US008969357B2

(12) United States Patent (10) Patent No.: US 8,969,357 B2 Bernstein et al. (45) Date of Patent: Mar. 3, 2015

(54) METHODS FORTREATING HCV (58) Field of Classification Search CPC ...... A61K 2300/00; A61 K31/497; A61 K (71) Applicant: AbbVie Inc., North Chicago, IL (US) 31/401; A61 K31/664 (72) Inventors: Barry M. Bernstein, Mequon, WI (US); USPC ...... 514/255.05, 269,309, 314, 394,397, Rajeev M. Menon, Buffalo Grove, IL 514/422.81, 43, 4.3 (US); Amit Khatri, Waukegan, IL (US); See application file for complete search history. Sven Mensing, Mannheim (DE); Sandeep Dutta, Lincolnshire, IL (US); (56) References Cited Daniel E. Cohen, Wilmette, IL (US); Scott C. Brun, Green Oaks, IL (US); U.S. PATENT DOCUMENTS Walid M.Awni, Green Oaks, IL (US); 6,056,961 A 5, 2000 Lavie et al. Emily O. Dumas, Libertyville, IL (US); 6,143,752 A 11/2000 Oren Cheri E. Klein, Northbrook, IL (US); Thomas J. Podsadecki, Northbrook, IL (Continued) (US) FOREIGN PATENT DOCUMENTS (73) Assignee: AbbVie Inc., North Chicago, IL (US) AU 200426.1455 B2 12/2010 (*) Notice: Subject to any disclaimer, the term of this CA 2589.935 A1 6, 2006 patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. (Continued) (21) Appl. No.: 14/138,515 OTHER PUBLICATIONS (22) Filed: Dec. 23, 2013 Gane et al. “Oral combination therapy with nucleoside polymerase (65) Prior Publication Data inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype I infection (INFORM-1): a randomised double-blind, placebo-con US 2014/O1 O7017 A1 Apr. 17, 2014 trolled, dose-escalation trial.” Lancet, Oct. 15, 2010, vol. 376, pp. 1467-1475* Related U.S. Application Data (Continued) (63) Continuation of application No. 13/935,983, filed on Jul. 5, 2013, which is a continuation of application No. Primary Examiner — Shengjun Wang 13/912,601, filed on Jun. 7, 2013, now abandoned, (57) ABSTRACT (Continued) The present invention features interferon-free therapies for the treatment of HCV. Preferably, the treatment is over a (51) Int. Cl. shorter duration, such as no more than 12 weeks. In one A6 IK3I/4965 (2006.01) aspect, the therapies comprise administering at least two A6 IK3I/70 (2006.01) direct acting antiviral agents and ribavirin to a subject with (Continued) HCV infection. For example, the therapies comprise admin (52) U.S. Cl. istering to the Subject effective amounts of therapeutic agent CPC ...... A61K 38/12 (2013.01); A61 K38/07 1, therapeutic agent 2 (or therapeutic agent 3), an inhibitor of (2013.01); A61 K3I/7056 (2013.01); cytochrome P450 (e.g., ritonavir), and ribavirin. (Continued) 2 Claims, 21 Drawing Sheets

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Related U.S. Application Data 7,601,820 B2 10, 2009 Wang et al. 7,608,600 B2 10, 2009 Storer et al. which is a continuation of application No. 13/603,022, 7,648,998 B2 1, 2010 Bondy et al. filed on Sep. 4, 2012, now Pat. No. 8,466,159. 7,728,027 B2 6, 2010 Packet al. 7,754,699 B2 T/2010 Chun et al. (60) Provisional application No. 61/656,251, filed on Jun. 7,772,178 B2 8, 2010 Malcolm et al. 6, 2012, provisional application No. 61/619,870, filed 7,777.395 B2 8, 2010 Xu et al. 7,793,040 B2 9, 2010 Bittner, Jr. et al. on Apr. 3, 2012, provisional application No. 61/600, 7,820,671 B2 10, 2010 Babine et al. 276, filed on Feb. 17, 2012, provisional application 7,893,264 B2 2, 2011 Casarez et al. No. 61/587.225, filed on Jan. 17, 2012, provisional 7,906.619 B2 3, 2011 Phadke et al. application No. 61/562,181, filed on Nov. 21, 2011, 7,910,728 B2 3, 2011 Hildbrand et al. provisional application No. 61/550,352, filed on Oct. 7,915,291 B2 3, 2011 Wang et al. 7,939,667 B2 5, 2011 Llinas-Brunet et al. 21, 2011. 7,951,787 B2 5, 2011 McGuigan 7,951,789 B2 5, 2011 Sommadossi et al. (51) Int. C. 7,964,580 B2 6, 2011 Sofia et al. A6 IK3I/425 (2006.01) 7,973,040 B2 T/2011 Harper et al. A6 IK3I/40 (2006.01) 8,017,771 B2 9, 2011 Busacca et al. 8,067,438 B2 11, 2011 Llinas-Brunet et al. A6 IK3I/675 (2006.01) 8,080,654 B2 12/2011 Harper et al. A6 IK38/00 (2006.01) 8,088,368 B2 1, 2012 Guo et al. A6 IK38/2 (2006.01) 8, 101,765 B2 1, 2012 Busacca et al. A6 IK38/07 (2006.01) 8, 106,187 B2 1, 2012 Scalone et al. A6 IK3I/7056 (2006.01) 8,119,602 B2 2, 2012 Zhang et al. RE43,298 4, 2012 Saksena et al. A6 IK3I/402 (2006.01) 8,148,399 B2 4, 2012 Simmen et al. A6 IK3I/484 (2006.01) 8, 178.491 B2 5, 2012 Cho et al. A6 IK3I/426 (2006.01) 8,216.999 B2 T/2012 Holloway et al. A 6LX3L/24709 (2006.01) 8,252,923 B2 8, 2012 Babine et al. A 6LX3L/2197 (2006.01) 8,466,159 B2 6, 2013 Bernstein et al. 8.492.386 B2 T/2013 Bernstein et al. A6 IK3I/53 (2006.01) 8,680, 106 B2 3, 2014 Bernstein et al. A6 IK 45/06 (2006.01) 8,685,984 B2 4, 2014 Bernstein et al. A6 IK3I/427 (2006.01) 8,809,265 B2 8, 2014 Bernstein et al. A6 IK38/05 (2006.01) 2002/0022O15 A1 2, 2002 Okushin 2002O119122 A1 8, 2002 Stalgis et al. A63L/24025 (2006.01) 2002/0183690 A1 12, 2002 Arnisolle A 6LX3L/7072 (2006.01) 2003, OOO4119 A1 1, 2003 Ganguly et al. (52) U.S. C. 2003/OO32590 A1 2, 2003 Dieterich CPC ...... A61K 31/402 (2013.01); A61 K3I/4184 2003/0044824 A1 3, 2003 Abe 2003.0109697 A1 6, 2003 Shepard et al. (2013.01); A61 K3I/426 (2013.01); A61 K 2003. O138403 A1 T/2003 Drustrup 31/4709 (2013.01); A61K3I/497 (2013.01); 2003/O187OOO A1 10, 2003 Yao et al. A6 IK3I/513 (2013.01); A61 K3I/675 2003/O1995.18 A1 10, 2003 Dubuisson et al. (2013.01); A61K 45/06 (2013.01); A61 K 2004/O198840 A1 10, 2004 Deloach 2004/0202641 A1 10, 2004 Wei et al. 3 1/427 (2013.01); A61K38/05 (2013.01); 2005/0O85528 A1 4, 2005 Ahola et al. A6 IK3I/4025 (2013.01); A61 K3I/7072 2005/O123628 A1 6, 2005 Zabrecky (2013.01) 2005/O1871.70 A1 8, 2005 Bantia et al. USPC ...... 514/255.05:514/4.3: 514/43: 514/365; 2005.02455O2 A1 11/2005 Keller 514/422: 514/81 2005/02497 O2 A1 11/2005 Noroge et al. 2005/0288245 A1 12, 2005 Sarnow et al. References Cited 2006/0O83785 A1 4, 2006 Kerrish et al. (56) 2006/0100148 A1 5/2006 Liu et al. 2006/0105063 A1 5/2006 Hann et al. U.S. PATENT DOCUMENTS 2006, O142238 A1 6, 2006 McGuigan 2006/0228.333 A1 10, 2006 Paik 6,403,564 B1 6/2002 Ganguly et al. 2006/0229.293 A1 10, 2006 Lotsof 6,475,985 B1 1 1/2002 Wagner et al. 2006/0275366 A1 12, 2006 Malcolm et al. 6,689,814 B1 2/2004 Argy et al. 2006/02764.04 A1 12, 2006 Ghosal et al. 6,849,254 B1 2/2005 Brass et al. 2006/0276406 A1 12, 2006 Gupta et al. 6,936,629 B2 8/2005 Kong et al. 2006/02764O7 A1 12, 2006 Albrecht et al. 6,995,174 B2 2/2006 Wang et al. 2006/0281689 A1 12, 2006 Malcolm 7,012,066 B2 3/2006 Saksena et al. 2006/0287248 A1 12, 2006 Malcolm 7,105,499 B2 9, 2006 Carroll et al. 2006/0293.267 A1 12, 2006 Zamore et al. 7,125,855 B2 10/2006 Bhat et al. 2007/OOO4635 A1 1/2007 Albrecht et al. 7,153,848 B2 12/2006 Hudyma et al. 2007/0021351 A1 1/2007 White et al. 7,202,224 B2 4/2007 Eldrup et al. 2007/0092512 A1 4, 2007 Daaka et al. 7,205.330 B2 4/2007 Bogen et al. 2007/0105781 A1 5/2007 7,244,721 B2 7/2007 Saksena et al. Lyons et al. 7,348,425 B2 3/2008 Hudyma et al. 2007/02O7949 A1 9, 2007 Ghosal et al. RE40,525 E 9/2008 Llinas-Brunet et al. 2007/0224167 A1 9, 2007 Emini et al. 7,423,058 B2 9/2008 Bogen et al. 2007/O232527 A1 10, 2007 Ghosal et al. 7,429,572 B2 9, 2008 Clark 2007/0237818 A1 10, 2007 Malcolm et al. 7,470,664 B2 12/2008 Holloway et al. 2007/027.4951 A1 11/2007 Tong et al. 7,491,794 B2 2/2009 Blatt et al. 2007/0287664 A1 12, 2007 Ralston et al. 7,514,557 B2 4/2009 Busacca et al. 2008.0004236 A1 1, 2008 Comper 7,585,845 B2 9/2009 Llinas-Brunet et al. 2008, OO1995.0 A1 1, 2008 Heins et al. 7,592,316 B2 9/2009 Njoroge et al. 2008/0050336 A1 2, 2008 Bachand et al. US 8,969,357 B2 Page 3

