(12) Patent Application Publication (10) Pub. No.: US 2014/0275099 A1 Bernstein Et Al

US 20140275099A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0275099 A1 Bernstein et al. (43) Pub. Date: Sep. 18, 2014

(54) METHODS FOR TREATING HCV Publication Classification (71) Applicant: AbbVie Inc., North Chicago, IL (US) (51) Int. Cl. A613 L/4985 (2006.01) (72) Inventors: Barry M. Bernstein, Mequon, WI (US); A613 L/454 (2006.01) Sandeep Dutta, Lincolnshire, IL (US); (52) U.S. Cl. Wei Liu, Mundelein, IL (US); Thomas CPC ...... A6 IK3I/4985 (2013.01); A61 K3I/454 J. Podsadecki, Chicago, IL (US); (2013.01) Andrew L. Campbell, Lake Forest, IL USPC ...... S14/250 (US); Rajeev M. Menon, Buffalo Grove, IL (US); Chih-Wei Lin, Vernon Hills, IL (57) ABSTRACT (US); Tianli Wang, Lake Bluff, IL (US); The present invention features interferon- and ribavirin-free Walid M.Awni, Green Oaks, IL (US) therapies for the treatment of HCV. Preferably, the treatment is over a shorter duration of treatment, such as no more than (21) Appl. No.: 14/210,870 12 weeks. In one aspect, the treatment comprises administer ing at least two direct acting antiviral agents without inter (22) Filed: Mar 14, 2014 feron and ribavirin to a subject with HCV infection, wherein the treatment lasts for 12 weeks, and said at least two direct Related U.S. Application Data acting antiviral agents comprise (a) Compound 1 or a phar (60) Provisional application No. 61/783,376, filed on Mar. maceutically acceptable salt thereofand (b) Compound 2 or a 14, 2013. pharmaceutically acceptable salt thereof. Patent Application Publication Sep. 18, 2014 Sheet 1 of 7 US 2014/0275099 A1

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METHODS FOR TREATING HCV 0007. In any method described herein, the at least two DAAS comprise (a) Compound 1 or a pharmaceutically 0001. This application claims the benefit of U.S. Provi acceptable salt thereof, and (b) Compound 2 or a pharmaceu sional Application No. 61/783,376, filed Mar. 14, 2013, tically acceptable salt thereof. The at least two DAAs can also which is incorporated herein by reference in its entirety. optionally comprise another anti-HCV agent. The other optional anti-HCV agent can be selected from protease FIELD OF THE INVENTION inhibitors, nucleoside or nucleotide polymerase inhibitors, non-nucleoside polymerase inhibitors, NS3B inhibitors, 0002 The present invention relates to interferon-free and NS4A inhibitors, NS5A inhibitors, NS5B inhibitors, cyclo ribavirin-free treatment for hepatitis C virus (HCV). philin inhibitors, or combinations thereof. For example, in some embodiments, the DAAs used in a method of the present BACKGROUND OF THE INVENTION invention comprise or consist of (a) Compound 1 or a phar 0003. The HCV is an RNA virus belonging to the Hepa maceutically acceptable salt thereof, and (b) Compound 2 or civirus genus in the Flaviviridae family. The enveloped HCV a pharmaceutically acceptable salt thereof. For another virion contains a positive stranded RNA genome encoding all example, the DAAs used in a method of the present invention known virus-specific proteins in a single, uninterrupted, open comprise or consist of (a) Compound 1 or a pharmaceutically reading frame. The open reading frame comprises approxi acceptable salt thereof, (b) Compound 2 or a pharmaceuti mately 9500 nucleotides and encodes a single large polypro cally acceptable salt thereof, and (c) a HCV polymerase tein of about 3000 amino acids. The polyprotein comprises a inhibitor, wherein said HCV polymerase inhibitor can be a core protein, envelope proteins E1 and E2, a membrane nucleotide or nucleoside polymerase inhibitor or a non bound protein p7, and the non-structural proteins NS2. NS3, nucleoside or non-nucleotide polymerase inhibitor. NS4A, NS4B, NS5A and NS5B. 0008. Non-limiting examples of the other optional antic 0004 Chronic HCV infection is associated with progres HCV agent include PSI-7977 (sofosbuvir), PSI-938, BMS sive liver pathology, including cirrhosis and hepatocellular 790052 (daclatasvir), BMS-650032 (asunaprevir), BMS carcinoma. Chronic hepatitis C may be treated with peginter 791325, GS-5885 (ledipasvir), GS-9451 (tegobuvir), feron-alpha in combination with ribavirin. Substantial limi GS-9190, GS-9256, BI-201335. BI-27127, telaprevir, tations to efficacy and tolerability remain as many users Suffer VX-222, TMC-435 (simepravir), MK-5172, MK-7009 (vani from side effects, and viral elimination from the body is often previr), danoprevir, R7128 (mericitabine), and any combina incomplete. Therefore, there is a need for new therapies to tion thereof. treat HCV infection. 0009. In any method described herein, the DAAS can be administered in any effective dosing schemes and/or frequen BRIEF SUMMARY OF THE INVENTION cies; for example, they can each be administered daily. Each DAA can be administered either separately or in combina 0005 One aspect of the present invention features meth tion, and each DAA can be administered once a day, twice a ods for treating HCV infection in a subject in need of such day, or three times a day. Preferably, Compound 1 (or a treatment. The methods comprise administering at least two pharmaceutically acceptable salt thereof) and Compound 2 direct acting antiviral agents (DAAS) to the Subject for a (or a pharmaceutically acceptable salt thereof) are adminis duration of no more than 12 weeks, or for another duration as tered once daily. set forth herein. The at least two DAAs comprise Compound 0010 Preferably, Compound 1 (or a pharmaceutically 1 (or a pharmaceutically acceptable salt thereof) and Com acceptable salt thereof) is administered from 100 mg to 600 pound 2 (or a pharmaceutically acceptable salt thereof). Pref mg once daily, and Compound 2 (or a pharmaceutically erably, the duration of the treatment is 12 weeks. The duration acceptable salt thereof) is administered from 50 to 500 mg of the treatment can also be, for example, no more than 8 once daily. More preferably, Compound 1 (or a pharmaceu weeks. Preferably, the two or more DAAs are administered in tically acceptable salt thereof) is administered from 200 mg to amounts effective to provide a Sustained Virological response 600 mg once daily, and Compound 2 (or a pharmaceutically (SVR) or achieve another desired measure of effectiveness in acceptable salt thereof) is administered from 100 to 500 mg the subject. The subject is not administered ribavirin during once daily. Highly preferably, Compound 1 (or a pharmaceu the treatment regimen. The Subject is also not administered tically acceptable salt thereof) is administered from 400 mg to interferon during the treatment regimen. Put another way, the 600 mg once daily, and Compound 2 (or a pharmaceutically methods exclude the administration of interferon or ribavirin acceptable salt thereof) is administered from 100 to 500 mg to the subject, thereby avoiding the side effects associated once daily. For instance, Compound 1 (or a pharmaceutically with interferon and ribavirin. acceptable salt thereof) can be administered 400 mg once 0006 Another aspect of the present invention features daily, and Compound 2 (or a pharmaceutically acceptable salt methods for treating a population of subjects having HCV thereof) is administered 120 mg once daily. For another infection. The methods comprise administering at least two instance, Compound 1 (or a pharmaceutically acceptable salt DAAS to the subjects for a duration of no more than 12 weeks. thereof) can be administered 400 mg once daily, and Com The at least two DAAS comprise Compound 1 (or a pharma pound 2 (or a pharmaceutically acceptable salt thereof) can be ceutically acceptable salt thereof) and Compound 2 (or a administered 240 mg once daily. pharmaceutically acceptable salt thereof). Preferably, the at 0011. In yet another aspect, the present invention features least two DAAS are administered to the Subjects in amounts a combination of Compound 1 (or a pharmaceutically accept effective to result in SVR or another measure of effectiveness able Salt thereof) and Compound 2 (or a pharmaceutically in at least about 70% of the population, preferably at least acceptable salt thereof) for use to treat HCV infection. The about 80% of the population, or more preferably at least about treatment comprises administering the DAAS to a subject 90%/o of the population. infected with HCV. The duration of the treatment regimen is US 2014/0275099 A1 Sep. 18, 2014

