most of the combinations of Compound 1 and Compound 4 listed in the table have statistically significant synergistic effects. A small amount of antagonism was seen with the lowest concentrations of Compound 1.

The results, which are presented in FIGS. 3 and 4 and Table 3, show that the combination of therapeutic agent 4 and therapeutic agent 1 achieves additivity at most in the

Concentration combinations of the two active ingredients and a synergy is achieved at certain concentration combinations, in particular at low concentrations of therapeutic active ingredient 4 and mid-range concentrations of therapeutic active ingredient 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.

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-1J76S ···· ···· ····

Table 3

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

<td>4, 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> 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>

<td colspan="3">Similar results were obtained</td><td>also for</td><td>the</td><td>combination of</td>

therapeutic agent 2 and therapeutic agent 4, where additivity was observed at most concentration combinations of the two agents and synergy was observed at low concentrations of therapeutic agent 2 and therapeutic agent 4.

Example 3. Reduction of HCV-infected cells with

Combinations of therapeutic agents 1, 2 and 4

To determine 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 derived from 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 derived from the human hepatoma cell line Huh-7. The replicon also has a firefly luciferase reporter and a neomycin phosphotransferase (Neo) selectable marker. The

177 / 223

-1174: : .

• · · · • · · · 9 two coding regions, separated by the FMDV 2a protease, comprise the first cistron of the bicistronic replicon construct, the second cistron being the HCV NS3-NS5B coding region with the addition of adaptive mutations E1202G, K1691R, K2040R and Includes S2204I. This HCV replicon cell line was kept 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 placed in the presence of G418 (400 pg / ml) and Compound 1, Compound 2 and / or Compound 4 at concentrations that were either 10-fold (10X ) or 100 times (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

Treatment freed the majority of replicon cells from 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- Score to significantly fewer colonies than either Compound 1, Compound 2, or Compound 4 alone at 10-fold or 100-fold above their corresponding EC₅₀Value.

Figure 5B illustrates the percentage of colonies that survived two vs. three DAA combinations. In colony survival assays, la-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.

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<td></td><td rowspan="2">-178: - ::: • · · ft</td><td> • · • ·</td><td>• ft e ···</td><td></td>

<td></td><td> • ·</td><td> ·· *</td><td></td>

<td>“Triple combination</td><td>is either</td><td>a</td><td>combination</td><td>out</td>

<td>Connections 1, 2 and 4</td><td colspan="3">at concentrations of 5-fold (5X)</td><td>above</td>

<td>their corresponding</td><td>EC₅₀Values ​​or</td><td>a</td><td>combination</td><td>out</td>

<td>Connections 1, 2 and</td><td colspan="2">4 at concentrations</td><td>of 10 times</td><td>(10X)</td>

either 10-fold (10X) corresponding EC₅₀- Fold resistance values ​​of 48 in lb-Conl replicons, which were predominant over 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 of or 100X (100X) above theirs were added and the 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-PCRAssay. 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 la-H77 replicons include R155K, D168A and D168V with fold resistance of

26, 48 and 128 respectively; and the predominant variants of resistance include R155K, A156T and D168V with 190, respectively. For compound 2, resistance variants close in la-H77 replicons

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

Wrinkle 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 prevailing

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-179-:

Variants of resistance in Ib Coni 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 4. Use of a 2-DAA combination without interferon and ribavirin to treat treatment naïve subjects infected with genotype 1, 2 or 3

Genotype 1

Ten previously untreated subjects infected with HCV genotype 1 were treated with a 2-DAA combination for 12 weeks. Treatment was interferon and ribavirin free and was designed to last for 12 weeks, the 2-DAA combination included compound 1 / r (200/100 mg QD) and compound 4 (25 mg QD). At week 3 of treatment, seven of the ten subjects showed no detectable HCV RNA; and the

180/223 • · • ···

-Where:-:

• · ·· ·· · ·· ·· remaining three subjects had HCV-RNA levels less than 25 IU / ml. At week 4, eight subjects showed no detectable HCV RNA and the remaining two showed (or were believed to have) an HCV RNA level of less than 25 IU / ml. At week 5, new subjects had no detectable HCV RNA and the remaining subject had an HCV RNA level of less than 25 IU / ml. At weeks 6 and 7 of treatment, all ten subjects were tested and no detectable HCV RNA was found. At weeks 9, 10, 11 and 12 of treatment, one subject showed a viral breakthrough and the remaining new subjects showed no detectable HCV RNA.