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(56) References Cited Vertex Announces Positive Results from Viral Kinetic Study of the NucleotideAnalogue ALS-2200 in People with Hepatitis C, Jul. 30, OTHER PUBLICATIONS 2012. Vertex Pharmaceutical Incorporated, Second Quarter Financial Study to Determine the Safety and Effectiveness of Antiviral Com Results, Jul. 30, 2012. bination Therapy to Treat Hepatitis C Virus (HCV) Infected Patients Vertex Starts Global Phase 3b Study to Evaluate the Potential for Who Have Previously not been Treated with Standard of Care, People with Hepatitis C to Achieve a Viral Cure (SVR) with a Total Pharmasset, ClinicalTrials.gov Identifier: NCT01359644. Aug. 30. Treatment Duration of 12Weeks of INCIVEKCombination Therapy, 2011. Oct. 24, 3011. Sulkowski M., et al., High Sustained Virologic Response Rate in Victrelis (Boceprevir) Capsules for Oral Use, 2011. 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2 Time (weeks)

Figure 6 US 8,969,357 B2 1. 2 METHODS FOR TREATING HCV and (d) an inhibitor of cytochrome P-450 to the subject for a duration of no more than twelve weeks, or for another dura This application is a continuation of U.S. patent applica tion as set forth herein (e.g., the treatment regimen can last a tion Ser. No. 13/935,983, filed Jul. 5, 2013, which is a con duration of for no more than 8 weeks). Preferably, therapeutic tinuation of U.S. patent application Ser. No. 13/912,601 filed agent 1, the polymerase inhibitor(s), ribavirin and the inhibi Jun. 7, 2013, now abandoned, which is a continuation of U.S. tor of cytochrome P-450 are administered in amounts effec patent application Ser. No. 13/603,022 filed Sep. 4, 2012, now tive to provide high rates of SVR or another measure of U.S. Pat. No. 8,466,159, which claims the benefit of U.S. effectiveness in the Subject. As non-limiting examples, thera Provisional Application No. 61/550,352 filed Oct. 21, 2011, peutic agent 1 and the inhibitor of cytochrome P-450 can be U.S. Provisional Application No. 61/562,181 filed Nov. 21, 10 co-formulated and administered once daily, and the poly 2011, U.S. Provisional Application No. 61/587.225 filed Jan. merase inhibitor(s) can be administered once daily or twice 17, 2012, U.S. Provisional Application No. 61/600,276 filed daily, and the treatment regimen preferably lasts for twelve Feb. 17, 2012, U.S. Provisional Application No. 61/619,870 weeks (the treatment regimen can also last, for example, for filed Apr. 3, 2012, and U.S. Provisional Application No. 15 eight weeks). 61/656,251 filed Jun. 6, 2012. As still another aspect, methods for treating a population of subjects having HCV infection are provided. The methods FIELD OF THE INVENTION comprise administering at least two DAAS, together with The present invention relates to interferon-free treatment ribavirin, to the subjects for a duration of no more than 12 for hepatitis C virus (HCV). weeks. Preferably, the at least two DAAs are administered to the subjects in amounts effective to result in SVR or another BACKGROUND OF THE INVENTION measure of effectiveness in at least about 50% of the popula tion, preferably at least about 70% of the population. The HCV is an RNA virus belonging to the Hepacivirus In the foregoing methods as well as methods described genus in the Flaviviridae family. The enveloped HCV virion 25 hereinbelow, the DAAs can be selected from the group con contains a positive Stranded RNA genome encoding all sisting of protease inhibitors, nucleoside or nucleotide poly known virus-specific proteins in a single, uninterrupted, open merase inhibitors, non-nucleoside polymerase inhibitors, reading frame. The open reading frame comprises approxi NS3B inhibitors, NS4A inhibitors, NS5A inhibitors, NS5B mately 9500 nucleotides and encodes a single large polypro inhibitors, cyclophilin inhibitors, and combinations of any of tein of about 3000 amino acids. The polyprotein comprises a 30 the foregoing. For example, in Some embodiments, the DAAS core protein, envelope proteins E1 and E2, a membrane used in the present methods comprise or consist of at least one bound protein p7, and the non-structural proteins NS2. NS3, HCV protease inhibitor and at least one HCV polymerase NS4A, NS4B, NS5A and NS5B. inhibitor. The HCV polymerase inhibitor can be a nucleotide Chronic HCV infection is associated with progressive liver or nucleoside polymerase inhibitor or a non-nucleoside poly pathology, including cirrhosis and hepatocellular carcinoma. 35 merase inhibitor. The HCV polymerase inhibitor can also be Chronic hepatitis C may be treated with peginterferon-alpha a non-nucleotide polymerase inhibitor. in combination with ribavirin. Substantial limitations to effi In some embodiments, the HCV protease inhibitor is thera cacy and tolerability remain as many users suffer from side peutic agent 1 (described below) and the HCV polymerase effects, and viral elimination from the body is often incom inhibitor is therapeutic agent 2 and/or therapeutic agent 3 plete. Therefore, there is a need for new therapies to treat 40 (also described below). By way of example, therapeutic agent HCV infection. 1 can be administered a total daily dose of from about 100 mg to about 250 mg, or administered at least once daily at a dose BRIEF SUMMARY OF THE INVENTION of from about 150 mg to about 250 mg, and therapeutic agent 2 is administered in a total daily dose of from about 300 mg to As one aspect of the present invention, methods for treating 45 about 1800 mg or administered at least twice daily at doses HCV infection in a subject are provided. The methods com from about 200 mg to about 400 mg. For some embodiments, prise administering at least two direct acting antiviral agents the HCV protease inhibitor is therapeutic agent 1 and the (DAAS) and ribavirin for a duration of no more than twelve non-nucleoside HCV polymerase inhibitor is therapeutic weeks, or for another duration as set forth herein. Preferably, agent 3. By way of example, therapeutic agent 1 can be the duration of the treatment is twelve weeks. The duration of 50 administered at a total daily dose of about 100 mg, alterna the treatment can also be no more than eight weeks. Prefer tively about 200 mg. or alternatively about 250 mg; and ably, the two or more direct acting antiviral agents (DAAS) therapeutic agent 3 is administered at a total daily dose of and ribavirin are administered in amounts effective to provide about 400 mg. Ritonavir (or another cytochrome P-4503A4 a sustained virological response (SVR) or achieve another inhibitor) can be co-administered with therapeutic agent 1 to desired measure of effectiveness in a subject. The subject is 55 improve the pharmacokinetics and bioavailability of thera not administered interferon during the treatment regimen. Put peutic agent 1. another way, the methods exclude the administration of inter In some embodiments, the at least two DAAS comprise at feron to the subject, thereby avoiding the side effects associ least one HCV protease inhibitor and at least one NS5A ated with interferon. In some embodiments, the methods fur inhibitor. Preferably, the HCV protease inhibitor is therapeu ther comprise administering an inhibitor of cytochrome 60 tic agent 1 and the NS5A inhibitor is therapeutic agent 4. By P-450 (such as ritonavir) to the subject to improve the phar way of example, therapeutic agent 1 can be administered at a macokinetics or bioavailability of one or more of the DAAs. total daily dosage from about 