no more than twelve weeks (e.g., the duration being 12 a null responder) infected with HCV genotype 1. In yet weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 another example, the treatment lasts for 8 weeks, and the weeks). Preferably, the duration of the treatment regimen is Subject being treated is a non-responder (e.g., a null twelve weeks. The duration of the treatment can also last, for responder) infected with HCV genotype 1. In yet another example, no more than eight weeks (e.g., the duration being 8 example, the treatment lasts for 12 weeks, and the Subject being treated is a non-responder (e.g., a null responder) weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The infected with HCV genotype 3. In another example, the treat treatment does not include administering interferon or ribavi ment lasts for 11 weeks, and the Subject being treated is a rin. Compound 1 (or the salt thereof) and Compound 2 (or the non-responder (e.g., a null responder) infected with HCV salt thereof) can be administered concurrently or sequentially. genotype 3. In still another example, the treatment lasts for 10 Preferably, Compound 1 (or the salt thereof) and Compound weeks, and the Subject being treated is a non-responder (e.g., 2 (or the salt thereof) can be administered once daily. As a a null responder) infected with HCV genotype 3. In yet non-limiting example, the patient being treated is infected another example, the treatment lasts for 9 weeks, and the with HCV genotype 1. Such as genotype 1a or 1b. As another Subject being treated is a non-responder (e.g., a null non-limiting example, the patient is infected with HCV geno responder) infected with HCV genotype 3. In yet another type 2. As another non-limiting example, the patient is example, the treatment lasts for 8 weeks, and the subject infected with HCV genotype 3. As another non-limiting being treated is a non-responder (e.g., a null responder) example, the patient is infected with HCV genotype 4. As infected with HCV genotype 3. another non-limiting example, the patient is infected with 0012. A treatment regimen of the present invention gen HCV genotype 5. As another non-limiting example, the erally constitutes a complete treatment regimen, i.e., no Sub patient is infected with HCV genotype 6. As yet another sequent interferon-containing regimen is intended. Thus, a non-limiting example, the patient is a HCV-treatment naive treatment or use described herein generally does not include patient, a HCV-treatment experienced patient, an interferon any Subsequent interferon-containing treatment. Preferably, a non-responder (e.g., a null responder), or not a candidate for treatment or use described herein does not include any Sub interferon treatment. As used in this application, the inter sequent ribavirin-containing treatment. feron non-responder patients include partial interferon 0013. Other features, objects, and advantages of the responders and interferon rebound patients. See GUIDANCE FOR present invention are apparent in the detailed description that INDUSTRY CHRONIC HEPATITIS C VIRUS INFECTION: DEVELOPING follows. It should be understood, however, that the detailed DIRECT-ACTING ANTIVIRAL AGENTS FOR TREATMENT (FDA, Sep description, while indicating preferred embodiments of the tember 2010, draft guidance) for the definitions of naive, invention, are given by way of illustration only, not limitation. partial responder, responder relapser (i.e., rebound), and null Various changes and modifications within the scope of the responder patients. The interferon non-responder patients invention will become apparent to those skilled in the art from also include null responder patients. In one example of this the detailed description aspect of the invention, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV BRIEF DESCRIPTION OF THE DRAWINGS genotype 1. In another example, the treatment lasts for 11 0014. The drawings are provided for illustration, not limi weeks, and the Subject being treated is a naive patient infected tation. with HCV genotype 1. In still another example, the treatment (0015 FIG. 1 shows the predicted median SVR percent lasts for 10 weeks, and the subject being treated is a naive ages and 90% SVR confidence intervals for interferon/ribavi patient infected with HCV genotype 1. In yet another rin-free, 2-DAA regimens comprising the use of Compound 1 example, the treatment lasts for 9 weeks, and the subject (400 mg once daily) and Compound 2 (120 mg once daily) to being treated is a naive patient infected with HCV genotype 1. treat genotype 1 naive subjects. In yet another example, the treatment lasts for 8 weeks, and (0016 FIG. 2 illustrates the predicted median SVR per the subject being treated is a naive patient infected with HCV centages and 90% SVR confidence intervals for interferon/ genotype 1. In yet another example, the treatment lasts for 12 ribavirin-free, 2-DAA regimens comprising the use of Com weeks, and the Subject being treated is a naive patient infected pound 1 (400 mg once daily) and Compound 2 (60 mg once with HCV genotype 3. In another example, the treatment lasts daily) to treat genotype 1 naive Subjects. for 11 weeks, and the Subject being treated is a naive patient (0017 FIG. 3 depicts the predicted median SVR percent infected with HCV genotype 3. In still another example, the ages and 90% SVR confidence intervals for interferon/ribavi treatment lasts for 10 weeks, and the subject being treated is rin-free, 2-DAA regimens comprising the use of Compound 1 a naive patient infected with HCV genotype 3. In yet another (600 mg once daily) and Compound 2 (480 mg once daily) to example, the treatment lasts for 9 weeks, and the subject treat genotype 1 naive subjects. being treated is a naive patient infected with HCV genotype 3. (0018 FIG. 4 shows the predicted median SVR percent In yet another example, the treatment lasts for 8 weeks, and ages and 90% SVR confidence intervals for interferon/ribavi the subject being treated is a naive patient infected with HCV rin-free, 2-DAA regimens comprising the use of Compound 1 genotype 3. In yet another example, the treatment lasts for 12 (400 mg once daily) and Compound 2 (120 mg once daily) to weeks, and the Subject being treated is a non-responder (e.g., treat genotype 3 naive subjects. a null responder) infected with HCV genotype 1. In another (0019 FIG. 5 illustrates the predicted median SVR per example, the treatment lasts for 11 weeks, and the Subject centages and 90% SVR confidence intervals for interferon/ being treated is a non-responder (e.g., a null responder) ribavirin-free, 2-DAA regimens comprising the use of Com infected with HCV genotype 1. In still another example, the pound 1 (400 mg once daily) and Compound 2 (60 mg once treatment lasts for 10 weeks, and the subject being treated is daily) to treat genotype 3 naive Subjects. a non-responder (e.g., a null responder) infected with HCV (0020 FIG. 6 shows the predicted median SVR percent genotype 1. In yet another example, the treatment lasts for 9 ages and 90% SVR confidence intervals for interferon/ribavi weeks, and the Subject being treated is a non-responder (e.g., rin-free, 2-DAA regimens comprising the use of Compound 1 US 2014/0275099 A1 Sep. 18, 2014

(600 mg once daily) and Compound 2 (480 mg once daily) to Compound 1 is a potent HCV protease inhibitor and is treat genotype 3 naive subjects. described in U.S. Patent Application Publication No. 0021 FIG. 7 depict the synergistic effect of the combina 2012OO70416. tion of Compound 1 and Compound 2 on HCV inhibition in vitro. 0023 Compound 2 has the following structure:

Compound 2 F

F F

NO vsk O

DETAILED DESCRIPTION OF THE INVENTION Compound 2 is a potent NS5A inhibitor and is described in U.S. Patent Application Publication No. 2012/0220562. 0022. The methods of the present invention include 0024. The current standard of care (SOC) for the treatment administering Compound 1 (or a pharmaceutically accept of HCV includes a course of treatment of interferon, e.g. pegylated interferon (e.g., pegylated interferon-alpha-2a or able salt thereof) and Compound 2 (or a pharmaceutically pegylated interferon-alpha-2b, such as PEGASYS by Roche, acceptable salt thereof) to a subject in need thereof. Com or PEG-INTRON by Schering-Plough) and the antiviral drug pound 1 has the following structure: ribavirin (e.g., COPEGUS by Roche, REBETOL by Scher ing-Plough, or RIBASPHERE by Three Rivers Pharmaceu ticals). The treatment often lasts for 24-48 weeks, depending Compound 1 on hepatitis C virus genotype. Other interferons include, but are not limited to, interferon-alpha-2a (e.g., Roferon-A by Roche), interferon-alpha-2b (e.g., Intron-A by Schering Plough), and interferon alfacon-1 (consensus interferon) (e.g., Infergen by Valeant). 0025. The interferon/ribavirin-based treatment may be physically demanding, and can lead to temporary disability in Some cases. A substantial proportion of patients will experi ence a panoply of side effects ranging from a "flu-like Syn drome (the most common, experienced for a few days after the weekly injection of interferon) to severe adverse events including anemia, cardiovascular events and psychiatric problems such as suicide or suicidal ideation. The latter are exacerbated by the general physiological stress experienced by the patients. Ribavirin also has a number of side effects, including, anemia, high pill burden (e.g. 5-6 pills a day split BID) and teratogenicity restricting use in women of child bearing age. US 2014/0275099 A1 Sep. 18, 2014