At post-treatment week 2, at least seven subjects found no detectable HCV RNA. At post-treatment week 4, seven subjects found no detectable HCV RNA. At post-treatment week 8, seven subjects found no detectable HCV RNA. At post-treatment week 12, six subjects found no detectable HCV RNA. At treatment week 24, at least two subjects found no detectable HCV RNA.

Genotype 2

Ten previously untreated subjects infected with HCV genotype 2 were treated with the same regimen from this example. At week 3 of treatment, eight of the ten subjects showed no detectable HCV RNA, one had viral kickback, and one had HCV RNA levels less than 25 IU / ml. At week 5 of treatment, nine of the ten subjects showed no detectable HCV RNA and one had breakthrough. At weeks 10, 11 and 12 of treatment, at least seven of the ten subjects were tested and no detectable HCV RNA was found.

At post-treatment week 2, six subjects found no detectable HCV RNA; and two more subjects had a breakthrough. At post-treatment week 4, five subjects found no detectable HCV RNA. At post-treatment week 8, six subjects found no detectable HCV RNA. At post-treatment week 4, at least five subjects found no detectable HCV RNA.

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-181 • φ φ φφφ φ φ

Genotype 3

Similarly, ten previously untreated subjects infected with HCV genotype 3 were treated with the same regimen of this example. At weeks 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 of treatment, two subjects showed no detectable HCV RNA. At post-treatment weeks 2 and 4, the same two subjects were confirmed to have no detectable HCV RNA. A number of subjects appeared to have had a breakthrough while on treatment.

At post-treatment week 24, at least three subjects showed no detectable HCV RNA.

Example 5. Use of a 3-DAA combination without interferon and ribavirin to treat treatment naïve subjects infected with genotype 1

Twelve previously untreated subjects with HCV genotype 1 infection were treated with a 3-DAA combination for 12 weeks. The treatment was interferon and ribavirin free. The 3-DAA combination includes 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 3 of treatment, seven of the twelve subjects had no detectable HCV RNA and the five remaining subjects had HCV RNA levels less than 25 IU / ml. At week 4 of treatment, nine of the twelve subjects had no detectable HCV RNA and the three remaining subjects had HCV RNA levels less than 25 IU / ml. At weeks 6 and 8, all twelve subjects had no detectable HCV RNA. At weeks 10 and 12, eleven of the twelve subjects showed no detectable HCV RNA and one subject had detectable HCV RNA.

At post-treatment weeks 2 and 4, at least ten of the twelve subjects were tested and no detectable HCV RNA was found. At post-treatment week 8, at least seven of the twelve subjects were tested and no detectable HCVRNA was found. Two subjects appeared to have a breakthrough during or after treatment. Further testing showed that the

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Follow-up week 12 at least 9 of the initial twelve

Subjects found no detectable HCV RNA.

A larger clinical study using the same drug combination showed about 91% (or about 97% if non-virological errors were removed) SVR4 rate and about 82% (or about 90% if non-virological errors were removed) SVR12 rate, after 12 weeks Treatment regimen in treatment-naïve patients. Among these patients, the SVR4 and SVR12 rates (virologic errors removed) in genotype la patients were approximately 96% and 86%, respectively. All of these SVR4 and SVR12 rates were based on observed data.

Example 6. Building a clinical model for interferon-free DAA combination therapies by combining said, acceptable those

This example describes a new clinical model for estimating optimal doses and durations of interferon-free HCV therapies using different DAAs. This model

Effectiveness 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 DAAs. Thus, a 2-DAA (for example a combination of a

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Combination regime

Combination regime

-183-

<img file="AT514002A2_D0040.tif" />

Protease inhibitor and an NS5A inhibitor) 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) Hepatocyte (uninfected or target cell) dynamics dT / dt = s - de * T- (li]) * ß * T * (VLWT + VLPoly + VLProt + VLNS5A + VLNSSAProt + VLPolyProt) (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 - 5 * IPoly (c) (d) (e)

Infected with protease mutant virus d IProt / dt = (1-η) * β * T * VLProt - δ * IProt

Infected with NS5A mutant virus d INS5A / dt = (1 -η) * β * T * VLNS5A - δ * INS5A

Infected with protease NS5A double mutant virus

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<img file="AT514002A2_D0041.tif" />