100 mg to about 250 mg, and As another aspect, methods for treating HCV infection in a therapeutic agent 4 can be administered in a total daily dose Subject are provided. The methods comprise administering from about 25 mg to about 200 mg. Ritonavir (or another (a) therapeutic agent 1, (b) at least one polymerase inhibitor 65 cytochrome P-450 3A4 inhibitor) can be co-administered selected from the group consisting of therapeutic agent 2, with therapeutic agent 1 to improve the pharmacokinetics and therapeutic agent 3, and combinations thereof, (c) ribavirin bioavailability of therapeutic agent 1. US 8,969,357 B2 3 4 In the foregoing methods as well as methods described inhibitor, the ribavirin and the inhibitor of cytochrome P450 herein, the DAAs and ribavirin can be administered in any are administered in amounts effective to result in Sustained effective dosing schemes and/or frequencies, for example, Virological response (SVR) in the subject. they can each be administered daily. Each DAA can be In yet another aspect, the present technology provides a administered either separately or in combination, and each method for treating a population of subjects having HCV DAA can be administered at least once a day, at least twice a infection, the method comprising administering at least two day, or at least three times a day. Likewise, the ribavirin can be DAAs to the subjects for a duration of no more than 12 weeks, administered at least once a day, at least twice a day, or at least wherein the at least two DAAS are administered to the sub three times a day, either separately or in combination with one jects in amounts and for a duration effective to provide a SVR or more of the DAAs. In some preferred embodiments, thera 10 in at least about 70% of the population. peutic agent 3 is administered once daily (QD) or twice daily In another aspect, the present technology features a com (BID), and therapeutic agent 1 is administered once daily. bination of at least two DAAs for use in treating HCV infec In Some aspects, the present technology provides a method tion, wherein the duration of the treatment regimen is no more for treating HCV infection comprising administering to a than twelve weeks (e.g., the duration being 12 weeks; or the subject in need thereof at least two DAAs and ribavirin for a 15 duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). The duration of no more than twelve weeks, wherein the subject is treatment comprises administering the at least two DAAS to a not administered with interferon during said duration. In subject infected with HCV. Preferably, the duration of the Some aspects, the at least two DAAS and ribavirin are admin treatment regimen is twelve weeks. The duration of the treat istered in an amount effective to result in SVR. Some methods ment can also last, for example, no more than eight weeks further comprise administering an inhibitor of cytochrome (e.g., the duration being 8 weeks; or the duration being 7, 6, 5. P450 to the subject. In some aspects, the duration is no more 4, or 3 weeks). The treatment includes administering ribavirin than eight weeks. but does not include administering interferon. The treatment In some aspects of the present technology, the at least two may also include administering ritonavir or another CYP3A4 direct acting antiviral agents comprise (i) Compound 1 or a inhibitor (e.g., cobicistat) if one of the DAAS requires phar pharmaceutically acceptable salt thereof, which is co-admin 25 macokinetic enhancement. The at least two DAAS can be istered or co-formulated with ritonavir, and (ii) Compound 2 administered concurrently or sequentially. For example, one or a pharmaceutically acceptable salt thereof. DAA can be administered once daily, and another DAA can In other aspects, the at least two direct acting antiviral be administered twice daily. For another example, the two agents comprise (i) Compound 1 or a pharmaceutically DAAS are administered once daily. For yet another example, acceptable salt thereof, which is co-administered or co-for 30 the two DAAS are co-formulated in a single composition and mulated with ritonavir, and (ii) Compound 3 or a pharmaceu administered concurrently (e.g., once daily). As a non-limit tically acceptable salt thereof. ing example, the patient being treated can be infected with In yet another aspect, the at least two direct acting antiviral HCV genotype 1. Such as genotype 1a or 1b. As another agents comprise (i) Compound 1 or a pharmaceutically non-limiting example, the patient can be infected with HCV acceptable salt thereof, which is co-administered or co-for 35 genotype 2 or 3. As yet another non-limiting example, the mulated with ritonavir, and (ii) compound 4 or a pharmaceu patient can be a HCV-treatment naive patient, a HCV-treat tically acceptable salt thereof. ment experienced patient, an interferon non-responder (e.g., a In yet a further aspect, the at least two direct acting antiviral null responder, a partial responder or a relapser), or not a agents comprise (i) Compound 1 or a pharmaceutically candidate for interferon treatment. acceptable salt thereof, which is co-administered or co-for 40 In another aspect, the present technology features a com mulated with ritonavir, (ii) Compound 2 or a pharmaceuti bination of Compound 1 (or a pharmaceutically acceptable cally acceptable salt thereof, and (iii) compound 4 or a phar salt thereof) and Compound 2 (or a pharmaceutically accept maceutically acceptable salt thereof. able salt thereof) for use in treating HCV infection. The In yet another aspect, the at least two direct acting antiviral treatment comprises administering the DAAS to a subject agents comprises a drug combination selected from the group 45 infected with HCV. The duration of the treatment regimen is consisting of: a combination of PSI-7977 and PSI-938, a no more than twelve weeks (e.g., the duration being 12 combination of BMS-790052 and BMS-650032, a combina weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 tion of GS-5885 and GS-9451, a combination of GS-5885, weeks). Preferably, the duration of the treatment regimen is GS-9190 and GS-9451, a combination of BI-201335 and twelve weeks. The duration of the treatment can also last, for BI-27127, a combination of telaprevir and VX-222, a combi 50 example, no more than eight weeks (e.g., the duration being 8 nation of PSI-7977 and TMC-435, and a combination of weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The danoprevir and R7128. In yet another aspect, the at least two treatment includes administering ribavirin but does not direct acting antiviral agents comprises a combination of include administering interferon; and ritonavir or another PSI-7977 and BMS-790052 (daclatasvir). In yet another CYP3A4 inhibitor (e.g., cobicistat) is administered with aspect, the at least two direct acting antiviral agents comprises 55 Compound 1 (or the salt thereof) to improve the pharmaco a combination of PSI-7977 and BMS-650032 (asunaprevir). kinetics of the latter. Compound 1 (or the salt thereof) and In still another aspect, the at least two direct acting antiviral Compound 2 (or the salt thereof) can be administered con agents comprises a combination of PSI-7977, BMS-650032 currently or sequentially. For example, Compound 1 (or the (asunaprevir) and BMS-790052 (daclatasvir). salt thereof) can be administered once daily, together with In other aspects, the present technology provides a method 60 ritonavir or another CYP3A4 inhibitor (e.g., cobicistat), and for treating HCV