0026. The methods of the present invention provide effec population, alternatively at least about 55% of the population, tive treatment of HCV infection without the use of interferon alternatively at least about 60% of the population, alterna or ribavirin and for a shorter period of time, for example and tively at least about 65% of the population, alternatively at without limitation, a treatment duration of no more than least about 70% of the population, alternatively at least about twelve weeks, alternatively no more than eleven weeks, alter 75% of the population, alternatively at least about 80% of the natively no more than ten weeks, alternatively no more than population, alternatively at least about 85% of the population, nine weeks, alternatively no more than eight weeks, alterna alternatively at least about 90% of the population, alterna tively no more than seven weeks, alternatively no more than tively at least about 95% of the population, or alternatively six weeks, alternatively no more than five weeks, alterna about 100% of the population. tively no more than four weeks, or alternatively, no more than 0030. It was unexpected that an interferon-free and ribavi three weeks. rin-free treatment using a combination of Compound 1 (or a 0027. In one aspect, the present invention features meth pharmaceutically acceptable salt thereof) and Compound 2 ods for treating HCV infection in a subject comprising (or a pharmaceutically acceptable salt thereof), and for a administering at least two DAAs, in the absence of interferon duration of no more than 12 weeks, can achieve significant and ribavirin, to the subject for a duration of no more than SVR. twelve weeks, alternatively no more than eight weeks. Put 0031. Accordingly, in one aspect, the present invention another way, the methods exclude interferon and ribavirin. features a method of treating HCV infection, comprising The at least two DAAS comprise Compound 1 (or a pharma administering to a patient in need thereofan effective amount ceutically acceptable salt thereof) and Compound 2 (or a of a combination of at least two DAAs, wherein said at least pharmaceutically acceptable Salt thereof), which can be co two DAAS comprise Compound 1 (or a pharmaceutically administered, or administered separately or independently, acceptable salt thereof) and Compound 2 (or a pharmaceuti with the same or different dosing frequencies. Preferably, the cally acceptable salt thereof). The treatment lasts 8 weeks and at least two DAAS are administered once a day. They can also does not include administration of any interferon or ribavirin. be administered, for example, twice a day or three times a day. The DAAs can be administered at the same or different dosing 0028. Various measures may be used to express the effec frequencies. The patient being treated can be a treatment tiveness of a method of the present invention. One such mea naive patient; a treatment experienced patient, including, but sure is SVR, which, as used herein, means that the virus is not limited to, a relapser, an interferon partial responder, an undetectable at the end of therapy and for at least 8 weeks interferon non-responder, or a null responder; or a patient after the end of therapy (SVR8); preferably, the virus is unde unable to take interferon. The patient may be infected with, tectable at the end of therapy and for at least 12 weeks after the for example and without limitation, HCV genotype 1. Such as end of therapy (SVR12); more preferably, the virus is unde HCV genotype 1a or HCV genotype 1b; or HCV genotype 2 tectable at the end of therapy and for at least 16 weeks after the or 3; or HCV genotype 4, 5 or 6. The treatment according to end of therapy (SVR16); and highly preferably, the virus is this aspect of the technology may also be effective against undetectable at the end of therapy and for at least 24 weeks other HCV genotypes. The DAAS can be administered around after the end of therapy (SVR24). SVR24 is often considered the same time or at different times. In addition to Compound as a functional definition of cure; and a high rate of SVR at 1 (or a salt thereof) and Compound 2 (or a salt thereof), said less than 24 week post-treatment (e.g., SVR8 or SVR12) can at least two DAAS can also include one or more additional be predictive of a high rate of SVR24. DAAs selected from, for example, HCV protease inhibitors, 0029. In some embodiments, a treatment regimen of the HCV polymerase inhibitors, or HCV NS5A inhibitors. Non invention comprises treating a population of Subjects having limiting examples of such additional DAAs include PSI HCV infection (e.g. treatment naive subjects), and the regi 7977, PSI-938, TMC-435, BMS-790052, BMS-650032, men comprises administering at least two DAAS to the Sub GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, tella jects for a duration of no more than 12 weeks, or for another previr, VX-222, mericitabine, and danoprevir. duration disclosed herein, wherein the at least two DAAS 0032. In another aspect, the present invention features a comprise Compound 1 (or a pharmaceutically acceptable salt method of treating HCV infection, comprising administering thereof) and Compound 2 (or a pharmaceutically acceptable to a patient in need thereof an effective amount of a combi salt thereof), and are administered to the Subjects in amounts nation of at least two DAAs, wherein said at least two DAAS effective to provide an SVR (e.g., SVR12 or SVR24) in at comprise Compound 1 (or a pharmaceutically acceptable salt least about 70% of the population, alternatively at least about thereof) and Compound 2 (or a pharmaceutically acceptable 75% of the population, alternatively at least about 80% of the salt thereof). The treatment lasts 7 weeks and does not include population, alternatively at least about 85% of the population, administration of any interferon or ribavirin. The DAAS can alternatively at least about 90% of the population, alterna be administered at the same or different dosing frequencies. tively at least about 95% of the population, alternatively about The patient being treated can be a treatment naive patient; a 100% of the population. In some embodiments, a treatment treatment experienced patient, including, but not limited to, a regimen of the invention comprises treating a population of relapser, an interferon partial responder, an interferon non IFN experienced Subjects (e.g., interferon non-responders) responder, or a null responder, or a patient unable to take having HCV infection, and the method comprises adminis interferon. The patient may be infected with, for example and tering at least two DAAS to the subjects for a duration of no without limitation, HCV genotype 1, such as HCV genotype more than 12 weeks, or for another duration disclosed herein, 1a or HCV genotype 1b; or HCV genotype 2 or 3; or HCV wherein the at least two DAAS comprise Compound 1 (or a genotype 4, 5 or 6. The treatment according to this aspect of pharmaceutically acceptable salt thereof) and Compound 2 the technology may also be effective against other HCV geno (or a pharmaceutically acceptable salt thereof), and are types. The DAAS can be administered around the same time administered to the subjects in amounts effective to provide or at different times. In addition to Compound 1 (or a salt an SVR (e.g., SVR 12 or SVR24) in at least about 50% of the thereof) and Compound 2 (or a salt thereof), said at least two US 2014/0275099 A1 Sep. 18, 2014