♦ » 9 · • · · · ··«· ···· ···· ·· • · · ·

<img file="AT514002A2_D0042.tif" />

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 * g) * p * ( l-Effl) * IWT + μ * (p * (l-Eff2) * Fitl * IPoly + p * (l-Eff3) * Fit2 * IProt + p * (lEff4) WINS5A) -c * VLWT (b) polymerase mutants -Virus d VLPoly / dt = (1- μ -φ) * p * (l-Eff2) * Fitl * IPoly + μ * p * (l-Effl) * IWT + φ * p * (l-Eff5) * Fit4 * IPolyProt - c * VLPoly (c) Protease Mutant Virus d VLProt / 'dt = (1- μ - 2 * φ) * p * (l-Efß) * Fit2 * IProt + μ * p * (l-Efß) * IWT + φ * (p * (1 Eff5) * Fit4 * IPolyProt + p * (l-Eff6) * Fit5 * INS5AProt) - c * VLProt (d) NS5A mutant virus d VLNS5A / dt = (1- μ - φ) * ρ * (1-ΕίΓ4) * Εΐβ * 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-ΕίΤ6) * ΡΚ5 * 1Ν85ΑΡΐΌί + φ * (p * (l-Eff4) * Fit3 * INS5A + p * (lEfß) * Fit2 * IProt) - c * VLNS5AProt (f) poly and protease mutant double mutant virus

185/223 • · ········· ♦ · · · · · · · • ft · · * »·· · ••• ft ·· • · • ftftft ft ft · • · · · ft · · ·

-Ϊ8 3-;

ft t · • · · • · d VLPolyProt / dt = (1-2 * &lt;|)) * p * (l-Eff5) * Fit4 * IPolyProt + φ * (p * (l-Eff2) * Fitl * IPoly + p * (lEffi) * Fit2 * IProt) - c * VLPolyProt

The parameters used in the equations above are described in Table 5.

Table 5. Viral dynamics parameters

<td>parameter</td><td>Honor exercise</td>

<td>s</td><td>Zero order production of Hepatocytes</td>

<td>T</td><td>Number of target or uninfected Hepatocytes</td>

<td>de</td><td>Rate constant first Order for the death of hepatocytes</td>

<td>z</td><td>Rate constant for the Infection of hepatocytes by the virus</td>

<td></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></td><td>Possibility of forming duplicates Mutants and mutation back too single mutant</td>

<td>m</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>

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<img file="AT514002A2_D0043.tif" />

<td>parameter</td><td>Honor exercise</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>

<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 the

Inhibits viral load production by 50%. Since the fold-change in the EC₅₀ for the mutants compared to the wild-type virus

187/223: -target • * · · • · · · · • · · · • ·

<img file="AT514002A2_D0044.tif" />

• ·

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-EffDAAOni-EffDAAlj ^ l-EffDAAl)

The effect of ribavirin (RBV) may also contribute to the

Infection Rate ”can be added as an Emax model. In the presence of ribavirin the infection rate decreases by a factor (1- ° ^ where η - ConcRBv / (ECso-rbv + Coücrbv)

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.

To predict the time required for healing to take place, a "threshold concept" was used. For simulations, it was assumed that an HCV-infected subject will achieve SVR when the viral load is less than 1 virion in the total plasma and the

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<img file="AT514002A2_D0045.tif" />

extracellular fluid volume (approx. 15000 ml) is reached, ie measurement of a viral load of &lt;1 Kople / 15000 ml or &lt;0.33 IU / 15000 ml. This translates into approx. 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, 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 the bioavailability of the drug.

A double mutant against compound 2 and compound 4 was not included in the model. In the 3-DAA regimen, 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, the compound 2 / compound 4 double mutant is not expected to be clinical

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<img file="AT514002A2_D0046.tif" />

Outcomes for treatments containing compound 1 influenced.

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 wild-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 old 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 ΙΟΟΟχ-fold change 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_2009.pdf;

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Results included: below the detection limit

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 simulations were carried out assuming 100% compliance. Covariates included in the simulations were genotype la / lb status. The simulated clinical (1) the percentage of subjects (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 (for example 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 in FIGS. 6A, 6B and 6C for two different doses of compound 1

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<img file="AT514002A2_D0047.tif" />

shown. 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 interval 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 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 (for example pegylated