infection in a Subject comprising adminis Compound 2 (or the salt thereof) can be administered twice tering (a) therapeutic agent 1, (b) at least one polymerase daily. For yet another example, Compound 1 (or the salt inhibitor selected from the group consisting of therapeutic thereof) and ritonavir (or another CYP3A4 inhibitor, e.g., agent 2, therapeutic agent 3 and combinations thereof, (c) cobicistat) are co-formulated in a single composition and ribavirin and (d) an inhibitor of cytochrome P450 to the 65 administered concurrently (e.g., once daily). For yet another subject and for a duration of no more than twelve weeks, example, Compound 1 (or the salt thereof), co-formulated wherein the therapeutic agent 1, the at least one polymerase with ritonavir (or another CYP3A4 inhibitor, e.g., cobicistat), US 8,969,357 B2 5 6 is administered once daily, and Compound 2 (or the salt weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The thereof) is administered twice daily. As a non-limiting treatment includes administering ribavirin but does not example, the patient being treated can be infected with HCV include administering interferon; and ritonavir or another genotype 1. Such as genotype 1a or 1b. As another non CYP3A4 inhibitor (e.g., cobicistat) is administered with limiting example, the patient can be infected with HCV geno Compound 1 (or the salt thereof) to improve the pharmaco type 2 or 3. As yet another non-limiting example, the patient kinetics of the latter. Compound 1 (or the salt thereof) and can be a HCV-treatment naive patient, a HCV-treatment expe Compound 3 (or the salt thereof) can be administered con rienced patient, an interferon non-responder (e.g., a null currently or sequentially. For example, Compound 1 (or the responder), or not a candidate for interferon treatment. In one salt thereof) can be administered once daily, together with example, the treatment lasts for 12 weeks, and the Subject 10 ritonavir or another CYP3A4 inhibitor (e.g., cobicistat), and being treated is a naive patient infected with HCV genotype 1. Compound 3 (or the salt thereof) can be administered twice In another example, the treatment lasts for 11 weeks, and the daily. For another example, Compound 1 (or the salt thereof) subject being treated is a naive patient infected with HCV and Compound 3 (or the salt thereof) are administered once genotype 1. In still another example, the treatment lasts for 10 daily. For yet another example, Compound 1 (or the salt weeks, and the Subject being treated is a naive patient infected 15 thereof) and ritonavir (or another CYP3A4 inhibitor, e.g., with HCV genotype 1. In yet another example, the treatment cobicistat) are co-formulated in a single composition and lasts for 9 weeks, and the subject being treated is a naive administered concurrently (e.g., once daily). For yet another patient infected with HCV genotype 1. In yet another example, Compound 1 (or the salt thereof), ritonavir (or example, the treatment lasts for 8 weeks, and the subject another CYP3A4 inhibitor, e.g., cobicistat), and Compound 3 being treated is a naive patient infected with HCV genotype 1. (or the Salt thereof) are co-formulated in a single composition In yet another example, the treatment lasts for 12 weeks, and and administered concurrently (e.g., once daily). As a non the subject being treated is a naive patient infected with HCV limiting example, the patient being treated can be infected genotype 2. In another example, the treatment lasts for 11 with HCV genotype 1. Such as genotype 1a or 1b. As another weeks, and the Subject being treated is a naive patient infected non-limiting example, the patient can be infected with HCV with HCV genotype 2. In still another example, the treatment 25 genotype 2 or 3. As yet another non-limiting example, the lasts for 10 weeks, and the subject being treated is a naive patient can be a HCV-treatment naive patient, a HCV-treat patient infected with HCV genotype 2. In yet another ment experienced patient, an interferon non-responder (e.g., a example, the treatment lasts for 9 weeks, and the subject null responder), or not a candidate for interferon treatment. In being treated is a naive patient infected with HCV genotype 2. one example, the treatment lasts for 12 weeks, and the Subject In yet another example, the treatment lasts for 8 weeks, and 30 being treated is a naive patient infected with HCV genotype 1. the subject being treated is a naive patient infected with HCV In another example, the treatment lasts for 11 weeks, and the genotype 2. In yet another example, the treatment lasts for 12 subject being treated is a naive patient infected with HCV weeks, and the Subject being treated is a naive patient infected genotype 1. In still another example, the treatment lasts for 10 with HCV genotype 3. In another example, the treatment lasts weeks, and the Subject being treated is a naive patient infected for 11 weeks, and the Subject being treated is a naive patient 35 with HCV genotype 1. In yet another example, the treatment infected with HCV genotype 3. In still another example, the lasts for 9 weeks, and the subject being treated is a naive treatment lasts for 10 weeks, and the subject being treated is patient infected with HCV genotype 1. In yet another a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 8 weeks, and the subject example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. being treated is a naive patient infected with HCV genotype 3. 40 In yet another example, the treatment lasts for 12 weeks, and In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV the subject being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 11 genotype 3. In yet another example, the treatment lasts for 12 weeks, and the Subject being treated is a naive patient infected weeks, and the Subject being treated is a non-responder (e.g., with HCV genotype 2. In still another example, the treatment a null responder) infected with HCV genotype 1. In another 45 lasts for 10 weeks, and the subject being treated is a naive example, the treatment lasts for 11 weeks, and the Subject patient infected with HCV genotype 2. In yet another being treated is a non-responder (e.g., a null responder) example, the treatment lasts for 9 weeks, and the subject infected with HCV genotype 1. In still another example, the being treated is a naive patient infected with HCV genotype 2. treatment lasts for 10 weeks, and the subject being treated is In yet another example, the treatment lasts for 8 weeks, and a non-responder (e.g., a null responder) infected with HCV 50 the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 9 genotype 2. In yet another example, the treatment lasts for 12 weeks, and the Subject being treated is a non-responder (e.g., weeks, and the Subject being treated is a naive patient infected a null responder) infected with HCV genotype 1. In yet with HCV genotype 3. In another example, the treatment lasts another example, the treatment lasts for 8 weeks, and the for 11 weeks, and the Subject being treated is a naive patient Subject being treated is a non-responder infected (e.g., a null 55 infected with HCV genotype 3. In still another example, the responder) with HCV genotype 1. treatment lasts for 10 weeks, and the subject being treated is In another aspect, the present technology features a com a naive patient infected with HCV genotype 3. In yet another bination of Compound 1 (or a pharmaceutically acceptable example, the treatment lasts for 9 weeks, and the subject salt thereof) and Compound 