DAAS can also include one or more additional DAAs selected 0035. In yet another aspect, the present invention features from, for example, HCV protease inhibitors, HCV poly a method of treating HCV infection, comprising administer merase inhibitors, or HCV NS5A inhibitors. Non-limiting ing to a patient in need thereof an effective amount of a examples of such additional DAAs include PSI-7977, PSI combination of at least two DAAs, wherein said at least two 938, TMC-435, BMS-790052, BMS-650032, GS-5885, DAAS comprise Compound 1 (or a pharmaceutically accept GS-9190, GS-9451, BI-201335, BI-207127, telaprevir, able Salt thereof) and Compound 2 (or a pharmaceutically VX-222, mericitabine, and danoprevir. acceptable salt thereof). The treatment lasts 4 weeks and does not include administration of any interferon or ribavirin. The 0033. In yet another aspect, the present invention features DAAs can be administered at the same or different dosing a method of treating HCV infection, comprising administer frequencies. The patient being treated can be a treatment ing to a patient in need thereof an effective amount of a naive patient; a treatment experienced patient, including, but combination of at least two DAAs, wherein said at least two not limited to, a relapser, an interferon partial responder, an DAAS comprise Compound 1 (or a pharmaceutically accept interferon non-responder, or a null responder; or a patient able salt thereof) and Compound 2 (or a pharmaceutically unable to take interferon. The patient may be infected with, acceptable salt thereof). The treatment lasts 6 weeks and does for example and without limitation, HCV genotype 1. Such as not include administration of any interferon or ribavirin. The HCV genotype 1a or HCV genotype 1b; or HCV genotype 2 DAAs can be administered at the same or different dosing or 3; or HCV genotype 4, 5 or 6. The treatment according to frequencies. The patient being treated can be a treatment this aspect of the technology may also be effective against naive patient; a treatment experienced patient, including, but other HCV genotypes. The DAAS can be administered around not limited to, a relapser, an interferon partial responder, an the same time or at different times. In addition to Compound interferon non-responder, or a null responder; or a patient 1 (or a salt thereof) and Compound 2 (or a salt thereof), said unable to take interferon. The patient may be infected with, at least two DAAS can also include one or more additional for example and without limitation, HCV genotype 1. Such as DAAs selected from, for example, HCV protease inhibitors, HCV genotype 1a or HCV genotype 1b; or HCV genotype 2 HCV polymerase inhibitors, or HCV NS5A inhibitors. Non or 3; or HCV genotype 4, 5 or 6. The treatment according to limiting examples of such additional DAAs include PSI this aspect of the technology may also be effective against 7977, PSI-938, TMC-435, BMS-790052, BMS-650032, other HCV genotypes. The DAAS can be administered around GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, tella the same time or at different times. In addition to Compound previr, VX-222, mericitabine, and danoprevir. 1 (or a salt thereof) and Compound 2 (or a salt thereof), said 0036. In yet another aspect, the present invention features at least two DAAS can also include one or more additional a method of treating HCV infection, comprising administer DAAs selected from, for example, HCV protease inhibitors, ing to a patient in need thereof an effective amount of a HCV polymerase inhibitors, or HCV NS5A inhibitors. Non combination of at least two DAAs, wherein said at least two limiting examples of such additional DAAs include PSI DAAS comprise Compound 1 (or a pharmaceutically accept 7977, PSI-938, TMC-435, BMS-790052, BMS-650032, able Salt thereof) and Compound 2 (or a pharmaceutically GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, tella acceptable salt thereof). The treatment lasts 3 weeks and does previr, VX-222, mericitabine, and danoprevir. not include administration of any interferon or ribavirin. The 0034. In yet another aspect, the present invention features DAAs can be administered at the same or different dosing a method of treating HCV infection, comprising administer frequencies. The patient being treated can be a treatment ing to a patient in need thereof an effective amount of a naive patient; a treatment experienced patient, including, but combination of at least two DAAs, wherein said at least two not limited to, a relapser, an interferon partial responder, an DAAS comprise Compound 1 (or a pharmaceutically accept interferon non-responder, or a null responder; or a patient able salt thereof) and Compound 2 (or a pharmaceutically unable to take interferon. The patient may be infected with, acceptable salt thereof). The treatment lasts 5 weeks and does for example and without limitation, HCV genotype 1. Such as not include administration of any interferon or ribavirin. The HCV genotype 1a or HCV genotype 1b; or HCV genotype 2 DAAs can be administered at the same or different dosing or 3; or HCV genotype 4, 5 or 6. The treatment according to frequencies. The patient being treated can be a treatment this aspect of the technology may also be effective against naive patient; a treatment experienced patient, including, but other HCV genotypes. The DAAS can be administered around not limited to, a relapser, an interferon partial responder, an the same time or at different times. In addition to Compound interferon non-responder, or a null responder; or a patient 1 (or a salt thereof) and Compound 2 (or a salt thereof), said unable to take interferon. The patient may be infected with, at least two DAAS can also include one or more additional for example and without limitation, HCV genotype 1. Such as DAAs selected from, for example, HCV protease inhibitors, HCV genotype 1a or HCV genotype 1b; or HCV genotype 2 HCV polymerase inhibitors, or HCV NS5A inhibitors. Non or 3; or HCV genotype 4, 5 or 6. The treatment according to limiting examples of such additional DAAs include PSI this aspect of the technology may also be effective against 7977, PSI-938, TMC-435, BMS-790052, BMS-650032, other HCV genotypes. The DAAS can be administered around GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, tella the same time or at different times. In addition to Compound previr, VX-222, mericitabine, and danoprevir. 1 (or a salt thereof) and Compound 2 (or a salt thereof), said 0037. In yet another aspect, the present invention features at least two DAAS can also include one or more additional a method of treating HCV infection, comprising administer DAAs selected from, for example, HCV protease inhibitors, ing to a patient in need thereof an effective amount of a HCV polymerase inhibitors, or HCV NS5A inhibitors. Non combination of at least two DAAs, wherein said at least two limiting examples of such additional DAAs include PSI DAAS comprise Compound 1 (or a pharmaceutically accept 7977, PSI-938, TMC-435, BMS-790052, BMS-650032, able Salt thereof) and Compound 2 (or a pharmaceutically GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, tella acceptable salt thereof). The treatment lasts 24 weeks and previr, VX-222, mericitabine, and danoprevir. does not include administration of any interferon or ribavirin. US 2014/0275099 A1 Sep. 18, 2014

The DAAs can be administered at the same or different dosing for example and without limitation, HCV genotype 1. Such as frequencies. The patient being treated can be a treatment HCV genotype 1a or HCV genotype 1b; or HCV genotype 2 naive patient; a treatment experienced patient, including, but or 3; or HCV genotype 4, 5 or 6. The treatment according to not limited to, a relapser, an interferon partial responder, an this aspect of the technology may also be effective against interferon non-responder, or a null responder; or a patient other HCV genotypes. The DAAS can be administered around unable to take interferon. The patient may be infected with, the same time or at different times. In addition to Compound for example and without limitation, HCV genotype 1. Such as 1 (or a salt thereof) and Compound 2 (or a salt thereof), said HCV genotype 1a or HCV genotype 1b; or HCV genotype 2 at least two DAAS can also include one or more additional or 3; or HCV genotype 4, 5 or 6. The treatment according to DAAs selected from, for example, HCV protease inhibitors, this aspect of the technology may also be effective against HCV polymerase inhibitors, or HCV NS5A inhibitors. Non other HCV genotypes. The DAAS can be administered around limiting examples of such additional DAAs include PSI the same time or at different times. In addition to Compound 7977, PSI-938, TMC-435, BMS-790052, BMS-650032, 1 (or a salt thereof) and Compound 2 (or a salt thereof), said GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, tella at least two DAAS can also include one or more additional previr, VX-222, mericitabine, and danoprevir. As used in this DAAs selected from, for example, HCV protease inhibitors, application, a HCV polymerase inhibitor can be a nucleoside HCV polymerase inhibitors, or HCV NS5A inhibitors. Non polymerase inhibitor, a nucleotide polymerase inhibitor, a limiting examples of such additional DAAs include PSI non-nucleoside polymerase inhibitor, or a non-nucleotide 7977, PSI-938, TMC-435, BMS-790052, BMS-650032, polymerase inhibitor. GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, tella 0040. In yet another aspect, the present invention features previr, VX-222, mericitabine, and danoprevir. a method of treating HCV infection, comprising administer 0038. In yet another aspect, the present invention features ing to a patient in need thereof an effective amount of a a method of treating HCV infection, comprising administer combination of at least two DAAs, wherein said at least two ing to a patient in need thereof an effective amount of a DAAS comprise Compound 1 (or a pharmaceutically accept combination of at least two DAAs, wherein said at least two able Salt thereof) and Compound 2 (or a pharmaceutically DAAS comprise Compound 1 (or a pharmaceutically accept acceptable salt thereof). The treatment lasts 11 weeks and able salt thereof) and Compound 2 (or a pharmaceutically does not include administration of any interferon or ribavirin. acceptable salt thereof). The treatment lasts 13 to 23 weeks The DAAs can be administered at the same or different dosing (e.g., the duration of the treatment is selected from 13, 14, 15, frequencies. The patient being treated can be a treatment 16, 17, 18, 19, 20, 21, 22 or 23 weeks) and does not include naive patient; a treatment experienced patient, including, but administration of any interferon or ribavirin. The DAAS can not limited to, a relapser, an interferon partial responder, an be administered at the same or different dosing frequencies. interferon non-responder, or a null responder; or a patient The patient being treated can be a treatment naive patient; a unable to take interferon. The patient may be infected with, treatment experienced patient, including, but not limited to, a for example and without limitation, HCV genotype 1. Such as relapser, an interferon partial responder, an interferon non HCV genotype 1a or HCV genotype 1b; or HCV genotype 2 responder, or a null responder, or a patient unable to take or 3; or HCV genotype 4, 5 or 6. The treatment according to interferon. The patient may be infected with, for example and this aspect of the technology may also be effective against without limitation, HCV genotype 1, such as HCV genotype other HCV genotypes. The DAAS can be administered around 1a or HCV genotype 1b; or HCV genotype 2 or 3; or HCV the same time or at different times. In addition to Compound genotype 4, 5 or 6. The treatment according to this aspect of 1 (or a salt thereof) and Compound 2 (or a salt thereof), said the technology may also be effective against other HCV geno at least two DAAS can also include one or more additional types. The DAAS can be administered around the same time DAAs selected from, for example, HCV protease inhibitors, or at different times. In addition to Compound 1 (or a salt HCV polymerase inhibitors, or HCV NS5A inhibitors. Non thereof) and Compound 2 (or a salt thereof), said at least two limiting examples of such additional DAAs include PSI DAAS can also include one or more additional DAAs selected 7977, PSI-938, TMC-435, BMS-790052, BMS-650032, from, for example, HCV protease inhibitors, HCV poly GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, tella merase inhibitors, or HCV NS5A inhibitors. Non-limiting previr, VX-222, mericitabine, and danoprevir. examples of such additional DAAs include PSI-7977, PSI 0041. In yet another aspect, the present invention features 938, TMC-435, BMS-790052, BMS-650032, GS-5885, a method of treating HCV infection, comprising administer GS-9190, GS-9451, BI-201335, BI-207127, telaprevir, ing to a patient in need thereof an effective amount of a VX-222, mericitabine, and danoprevir. combination of at least two DAAs, wherein said at least two 0039. In yet another aspect, the present invention features DAAS comprise Compound 1 (or a pharmaceutically accept a method of treating HCV infection, comprising administer able Salt thereof) and Compound 2 (or a pharmaceutically ing to a patient in need thereof an effective amount of a acceptable salt thereof). The treatment lasts 10 weeks and combination of at least two DAAs, wherein said at least two does not include administration of any interferon or ribavirin. DAAS comprise Compound 1 (or a pharmaceutically accept The DAAs can be administered at the same or different dosing able salt thereof) and Compound 2 (or a pharmaceutically frequencies. The patient being treated can be a treatment acceptable salt thereof). The treatment lasts 12 weeks and naive patient; a treatment experienced patient, including, but does not include administration of any interferon or ribavirin. not limited to, a relapser, an interferon partial responder, an The DAAs can be administered at the same or different dosing interferon non-responder, or a null responder; or a patient frequencies. The patient being treated can be a treatment unable to take interferon. The patient may be infected with, naive patient; a treatment experienced patient, including, but for example and without limitation, HCV genotype 1. Such as not limited to, a relapser, an interferon partial responder, an HCV genotype 1a or HCV genotype 1b; or HCV genotype 2 interferon non-responder, or a null responder; or a patient or 3; or HCV genotype 4, 5 or 6. The treatment according to unable to take interferon. The patient may be infected with, this aspect of the technology may also be effective against US 2014/0275099 A1 Sep. 18, 2014