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-182SInterferon) can 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 that included 150/100 mg Compound 1 / ritonavir QD + 400 mg Compound 3 QD + weight-dependent amounts of RBV BID for 12 weeks. Subjects on treatment included 11 treatment-naive subjects between the ages of 18 and 65. All subjects completed 12 weeks of therapy with Compound 1 and ritonavir (Compound 1 / r) dosed in combination with Compound 3 and ribavirin (RBV). Compound 1 (150 mg once daily (QD)) was dosed with 100 mg ritonavir, 400 mg QD compound 3, and weight-dependent amounts of RBV in treatment-naive subjects infected with genotype (GT) 1 HCV. The percentage of subjects with HCV RNA less than LOD at 2, 4, 8, 10 and 12 weeks was summarized in FIG. The mean predicted versus observed percentage of subjects with below LOD (“% LOD) at corresponding 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 a different treatment regimen. The regimen included three groups of patients. In Group 1, previously untreated subjects with HCV infection were treated with a protease inhibitor (in combination with ritonavir), a polymerase inhibitor, and ribavirin. The treatment was without interferon. The subjects included 19 treatment-naive subjects between the

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-iS3i

Ages 18 and 65 a. One subject discontinued the study at week 3. All remaining subjects 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 subjects infected with GTl-HCV.

In Group 2, previously untreated subjects with HCV infection were treated with a protease inhibitor (in combination with ritonavir), a polymerase inhibitor, and ribavirin. The treatment was without interferon. Subjects included 14 treatment-naive subjects between the ages of 18 and 65. One subject stopped the study at week 1. Therefore, there were a total of 13 subjects in the study. All 13 subjects completed 12 weeks of Compound 1 / r therapy 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 subjects infected with GTl-HCV.

In group 3, peginterferon + ribavirin (P / RBV) -NonResponder were treated with a protease inhibitor (in combination with ritonavir), a polymerase inhibitor, and ribavirin. The treatment was without interferon. Subjects included 17 P / RBV Non-REsponders between the ages of 18 and 65. Subjects 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 non-responders infected with GTl-HCV. Four patients had breakthroughs during treatment and discontinued the study before week 7.

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 the same treatment regimen but without

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Ribavirin, has similar or comparable LOD percentages for different treatment durations.

The viral dynamic exposure-response model of this

The example provided a reasonably predictable antiviral compound.

quantitative method to

SVR

Based on antiviral response modeling and combinations of the exposure clinical's for different ones

Experimental simulations showed that (1) adding a 3rd DAA to a 2-DAA combination can reduce the optimal duration of treatment and / or the increase in SVR; (2) 8-12 weeks

Dosage 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.

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 BMS -790052 and a phase 1 and a phase 2a study of BMS650032. Figure 9 shows the predicted mean SVR percentage and 90% SVR confidence interval for various treatment durations of a 2-DAA regimen containing BMS-790052 (60 mg QD) and BMS-650032 (600 BID) in genotype 1 naive subjects. It was predicted that 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 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.

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Interferon-free

Example 8. Clinical Modeling 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 predict SVR for regimens containing 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).

for the predicted SVR (the top of each corresponding one in Figure 11 already

The 90% confidence interval vertical bar on the predicted SVR percentage column) is also given. The prediction was based on 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 containing similar PSI-7977 QD dosages (e.g. 200-600 QD) but without ribavirin.

Data from two Phase 1 and a Phase 2 study of daclatasvir (BMS-790052) and a Phase 1 and a Phase 2196/223: -sm-.

Study from PSI-7977 were used to estimate pharmacokinetics and viral dynamics model parameters. The predictions for a 2-DAA combination with daclatasvir (BMS790052) and PSI-7977 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.

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 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.

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 the 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.

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 model197/223 • · • ··· • · • · · · • · · · ·

Parameter. The predictions for the combination with GS-9190 (tegobuvir), GS-9451 and GS-5885 and without ribavirin 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 and without ribavirin, approximately 70% of genotype 1 naive patients can achieve SVR, and after 24 weeks of treatment Over 80% of genotype 1 naive patients can achieve SVR.

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 (PSI7977) and without ribavirin 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 (PSI7977) and without ribavirin 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) and without ribavirin 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), and in the absence of ribavirin at least 90% of genotype 1 naive patients can achieve SVR.

Example 12. Clinical Modeling for Interferon-Free DAA198 / 223

<img file="AT514002A2_D0048.tif" />

···· · «« · ··· «·· • · · · • β · * ·· • · · ·

Combination therapies that contain 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), approximately 80% of genotype 1 naive patients can achieve SVR.

The foregoing description of the present invention has provided an illustration and description, but is not intended to be exhaustive or to limit the invention to the precise point 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.