3 (or a pharmaceutically accept being treated is a naive patient infected with HCV genotype 3. able salt thereof) for use in treating HCV infection. The 60 In yet another example, the treatment lasts for 8 weeks, and treatment comprises administering the DAAS to a subject the subject being treated is a naive patient infected with HCV infected with HCV. The duration of the treatment regimen is genotype 3. In yet another example, the treatment lasts for 12 no more than twelve weeks (e.g., the duration being 12 weeks, and the Subject being treated is a non-responder (e.g., weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 a null responder) infected with HCV genotype 1. In another weeks). Preferably, the duration of the treatment regimen is 65 example, the treatment lasts for 11 weeks, and the Subject twelve weeks. The duration of the treatment can also last, for being treated is a non-responder (e.g., a null responder) example, no more than eight weeks (e.g., the duration being 8 infected with HCV genotype 1. In still another example, the US 8,969,357 B2 7 8 treatment lasts for 10 weeks, and the subject being treated is In yet another example, the treatment lasts for 8 weeks, and a non-responder (e.g., a null responder) infected with HCV the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 9 genotype 2. In yet another example, the treatment lasts for 12 weeks, and the Subject being treated is a non-responder (e.g., weeks, and the Subject being treated is a naive patient infected a null responder) infected with HCV genotype 1. In yet with HCV genotype 3. In another example, the treatment lasts another example, the treatment lasts for 8 weeks, and the for 11 weeks, and the Subject being treated is a naive patient Subject being treated is a non-responder (e.g., a null infected with HCV genotype 3. In still another example, the responder) infected with HCV genotype 1. treatment lasts for 10 weeks, and the subject being treated is In another aspect, the present technology features a com a naive patient infected with HCV genotype 3. In yet another bination of Compound 1 (or a pharmaceutically acceptable 10 example, the treatment lasts for 9 weeks, and the subject salt thereof) and compound 4 (or a pharmaceutically accept being treated is a naive patient infected with HCV genotype 3. able salt thereof) for use in treating HCV infection. The In yet another example, the treatment lasts for 8 weeks, and treatment comprises administering the DAAS to a subject the subject being treated is a naive patient infected with HCV infected with HCV. The duration of the treatment regimen is genotype 3. In yet another example, the treatment lasts for 12 no more than twelve weeks (e.g., the duration being 12 15 weeks, and the Subject being treated is a non-responder (e.g., weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 a null responder) infected with HCV genotype 1. In another weeks). Preferably, the duration of the treatment regimen is example, the treatment lasts for 11 weeks, and the Subject twelve weeks. The duration of the treatment can also last, for being treated is a non-responder (e.g., a null responder) example, no more than eight weeks (e.g., the duration being 8 infected with HCV genotype 1. In still another example, the weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The treatment lasts for 10 weeks, and the subject being treated is treatment includes administering ribavirin but does not a non-responder (e.g., a null responder) infected with HCV include administering interferon; and ritonavir or another genotype 1. In yet another example, the treatment lasts for 9 CYP3A4 inhibitor (e.g., cobicistat) is administered with weeks, and the Subject being treated is a non-responder (e.g., Compound 1 (or the salt thereof) to improve the pharmaco a null responder) infected with HCV genotype 1. In yet kinetics of the latter. Compound 1 (or the salt thereof) and 25 another example, the treatment lasts for 8 weeks, and the compound 4 (or the salt thereof) can be administered concur Subject being treated is a non-responder (e.g., a null rently or sequentially. For example, Compound 1 (or the salt responder) infected with HCV genotype 1. thereof) can be administered once daily, together with In another aspect, the present technology features a com ritonavir or another CYP3A4 inhibitor (e.g., cobicistat), and bination of Compound 1 (or a pharmaceutically acceptable compound 4 (or the salt thereof) can be administered twice 30 salt thereof), Compound 2 (or a pharmaceutically acceptable daily. For another example, Compound 1 (or the salt thereof) salt thereof), and compound 4 (or a pharmaceutically accept and compound 4 (or the salt thereof) are administered once able salt thereof) for use in treating HCV infection. The daily. For yet another example, Compound 1 (or the salt treatment comprises administering the DAAS to a subject thereof) and ritonavir (or another CYP3A4 inhibitor, e.g., infected with HCV. The duration of the treatment regimen is cobicistat) are co-formulated in a single composition and 35 no more than twelve weeks (e.g., the duration being 12 administered concurrently (e.g., once daily). For yet another weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 example, Compound 1 (or the salt thereof), ritonavir (or weeks). Preferably, the duration of the treatment regimen is another CYP3A4 inhibitor, e.g., cobicistat), and compound 4 twelve weeks. The duration of the treatment can also last, for (or the Salt thereof) are co-formulated in a single composition example, no more than eight weeks (e.g., the duration being 8 and administered concurrently (e.g., once daily). As a non 40 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The limiting example, the patient being treated can be infected treatment includes administering ribavirin but does not with HCV genotype 1. Such as genotype 1a or 1b. As another include administering interferon; and ritonavir or another non-limiting example, the patient can be infected with HCV CYP3A4 inhibitor (e.g., cobicistat) is administered with genotype 2 or 3. As yet another non-limiting example, the Compound 1 (or the salt thereof) to improve the pharmaco patient can be a HCV-treatment naive patient, a HCV-treat 45 kinetics of the latter. Compound 1 (or the salt thereof), Com ment experienced patient, an interferon non-responder (e.g., a pound 2 (or the salt thereof), and compound 4 (or the salt null responder), or not a candidate for interferon treatment. In thereof) can be administered concurrently or sequentially. For one example, the treatment lasts for 12 weeks, and the Subject example, Compound 1 (or the salt thereof) can be adminis being treated is a naive patient infected with HCV genotype 1. tered once daily, together with ritonavir or another CYP3A4 In another example, the treatment lasts for 11 weeks, and the 50 inhibitor (e.g., cobicistat), and compound 4 (or the salt subject being treated is a naive patient infected with HCV thereof) can be administered once daily, and Compound 2 (or genotype 1. In still another example, the treatment lasts for 10 the salt thereof) can be administered twice daily. For yet weeks, and the Subject being treated is a naive patient infected another example, Compound 1 (or the salt thereof), com with HCV genotype 1. In yet another example, the treatment pound 4 (or the salt thereof), and ritonavir (or another lasts for 9 weeks, and the subject being treated is a naive 55 CYP3A4 inhibitor, e.g., cobicistat) are co-formulated in a patient infected