other HCV genotypes. The DAAS can be administered around method of the present invention can also be used to treat the same time or at different times. In addition to Compound patients who are not candidates for interferon treatment. 1 (or a salt thereof) and Compound 2 (or a salt thereof), said Patients who are not candidates for interferon treatment at least two DAAS can also include one or more additional include, but are not limited to, one or more of the following DAAs selected from, for example, HCV protease inhibitors, groups: patients intolerant to interferon, patients who refuse HCV polymerase inhibitors, or HCV NS5A inhibitors. Non to take interferon treatment, patients with medical conditions limiting examples of such additional DAAs include PSI which preclude them from taking interferon, and patients who 7977, PSI-938, TMC-435, BMS-790052, BMS-650032, have an increased risk of side effects or infection by taking GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, tella interferon. previr, VX-222, mericitabine, and danoprevir. 0045. In any method described herein, one or more addi 0042. In yet another aspect, the present invention features tional DAAS can be optionally used in the treatment regimen a method of treating HCV infection, comprising administer in addition to Compound 1 (or a salt thereof) and Compound ing to a patient in need thereof an effective amount of a 2 (or a salt thereof). These additional DAAS can be HCV combination of at least two DAAs, wherein said at least two protease inhibitors. HCV nucleoside or nucleotide poly DAAS comprise Compound 1 (or a pharmaceutically accept merase inhibitors, HCV non-nucleoside polymerase inhibi able salt thereof) and Compound 2 (or a pharmaceutically tors, HCV NS3B inhibitors, HCV NS4A inhibitors, HCV acceptable salt thereof). The treatment lasts 9 weeks and does NS5A inhibitors, HCV NS5B inhibitors, HCV entry inhibi not include administration of any interferon or ribavirin. The tors, cyclophilin inhibitors, or combinations thereof. DAAs can be administered at the same or different dosing 0046 Preferred HCV protease inhibitors for this purpose frequencies. The patient being treated can be a treatment include, but are not limited to, telaprevir (Vertex), boceprevir naive patient; a treatment experienced patient, including, but (Merck), BI-201335 (Boehringer Ingelheim), GS-9451 not limited to, a relapser, an interferon partial responder, an (Gilead), and BMS-650032 (BMS). Other suitable protease interferon non-responder, or a null responder; or a patient inhibitors include, but are not limited to, ACH-1095 (Achil unable to take interferon. The patient may be infected with, lion), ACH-1625 (Achillion), ACH-2684 (Achillion), AVL for example and without limitation, HCV genotype 1. Such as 181 (Avila), AVL-192 (Avila), BMS-650032 (BMS), dano HCV genotype 1a or HCV genotype 1b; or HCV genotype 2 previr (RG7227/ITMN-191, Roche), GS-9132 (Gilead), or 3; or HCV genotype 4, 5 or 6. The treatment according to GS-9256 (Gilead). IDX-136 (Idenix), IDX-316 (Idenix), this aspect of the technology may also be effective against IDX-320 (Idenix), MK-5172 (Merck), narlaprevir (Schering other HCV genotypes. The DAAS can be administered around Plough Corp), PHX-1766 (Phenomix), TMC-435 (Tibotec), the same time or at different times. In addition to Compound vaniprevir (MK-7009, Merck), VBY708 (Virobay), VX-500 1 (or a salt thereof) and Compound 2 (or a salt thereof), said (Vertex), VX-813 (Vertex), VX-985 (Vertex), or a combina at least two DAAS can also include one or more additional tion thereof. DAAs selected from, for example, HCV protease inhibitors, 0047 Preferred non-nucleoside HCV polymerase inhibi HCV polymerase inhibitors, or HCV NS5A inhibitors. Non tors for use in the present invention include, but are not limiting examples of such additional DAAs include PSI limited to, GS-9190 (Gilead), BI-207127 (Boehringer Ingel 7977, PSI-938, TMC-435, BMS-790052, BMS-650032, heim), and VX-222 (VCH-222) (Vertex & ViraChem). Pre GS-5885, GS-9190, GS-9451, BI-201335, BI-207127, tella ferred nucleotide HCV polymerase inhibitors include, but are previr, VX-222, mericitabine, and danoprevir. not limited to, PSI-7977 (Gilead), and PSI-938 (Gilead). 0043. In each aspect, embodiment, example or method Other suitable and non-limiting examples of suitable HCV described herein, Compound 1 (or a pharmaceutically accept polymerase inhibitors include ANA-598 (Anadys), able salt thereof) can be administered, for example and with BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer out limitation, from 100 mg to 600 mg once daily, and Com Ingelheim), BMS-791325 (BMS), filibuvir, GL59728 pound 2 (or a pharmaceutically acceptable salt thereof) can be (Glaxo), GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 administered, for example and without limitation, from 50 to (Idenix), MK-3281 (Merck), tegobuvir, TMC-647055 (Ti 500 mg once daily. More preferably, Compound 1 (or a phar botec), VCH-759 (Vertex & ViraChem), VCH-916 (Vi maceutically acceptable salt thereof) is administered from raChem), VX-759 (Vertex), GS-6620 (Gilead), IDX-102 200 mg to 600 mg once daily, and Compound 2 (or a phar (Idenix), IDX-184 (Idenix). INX-189 (Inhibitex), MK-0608 maceutically acceptable salt thereof) is administered from (Merck), RG7128 (Roche), TMC64912 (Medivir), 100 to 500 mg once daily. Highly preferably. Compound 1 (or GSK625433 (GlaxoSmithKline), BCX-4678 (BioCryst), a pharmaceutically acceptable salt thereof) is administered ALS-2200 (Alios BioPharma/Vertex), ALS-2158 (Alios from 400 mg to 600 mg once daily, and Compound 2 (or a BioPharma/Vertex), or a combination thereof. A polymerase pharmaceutically acceptable salt thereof) is administered inhibitor may be a nucleoside or nucleotide polymerase from 100 to 500 mg once daily. Preferably, Compound 1 (or inhibitor, such as GS-6620 (Gilead), IDX-102 (Idenix), IDX a pharmaceutically acceptable Salt thereof) can be adminis 184 (ldenix), INX-189 (Inhibitex), MK-0608 (Merck), PSI tered 400 mg once daily, and Compound 2 (or a pharmaceu 7977 (Gilead), PSI-938 (Gilead), RG7128 (Roche), tically acceptable salt thereof) is administered 120 mg once TMC64912 (Medivir), ALS-2200 (Alios BioPharma/Vertex), daily. Also preferably, Compound 1 (or a pharmaceutically ALS-2158 (Alios BioPharma/Vertex), or a combination acceptable salt thereof) can be administered 400 mg once therefore. A polymerase inhibitor may also be a non-nucleo daily, and Compound 2 (or a pharmaceutically acceptable salt side polymerase inhibitor, such as PF-00868554 (Pfizer), thereof) can be administered 240 mg once daily. ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), 0044. A method of the present invention can be used to BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), treat a nave patient or a treatment experienced patient. Treat filibuvir, GL59728 (Glaxo), GL60667 (Glaxo). GS-9669 ment experienced patients include interferon non-responders (Gilead), IDX-375 (Idenix), MK-3281 (Merck), tegobuvir (e.g., null responders), partial responders, and relapsers. A (Gilead), TMC-647055 (Tibotec). VCH-759 (Vertex & US 2014/0275099 A1 Sep. 18, 2014

ViraChem), VCH-916 (ViraChem), VX-222 (VCH-222) include, but are not limited to, AP-H005, A-831 (Arrow (Vertex & ViraChem), VX-759 (Vertex), or a combination Therapeutics) (NS5A inhibitor), A-689 (Arrow Therapeutics) thereof. (NS5A inhibitor), INX08189 (Inhibitex) (polymerase inhibi 0048 Preferred NS5A inhibitors include, but are not lim tor), ITMN-191 (Intermune/Roche) (NS3/4A Protease ited to, BMS-790052 (BMS) and GS-5885 (Gilead). Non inhibitor), VBY-376 (Protease Inhibitor) (Virobay), ACH limiting examples of suitable NS5A inhibitors include 1625 (Achillion. Protease inhibitor). IDX136 (Idenix, Pro GSK62336805 (GlaxoSmithKline), ACH-2928 (Achillion), tease Inhibitor), IDX316 (Idenix, Protease inhibitor), AZD2836 (Astra-Zeneca), AZD7295 (Astra-Zeneca), BMS VX-813 (Vertex), SCH 900518 (Schering-Plough). TMC 790052 (BMS), BMS-824393 (BMS). GS-5885 (Gilead), 435 (Tibotec), ITMN-191 (Intermune, Roche), MK-7009 PPI-1301 (Presidio), PPI-461 (Presidio) A-831 (Arrow (Merck), IDX-PI (Novartis), R7128 (Roche), PF-868554 Therapeutics), A-689 (Arrow Therapeutics) or a combination (Pfizer) (non-nucleoside polymerase inhibitor), PF-4878691 thereof. (Pfizer), IDX-184 (ldenix), IDX-375 (Idenix, NS5B poly 0049. Non-limiting examples of suitable cyclophilin merase inhibitor), PPI-461 (Presidio), BILB-1941 (Boe inhibitors include alisporovir (Novartis & Debiopharm). hiringer Ingelheim), GS-9190 (Gilead), BMS-790052 (BMS), NM-811 (Novartis), SCY-635 (Scynexis), or a combination CTS-1027 (Conatus), GS-9620 (Gilead). PF-4878691 thereof. (Pfizer), RO5303253 (Roche), ALS-2200 (Alios BioPharma/ 0050. Non-limiting examples of suitable HCV entry Vertex), ALS-2158 (Alios BioPharmaNertex). inhibitors include ITX-4520 (iTherx), ITX-5061 (iTherx), or GSK62336805 (GlaxoSmithKline), or any combinations a combination thereof. thereof. 0051 Specific examples of other DAA agents that are 0.052 The chemical structures of some of these optional suitable for inclusion in a method of the present invention HCV inhibitors are provided below:

Ol O

Telaprevir

HN Br =( O O N S

Cl O wO

O1. N N H O OH O N H O BI-201335 TMC-435 (TMC-435350) US 2014/0275099 A1 Sep. 18, 2014

-continued

BMS-650032 (Asunaprevir) danoprevir N F v-ric-s o1

O V/ N N Y -N N O. O O O O OH Y K

MK-5172 ANA-598 (Setrobuvir)

F O)21Ne.N. GS-333126 (GS-9190 or tegobuvir) US 2014/0275099 A1 Sep. 18, 2014 10

-continued

CH NH2 O HC N21

O O1. N O H3C CH O F HC O Mericitabine (R-4048 or RG7128)

GS-9451

IDX-184

filibuvir (PF-00868554)

BMS-790052 (daclatasvir) US 2014/0275099 A1 Sep 18, 2014 11

-continued

N O

O oHC O l N oHC No N

C N

BIT-225 % p-d 1. O || O PSI-352938

C CO o1 X N n N

INX-189

GS-92.56 O

No l N1 H F F "V H -N --N (co-cr) )-( )-( )- als H1 N r ON O GS-5885 US 2014/0275099 A1 Sep. 18, 2014