with HCV genotype 1. In yet another single composition and administered concurrently (e.g., once example, the treatment lasts for 8 weeks, and the subject daily). For yet another example, Compound 1 (or the salt being treated is a naive patient infected with HCV genotype 1. thereof), ritonavir (or another CYP3A4 inhibitor, e.g., cobi In yet another example, the treatment lasts for 12 weeks, and cistat), and compound 4 (or the Salt thereof) are co-formu the subject being treated is a naive patient infected with HCV 60 lated in a single composition and administered concurrently genotype 2. In another example, the treatment lasts for 11 (e.g., once daily), and Compound 2 (or the salt thereof) are weeks, and the Subject being treated is a naive patient infected administered twice daily. As a non-limiting example, the with HCV genotype 2. In still another example, the treatment patient being treated can be infected with HCV genotype 1, lasts for 10 weeks, and the subject being treated is a naive Such as genotype 1a or 1b. As another non-limiting example, patient infected with HCV genotype 2. In yet another 65 the patient can be infected with HCV genotype 2 or 3. As yet example, the treatment lasts for 9 weeks, and the subject another non-limiting example, the patient can be a HCV being treated is a naive patient infected with HCV genotype 2. treatment naive patient, a HCV-treatment experienced US 8,969,357 B2 10 patient, an interferon non-responder (e.g., a null responder), also last, for example, no more than eight weeks (e.g., the or not a candidate for interferon treatment. In one example, duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 the treatment lasts for 12 weeks, and the subject being treated weeks). The treatment includes administering ribavirin but is a naive patient infected with HCV genotype 1. In another does not include administering interferon. The treatment may example, the treatment lasts for 11 weeks, and the Subject also include administering ritonavir or another CYP3A4 being treated is a naive patient infected with HCV genotype 1. inhibitor (e.g., cobicistat) if one of the DAAS requires phar In still another example, the treatment lasts for 10 weeks, and macokinetic enhancement. The at least two DAAS can be the subject being treated is a naive patient infected with HCV administered concurrently or sequentially. For example, one genotype 1. In yet another example, the treatment lasts for 9 DAA can be administered once daily, and another DAA can weeks, and the Subject being treated is a naive patient infected 10 with HCV genotype 1. In yet another example, the treatment be administered twice daily. For another example, the two lasts for 8 weeks, and the subject being treated is a naive DAAS are administered once daily. For yet another example, patient infected with HCV genotype 1. In yet another the two DAAS are co-formulated in a single composition and example, the treatment lasts for 12 weeks, and the Subject administered concurrently (e.g., once daily). As a non-limit being treated is a naive patient infected with HCV genotype 2. 15 ing example, the patient being treated can be infected with In another example, the treatment lasts for 11 weeks, and the HCV genotype 1. Such as genotype 1a or 1b. As another subject being treated is a naive patient infected with HCV non-limiting example, the patient can be infected with HCV genotype 2. In still another example, the treatment lasts for 10 genotype 2 or 3. As yet another non-limiting example, the weeks, and the Subject being treated is a naive patient infected patient can be a HCV-treatment naive patient, a HCV-treat with HCV genotype 2. In yet another example, the treatment ment experienced patient, an interferon non-responder (e.g., a lasts for 9 weeks, and the subject being treated is a naive null responder), or not a candidate for interferon treatment. patient infected with HCV genotype 2. In yet another In yet another aspect, the present technology features a example, the treatment lasts for 8 weeks, and the subject combination of at least two DAAs for use in treating HCV being treated is a naive patient infected with HCV genotype 2. infection, wherein said combination comprises a combina In yet another example, the treatment lasts for 12 weeks, and 25 tion selected from: the subject being treated is a naive patient infected with HCV a combination of PSI-7977 and BMS-790052 genotype 3. In another example, the treatment lasts for 11 a combination of PSI-7977 and BMS-650032, weeks, and the Subject being treated is a naive patient infected a combination of PSI-7977, BMS-790052 and BMS with HCV genotype 3. In still another example, the treatment 650032, lasts for 10 weeks, and the subject being treated is a naive 30 a combination of INX-189 and BMS-790.052 patient infected with HCV genotype 3. In yet another a combination of INX-189 and BMS-650032, or example, the treatment lasts for 9 weeks, and the subject a combination of INX-189, BMS-790052 and being treated is a naive patient infected with HCV genotype 3. BMS-65OO32. In yet another example, the treatment lasts for 8 weeks, and The treatment comprises administering the DAA combina the subject being treated is a naive patient infected with HCV 35 tion to a subject infected with HCV. The duration of the genotype 3. In yet another example, the treatment lasts for 12 treatment regimen is no more than twelve weeks (e.g., the weeks, and the Subject being treated is a non-responder (e.g., duration being 12 weeks; or the duration being 11, 10,9,8,7, a null responder) infected with HCV genotype 1. In another 6, 5, 4, or 3 weeks). Preferably, the duration of the treatment example, the treatment lasts for 11 weeks, and the Subject regimen is twelve weeks. The duration of the treatment can being treated is a non-responder (e.g., a null responder) 40 also last, for example, no more than eight weeks (e.g., the infected with HCV genotype 1. In still another example, the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 treatment lasts for 10 weeks, and the subject being treated is weeks). The treatment includes administering ribavirin but a non-responder (e.g., a null responder) infected with HCV does not include administering interferon. The treatment may genotype 1. In yet another example, the treatment lasts for 9 include administering ritonavir or another CYP3A4 inhibitor weeks, and the Subject being treated is a non-responder (e.g., 45 (e.g., cobicistat) if one of the DAAS requires pharmacokinetic a null responder) infected with HCV genotype 1. In yet enhancement. The at least two DAAS can be administered another example, the treatment lasts for 8 weeks, and the concurrently or sequentially. For example, one DAA can be Subject being treated is a non-responder (e.g., a null administered once daily, and another DAA can be adminis responder) infected with HCV genotype 1. tered twice daily. For another example, the two DAAs are In another aspect, the present technology features a com 50 administered once daily. For yet another example, the two bination of at least two DAAs for use in treating HCV infec DAAS are co-formulated in a single composition and admin tion, wherein said combination comprises a combination istered concurrently (e.g., once daily). As a non-limiting selected from: example, the patient being treated can be infected with HCV a combination of PSI-7977 and PSI-938, genotype 1. Such as genotype 1a or 1b. As another non a combination of BMS-790052 and BMS-650032, 55 limiting example, the patient can be infected with HCV geno a combination of GS-5885 and GS-9451, type 2 or 3. As yet another non-limiting example, the patient a combination of GS-5885, GS-9190 and GS-9451, can be a HCV-treatment naive patient, a HCV-treatment expe a combination of BI-201335 and BI-27127, rienced patient, an interferon non-responder (e.g., a null a combination of telaprevir and VX-222, responder), or not a candidate for interferon treatment. a combination of PSI-7977 and TMC-435, and 60 In still another aspect, the present technology features PSI a combination of danoprevir and R7128. 