0053 Any HCV inhibitor or DAA described herein not limited to, no more than 11 weeks, no more than 10 weeks, encompasses its Suitable salt forms when it is used in thera no more than 9 weeks, but preferably no more than 8 weeks, peutic treatments or pharmaceutical formulations. no more than 7 weeks, no more than 6 weeks, no more than 5 0054. In some embodiments, the present invention fea weeks, no more than 4 weeks, or no more than 3 weeks, e.g., tures methods for treating patients infected with HCV geno the duration being 12 weeks, or the duration being 8 weeks. type 1. Such as 1a or 1b. The methods comprise administering 0057. In some embodiments, the present invention fea to such a patient a combination of at least 2 DAAS for no more tures methods for treating patients with HCV genotype 3 than 12 weeks (e.g., the duration being 12 weeks). Such as no infection. The methods comprise administering to Such a more than 8 weeks (e.g., the duration being 8 weeks), wherein patient a combination of at least 2 DAAs for no more than 12 the treatment does not include administration of either inter weeks (e.g., the duration being 12 weeks). Such as no more feron or ribavirin, and said at least 2 DAAS comprise Com than 8 weeks (e.g., the duration being 8 weeks), wherein the pound 1 (or a pharmaceutically acceptable salt thereof) and treatment does not include administration of either interferon Compound 2 (a pharmaceutically acceptable salt thereof). or ribavirin, and said at least 2 DAAS comprise Compound 1 Compound 1 (or a pharmaceutically acceptable salt thereof) (or a pharmaceutically acceptable salt thereof) and Com and Compound 2 (a pharmaceutically acceptable salt thereof) pound 2 (a pharmaceutically acceptable salt thereof). Com can be administered in therapeutically effective amounts to pound 1 (or a pharmaceutically acceptable salt thereof) and provide a SVR (for example, SVR12 or SVR24) after the Compound 2 (a pharmaceutically acceptable salt thereof) can completion of the treatment. The patients may be treatment be administered in therapeutically effective amounts to pro naive patients or treatment experienced patients. The treat vide a SVR (for example, SVR12 or SVR24) after the ment duration can be no more than 12 weeks, including but completion of the treatment. The patients may be treatment not limited to, no more than 11 weeks, no more than 10 weeks, naive patients or treatment experienced patients. The treat no more than 9 weeks, but preferably no more than 8 weeks, ment duration can be no more than 12 weeks, including but no more than 7 weeks, no more than 6 weeks, no more than 5 not limited to, no more than 11 weeks, no more than 10 weeks, weeks, no more than 4 weeks, or no more than 3 weeks, e.g., no more than 9 weeks, but preferably no more than 8 weeks, the duration being 12 weeks, or the duration being 8 weeks. no more than 7 weeks, no more than 6 weeks, no more than 5 0055. In some embodiments, the present invention fea weeks, no more than 4 weeks, or no more than 3 weeks, e.g., tures methods for treating patients with HCV genotype 2 or 3 the duration being 12 weeks, or the duration being 8 weeks. infection. The methods comprise administering to Such a 0058. In some embodiments, the present invention fea patient a combination of at least 2 DAAS for no more than 12 tures methods for treating patients with HCV genotype 4 weeks (e.g., the duration being 12 weeks). Such as no more infection. The methods comprise administering to Such a than 8 weeks (e.g., the duration being 8 weeks), wherein the patient a combination of at least 2 DAAs for no more than 12 treatment does not include administration of either interferon weeks (e.g., the duration being 12 weeks). Such as no more or ribavirin, and said at least 2 DAAS comprise Compound 1 than 8 weeks (e.g., the duration being 8 weeks), wherein the (or a pharmaceutically acceptable salt thereof) and Com treatment does not include administration of either interferon pound 2 (a pharmaceutically acceptable salt thereof). Com or ribavirin, and said at least 2 DAAS comprise Compound 1 pound 1 (or a pharmaceutically acceptable salt thereof) and (or a pharmaceutically acceptable salt thereof) and Com Compound 2 (a pharmaceutically acceptable salt thereof) can pound 2 (a pharmaceutically acceptable salt thereof). Com be administered in therapeutically effective amounts to pro pound 1 (or a pharmaceutically acceptable salt thereof) and vide a SVR (for example, SVR12 or SVR24) after the Compound 2 (a pharmaceutically acceptable salt thereof) can completion of the treatment. The patients may be treatment be administered in therapeutically effective amounts to pro naive patients or treatment experienced patients. The treat vide a SVR (for example, SVR12 or SVR24) after the ment duration can be no more than 12 weeks, including but completion of the treatment. The patients may be treatment not limited to, no more than 11 weeks, no more than 10 weeks, naive patients or treatment experienced patients. The treat no more than 9 weeks, but preferably no more than 8 weeks, ment duration can be no more than 12 weeks, including but no more than 7 weeks, no more than 6 weeks, no more than 5 not limited to, no more than 11 weeks, no more than 10 weeks, weeks, no more than 4 weeks, or no more than 3 weeks, e.g., no more than 9 weeks, but preferably no more than 8 weeks, the duration being 12 weeks, or the duration being 8 weeks. no more than 7 weeks, no more than 6 weeks, no more than 5 0056. In some embodiments, the present invention fea weeks, no more than 4 weeks, or no more than 3 weeks, e.g., tures methods for treating patients with HCV genotype 2 the duration being 12 weeks, or the duration being 8 weeks. infection. The methods comprise administering to Such a 0059. In some embodiments, the present invention fea patient a combination of at least 2 DAAs for no more than 12 tures methods for treating patients with HCV genotype 5 weeks (e.g., the duration being 12 weeks). Such as no more infection. The methods comprise administering to Such a than 8 weeks (e.g., the duration being 8 weeks), wherein the patient a combination of at least 2 DAAs for no more than 12 treatment does not include administration of either interferon weeks (e.g., the duration being 12 weeks). Such as no more or ribavirin, and said at least 2 DAAS comprise Compound 1 than 8 weeks (e.g., the duration being 8 weeks), wherein the (or a pharmaceutically acceptable salt thereof) and Com treatment does not include administration of either interferon pound 2 (a pharmaceutically acceptable salt thereof). Com or ribavirin, and said at least 2 DAAS comprise Compound 1 pound 1 (or a pharmaceutically acceptable salt thereof) and (or a pharmaceutically acceptable salt thereof) and Com Compound 2 (a pharmaceutically acceptable salt thereof) can pound 2 (a pharmaceutically acceptable salt thereof). Com be administered in therapeutically effective amounts to pro pound 1 (or a pharmaceutically acceptable salt thereof) and vide a SVR (for example, SVR12 or SVR24) after the Compound 2 (a pharmaceutically acceptable salt thereof) can completion of the treatment. The patients may be treatment be administered in therapeutically effective amounts to pro naive patients or treatment experienced patients. The treat vide a SVR (for example, SVR12 or SVR24) after the ment duration can be no more than 12 weeks, including but completion of the treatment. The patients may be treatment US 2014/0275099 A1 Sep. 18, 2014 naive patients or treatment experienced patients. The treat 0068. In any method described herein, the patient being ment duration can be no more than 12 weeks, including but treated can be a patient with compensated cirrhosis. not limited to, no more than 11 weeks, no more than 10 weeks, 0069. It should be understood that the above-described no more than 9 weeks, but preferably no more than 8 weeks, embodiments and the following examples are given by way of no more than 7 weeks, no more than 6 weeks, no more than 5 illustration, not limitation. Various changes and modifica weeks, no more than 4 weeks, or no more than 3 weeks, e.g., tions within the scope of the present invention will become the duration being 12 weeks, or the duration being 8 weeks. apparent to those skilled in the art from the present descrip 0060. In some embodiments, the present invention fea tion. tures methods for treating patients with HCV genotype 6 infection. The methods comprise administering to Such a Example 1 patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks). Such as no more Clinical Modeling for Interferon-Free DAA than 8 weeks (e.g., the duration being 8 weeks), wherein the Combination Therapies treatment does not include administration of either interferon or ribavirin, and said at least 2 DAAS comprise Compound 1 0070 Treatment regimens comprising administration of (or a pharmaceutically acceptable salt thereof) and Com Compound 1 and Compound 2 were evaluated using clinical pound 2 (a pharmaceutically acceptable salt thereof). Com models described in U.S. Patent Application Publication No. pound 1 (or a pharmaceutically acceptable salt thereof) and 2013/0102526, filed Oct. 19, 2012 and entitled “Methods for Compound 2 (a pharmaceutically acceptable salt thereof) can Treating HCV, which is incorporated herein by reference in be administered in therapeutically effective amounts to pro its entirety. These treatment regimens comprised administra vide a SVR (for example, SVR12 or SVR24) after the tion of Compound 1 and Compound 2, but did not include completion of the treatment. The patients may be treatment administration of either interferon or ribavirin. naive patients or treatment experienced patients. The treat (0071 FIG. 1 shows the predicted median SVR percent ment duration can be no more than 12 weeks, including but ages and 90% SVR confidence intervals for 2-DAA regimens not limited to, no more than 11 weeks, no more than 10 weeks, consisting of the use of Compound 1 (400 mg once daily) and no more than 9 weeks, but preferably no more than 8 weeks, Compound 2 (120 mg once daily) to treat genotype 1 naive no more than 7 weeks, no more than 6 weeks, no more than 5 subjects. Different treatment durations were assessed. The weeks, no more than 4 weeks, or no more than 3 weeks, e.g., predicted SVR rate for a 12-week treatment was about 95%. the duration being 12 weeks, or the duration being 8 weeks. As used in all of the figures of the present application, the 0061. It will be understood that the specific dose level for vertical bar at the top of each SVR percentage column repre any particular patient will depend upon a variety of factors sents the 90% SVR confidence interval, and the x-axis (“Time including the activity of the specific compound employed, the (weeks)') indicates the duration of each treatment regimen. age, body weight, general health, sex, diet, time of adminis (0072 FIG. 2 illustrates the predicted median SVR per centages and 90% SVR confidence intervals for 2-DAA regi tration, route of administration, rate of excretion, drug com mens consisting of the use of Compound 1 (400 mg once bination, and the severity of the disease undergoing therapy. daily) and Compound 2 (60 mg once daily) to treat genotype 0062. In any method described herein, Compound 1 (or a pharmaceutically acceptable salt thereof) and Compound 2 (a 1 naive subjects. Different treatment durations were assessed. pharmaceutically acceptable salt thereof) may be co-formu The predicted SVR rate for a 12-week treatment was about lated in a single dosage form. Non-limiting examples of Suit 85-90?o. able dosage forms include liquid or Solid dosage forms. Pref (0073 FIG. 3 shows the predicted median SVR percent erably, Compound 1 and Compound 2 are formulated in a ages and 90% SVR confidence intervals for 2-DAA regimens single solid dosage form in which at least one of the DAAS is consisting of the use of Compound 1 (600mg once daily) and in an amorphous form, or highly preferably molecularly dis Compound 2 (480 mg once daily) to treat genotype 1 naive persed, in a matrix which comprises a pharmaceutically subjects. Different treatment durations were assessed. The acceptable water-soluble polymer and a pharmaceutically predicted SVR rate for a 12-week treatment was about 100%. acceptable surfactant. The other DAAs can also be in an (0074 FIG. 4 depicts the predicted median SVR percent amorphous form or molecularly dispersed in the matrix, or ages and 90% SVR confidence intervals for 2-DAA regimen formulated in different form(s) (e.g., in a crystalline form). consisting of the use of Compound 1 (400 mg once daily) and More preferably, each of the two DAAs is in an amorphous Compound 2 (120 mg once daily) to treat genotype 3 naive form, or highly preferably molecularly dispersed, in a matrix subjects. Different treatment durations were assessed. The which comprises a pharmaceutically acceptable water predicted SVR rate for a 12-week treatment was about 95%. soluble polymer and a pharmaceutically acceptable Surfac (0075 FIG. 5 illustrates the predicted median SVR per tant. centages and 90% SVR confidence intervals for 2-DAA regi 0063. In any method described herein, the patient being men consisting of the use of Compound 1 (400 mg once daily) treated can be a treatment-naïve patient. and Compound 2 (60 mg once daily) to treat genotype 3 naive subjects. Different treatment durations were assessed. The 0064. In any method described herein, the patient being predicted SVR rate of a 12-week treatment was about treated can be an interferon non-responder. 85-90%. 0065. In any method described herein, the patient being (0076 FIG. 6 shows the predicted median SVR percent treated can be an interferon null-responder. ages and 90% SVR confidence intervals for 2-DAA regimens 0066. In any method described herein, the patient being consisting of the use of Compound 1 (600mg once daily) and treated can be without cirrhosis. Compound 2 (480 mg once daily) to treat genotype 3 naive 0067. In any method described herein, the patient being subjects. Different treatment durations were assessed. The treated can be a cirrhotic patient. predicted SVR rate of a 12-week treatment was about 100%. US 2014/0275099 A1 Sep. 18, 2014 14