7977, or a combination of at least two DAAs, for use in The treatment comprises administering the DAA combina treating HCV infection, wherein said combination comprises tion to a subject infected with HCV. The duration of the a combination selected from: treatment regimen is no more than twelve weeks (e.g., the a combination of mericitabine and danoprevir, duration being 12 weeks; or the duration being 11, 10,9,8,7, 65 a combination of INX-189, daclatasvir and BMS-791325, 6, 5, 4, or 3 weeks). Preferably, the duration of the treatment and regimen is twelve weeks. The duration of the treatment can a combination of PSI-7977 and GS-5885. US 8,969,357 B2 11 12 The treatment comprises administering PSI-7977 or the DAA The treatment comprises administering the DAA combina combination to a subject infected with HCV. The duration of tion to a subject infected with HCV. The duration of the the treatment regimen is no more than twelve weeks (e.g., the treatment regimen is no more than twelve weeks (e.g., the duration being 12 weeks; or the duration being 11, 10,9,8,7, duration being 12 weeks; or the duration being 11, 10,9,8,7, 6, 5, 4, or 3 weeks). For example, the duration of the treatment 5 6, 5, 4, or 3 weeks). Preferably, the duration of the treatment regimen is no more than eight weeks (e.g., the duration being regimen is twelve weeks. The duration of the treatment can 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The also last, for example, no more than eight weeks (e.g., the treatment includes administering ribavirin but does not duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 include administering interferon. The treatment may include weeks). The treatment includes administering ribavirin but administering ritonavir or another CYP3A4 inhibitor (e.g., 10 does not include administering interferon. The treatment may cobicistat) if one of the DAAs requires pharmacokinetic include administering ritonavir or another CYP3A4 inhibitor enhancement. The at least two DAAS can be administered (e.g., cobicistat) if one of the DAAS requires pharmacokinetic concurrently or sequentially. For example, one DAA can be enhancement. The at least two DAAS can be administered administered once daily, and another DAA can be adminis concurrently or sequentially. For example, one DAA can be tered twice daily. For another example, the two DAAs are 15 administered once daily, and another DAA can be adminis administered once daily. For yet another example, the two tered twice daily. For another example, the two DAAs are DAAS are co-formulated in a single composition and admin administered once daily. For yet another example, the two istered concurrently (e.g., once daily). As a non-limiting DAAS are co-formulated in a single composition and admin example, the patient being treated can be infected with HCV istered concurrently (e.g., once daily). As a non-limiting genotype 1. Such as genotype 1a or 1b. As another non example, the patient being treated can be infected with HCV limiting example, the patient can be infected with HCV geno genotype 1. Such as genotype 1a or 1b. As another non type 2 or 3. As yet another non-limiting example, the patient limiting example, the patient can be infected with HCV geno can be a HCV-treatment naive patient, a HCV-treatment expe type 2 or 3. As yet another non-limiting example, the patient rienced patient, an interferon non-responder (e.g., a null can be a HCV-treatment naive patient, a HCV-treatment expe responder), or not a candidate for interferon treatment. 25 rienced patient, an interferon non-responder (e.g., a null In still another aspect, the present technology features PSI responder), or not a candidate for interferon treatment. 7977, or a combination of at least two DAAs, for use in In yet another aspect, the present technology features a treating HCV infection, wherein said combination comprises combination of PSI-7977 and BMS-790.052 for use in treat a combination selected from: ing HCV infection. The treatment comprises administering a combination of mericitabine and danoprevir, 30 the DAA combination to a subject infected with HCV. The a combination of INX-189, daclatasvir and BMS-791325, duration of the treatment can last, for example, no more than and twelve weeks (e.g., the duration being 12 weeks; or the dura a combination of PSI-7977 and GS-5885. tion being 11, 10,9,8,7,6, 5, 4, or 3 weeks). Preferably, the The treatment comprises administering PSI-7977 or the DAA duration of the treatment regimen is twelve weeks. The dura combination to a subject infected with HCV. The duration of 35 tion of the treatment can also last, for example, no more than the treatment regimen is no more than twelve weeks (e.g., the eight weeks (e.g., the duration being 8 weeks; or the duration duration being 12 weeks; or the duration being 11, 10,9,8,7, being 7, 6, 5, 4, or 3 weeks). The treatment includes admin 6, 5, 4, or 3 weeks). Preferably, the duration of the treatment istering ribavirin but does not include administering inter regimen is twelve weeks. The duration of the treatment can feron. The treatment may include administering ritonavir or also last, for example, no more than eight weeks (e.g., the 40 another CYP3A4 inhibitor (e.g., cobicistat) if one of the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 DAAS requires pharmacokinetic enhancement. The two weeks). The treatment includes administering ribavirin but DAAS can be administered concurrently or sequentially. For does not include administering interferon. The treatment may example, one DAA can be administered once daily, and the include administering ritonavir or another CYP3A4 inhibitor other DAA can be administered twice daily. For another (e.g., cobicistat) if one of the DAAS requires pharmacokinetic 45 example, the two DAAs are administered once daily. For yet enhancement. The at least two DAAS can be administered another example, the two DAAS are co-formulated in a single concurrently or sequentially. For example, one DAA can be composition and administered concurrently (e.g., once daily). administered once daily, and another DAA can be adminis As a non-limiting example, the patient being treated can be tered twice daily. For another example, the two DAAs are infected with HCV genotype 1, such as genotype 1a or 1b. As administered once daily. For yet another example, the two 50 another non-limiting example, the patient can be infected DAAS are co-formulated in a single composition and admin with HCV genotype 2 or 3. As yet another non-limiting istered concurrently (e.g., once daily). As a non-limiting example, the patient can be a HCV-treatment naive patient, a example, the patient being treated can be infected with HCV HCV-treatment experienced patient, an interferon non-re genotype 1. Such as genotype 1a or 1b. As another non sponder (e.g., a null responder), or not a candidate for inter limiting example, the patient can be infected with HCV geno 55 feron treatment. In one example, the