Example 2 activity against many NS5A inhibitor and NS5B inhibitor resistance-associated variants in vitro (e.g., M28T, M28V. Combination of Compound 1 and Compound 2 In Q30D, Q30R, Y93C, Y93H, Y93N, L31V+Y93H, C316Y. Vitro M414T, Y448C, Y448H, S556G and S559G in GT 1a, and L28T, Y93H, S282T, C316Y.Y448H and S556G in GT1b). 0077 FIG. 7 shows that the combination of Compound 1 0080. The foregoing description of the present invention and Compound 2 exhibits significant synergistic effect on provides illustration and description, but is not intended to be HCV inhibition as tested in HCV GT 1b Con-1 replication exhaustive or to limit the invention to the precise one dis cells. The result was generated using Prichard and Shipman closed. Modifications and variations are possible in light of model (Prichard et al. ANTIVIRAL RESEARCH 14:181-205 the above teachings or may be acquired from practice of the (1990)). invention. Thus, it is noted that the scope of the invention is 0078 Compound 1 inhibited replication of HCV stable defined by the claims and their equivalents. Subgenomic replicons containing NS3 genes from GT 1a, 1b, What is claimed is: 2a, 3a, 4a, or 6a with ECso values ranging from 0.85 to 2.8 1. A method for treatment for HCV, comprising adminis nM. Of note, Compound 1 was potent against replicon con tering at least two direct acting antiviral agents (DAAS) to an taining GT3a protease, with an ECso value of 1.6 nM. Com HCV patient, wherein neither interferon nor ribavirin are pound 1 retained its activity against common GT1a and 1b administered to said patient during said treatment, and said variants at NS3 amino acid positions 155 and 168 that con treatment lasts for 8, 9, 10, 11 or 12 weeks, and wherein said ferred resistance to other HCV protease inhibitors (Pis). at least two DAAs comprise: Resistant colony selection studies in GT1a and 1b subge Compound 1 or a pharmaceutically acceptable salt thereof, nomic replicon cells identified A156T in GT1a and A156V in and GT1b as the most frequent variants, which conferred 1400 Compound 2 or a pharmaceutically acceptable salt thereof. and 1800-fold reduced susceptibility to Compound 1, respec 2. The method of claim 1, wherein said treatment lasts for tively. However, these variants had in vitro replication capaci 12 weeks. ties of only 1.5% and 9.2% that of their corresponding wild 3. The method of claim 1, wherein said patient is infected type replicons. In a replicon containing GT3a NS3 protease, with HCV genotype 1. Compound 1 selected very few colonies at concentra 4. The method of claim 1, wherein said patient is infected tions 100-fold over its EC50 value. The colonies that sur with HCV genotype 1a. vived the selection contained either A156G alone, or Q168R 5. The method of claim 1, wherein said patient is infected co-selected with Y56H, which conferred 1500- or 1100-fold with HCV genotype 2. loss in Susceptibility to Compound 1, respectively. 6. The method of claim 1, wherein said patient is infected with HCV genotype 3. TABLE 2 7. The method of claim 1, wherein said patient is infected Antiviral Activity of Compound 1 in the HCV with HCV genotype 4. Subgenomic Stable Replicon Cell Culture ASSay 8. The method of claim 1, wherein said patient is infected with HCV genotype 5. O% Human Plasma 9. The method of claim 1, wherein said patient is infected HCV Replicon Subtype Nb Mean ECso nM, it Std. Dev. with HCV genotype 6. Genotype 1a 9 O.85 O15 10. The method of claim 2, wherein said patient is infected Genotype 1b 8 O.94 O.35 with HCV genotype 1. Genotype 2a 2 2.71.1 Genotype 3a 2 1.6 0.49 11. The method of claim 2, wherein said patient is infected Genotype 4a 4 28 0.41 with HCV genotype 1a. Genotype 6a 4 O.86. O.11 12. The method of claim 2, wherein said patient is infected with HCV genotype 2. The 0% human plasma assay contains 5% fetal bovine serum 13. The method of claim 2, wherein said patient is infected Number of independent replicates with HCV genotype 3. 14. The method of claim 2, wherein said patient is infected TABLE 3 with HCV genotype 4. 15. The method of claim 2, wherein said patient is infected Antiviral Activity of Compound 1 in the HCV with HCV genotype 5. Subgenomic Stable Replicon Cell Culture Assay 16. The method of claim 2, wherein said patient is infected 40% Human Plasma with HCV genotype 6. HCV Replicon Subtype Nb Mean ECso nM, it Std. Dev. 17. The method of claim 1, wherein said patient is without Genotype 1a 10 5.3 1.O cirrhosis. Genotype 1b 8 10 S.O 18. The method of claim 1, wherein said patient is with compensated cirrhosis. The 0% human plasma assay contains 5% fetal bovine serum Number of independent replicates 19. The method of claim 2, wherein said patient is without cirrhosis. 0079. When tested against common HCV genotype 1 NS3 20. The method of claim 2, wherein said patient is with resistance-associated variants, such as V36M, R155K, compensated cirrhosis. D168A and D168V in GT 1a (H77), or T54A, R155K, 21. The method of claim 1, wherein said patient is a treat D168V and V170A in GT 1b (Con-1), Compound 1 showed ment-naïve patient. inhibitory activity nearly equivalent to that against wild-type 22. The method of claim 1, wherein said patient is an HCV replicon. Compound 1 was also shown to have potent interferon non-responder. US 2014/0275099 A1 Sep. 18, 2014 15

23. The method of claim 2, wherein said patient is a treat ment-naïve patient. 24. The method of claim 2, wherein said patient is an interferon non-responder. k k k k k