treatment lasts for 12 type 2 or 3. As yet another non-limiting example, the patient weeks, and the Subject being treated is a naive patient infected can be a HCV-treatment naive patient, a HCV-treatment expe with HCV genotype 1. In another example, the treatment lasts rienced patient, an interferon non-responder (e.g., a null for 11 weeks, and the Subject being treated is a naive patient responder), or not a candidate for interferon treatment. infected with HCV genotype 1. In still another example, the In still another aspect, the present technology features a 60 treatment lasts for 10 weeks, and the subject being treated is combination of at least two DAAs, for use in treating HCV a naive patient infected with HCV genotype 1. In yet another infection, wherein said combination comprises a combina example, the treatment lasts for 9 weeks, and the subject tion selected from: being treated is a naive patient infected with HCV genotype 1. a combination of tegobuvir and GS-9256. In yet another example, the treatment lasts for 8 weeks, and a combination of BMS-791325, asunaprevir and daclatas 65 the subject being treated is a naive patient infected with HCV Vir, and genotype 1. In yet another example, the treatment lasts for 12 a combination of TMC-435 and daclatasvir. weeks, and the Subject being treated is a naive patient infected US 8,969,357 B2 13 14 with HCV genotype 2. In another example, the treatment lasts weeks, and the Subject being treated is a naive patient infected for 11 weeks, and the Subject being treated is a naive patient with HCV genotype 1. In yet another example, the treatment infected with HCV genotype 2. In still another example, the lasts for 9 weeks, and the subject being treated is a naive treatment lasts for 10 weeks, and the subject being treated is patient infected with HCV genotype 1. In yet another a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 8 weeks, and the subject example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 12 weeks, In yet another example, the treatment lasts for 8 weeks, and and the subject being treated is a naive patient infected with the subject being treated is a naive patient infected with HCV HCV genotype 2. In another example, the treatment lasts for genotype 2. In yet another example, the treatment lasts for 12 10 11 weeks, and the Subject being treated is a naive patient weeks, and the Subject being treated is a naive patient infected infected with HCV genotype 2. In still another example, the with HCV genotype 3. In another example, the treatment lasts treatment lasts for 10 weeks, and the subject being treated is for 11 weeks, and the Subject being treated is a naive patient a naive patient infected with HCV genotype 2. In yet another infected with HCV genotype 3. In still another example, the example, the treatment lasts for 9 weeks, and the subject treatment lasts for 10 weeks, and the subject being treated is 15 being treated is a naive patient infected with HCV genotype 2. a naive patient infected with HCV genotype 3. In yet another In yet another example, the treatment lasts for 8 weeks, and example, the treatment lasts for 9 weeks, and the subject the subject being treated is a naive patient infected with HCV being treated is a naive patient infected with HCV genotype 3. genotype 2. In yet another example, the treatment lasts for 12 In yet another example, the treatment lasts for 8 weeks, and weeks, and the Subject being treated is a naive patient infected the subject being treated is a naive patient infected with HCV with HCV genotype 3. In another example, the treatment lasts genotype 3. In yet another example, the treatment lasts for 12 for 11 weeks, and the Subject being treated is a naive patient weeks, and the Subject being treated is a non-responder (e.g., infected with HCV genotype 3. In still another example, the a null responder) infected with HCV genotype 1. In another treatment lasts for 10 weeks, and the subject being treated is example, the treatment lasts for 11 weeks, and the Subject a naive patient infected with HCV genotype 3. In yet another being treated is a non-responder (e.g., a null responder) 25 example, the treatment lasts for 9 weeks, and the subject infected with HCV genotype 1. In still another example, the being treated is a naive patient infected with HCV genotype 3. treatment lasts for 10 weeks, and the subject being treated is In yet another example, the treatment lasts for 8 weeks, and a non-responder (e.g., a null responder) infected with HCV the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 9 genotype 3. In yet another example, the treatment lasts for 12 weeks, and the Subject being treated is a non-responder (e.g., 30 weeks, and the Subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet a null responder) infected with HCV genotype 1. In another another example, the treatment lasts for 8 weeks, and the example, the treatment lasts for 11 weeks, and the subject Subject being treated is a non-responder (e.g., a null being treated is a non-responder (e.g., a null responder) responder) infected with HCV genotype 1. infected with HCV genotype 1. In still another example, the In yet another aspect, the present technology features a 35 treatment lasts for 10 weeks, and the subject being treated is combination of PSI-7977 and TMC-435 for use in treating a non-responder (e.g., a null responder) infected with HCV HCV infection. The treatment comprises administering the genotype 1. In yet another example, the treatment lasts for 9 DAA combination to a subject infected with HCV. The dura weeks, and the Subject being treated is a non-responder (e.g., tion of the treatment regimen is no more than twelve weeks a null responder) infected with HCV genotype 1. In yet (e.g., the duration being 12 weeks; or the duration being 11, 40 another example, the treatment lasts for 8 weeks, and the 10,9,8,7,6, 5, 4, or 3 weeks). Preferably, the duration of the Subject being treated is a non-responder (e.g., a null treatment regimen is twelve weeks. The duration of the treat responder) infected with HCV genotype 1. ment can also last, for example, no more than eight weeks In yet another aspect, the present technology features a (e.g., the duration being 8 weeks; or the duration being 7, 6, 5. combination of danoprevir and mercitabine for use in treating 4, or 3 weeks). The treatment includes administering ribavirin 45 HCV infection. The treatment comprises administering the but does not include administering interferon. The treatment DAA combination to a subject infected with HCV. The dura may include administering ritonavir or another CYP3A4 tion of the treatment regimen is no more than sixteen weeks inhibitor (e.g., cobicistat) if one of the DAAS requires phar (e.g., the duration being 16 weeks; or the duration being 14. macokinetic enhancement. The two DAAS can be adminis 12 or 10 weeks). The duration of the treatment regimen may tered concurrently or sequentially. For example, one DAA 50 also be less than 10 weeks. The treatment includes adminis can be administered once daily, and the other DAA can be tering ribavirin but does not include administering interferon. administered twice daily. For another example, the two DAAS The treatment also includes co-administering ritonavir or are administered once daily. For yet another example, the two another CYP3A4 inhibitor (e.g., cobicistat) with danoprevir DAAS are co-formulated in a single composition and admin to improve the pharmacokinetics of danoprevir. The two istered concurrently (e.g., once daily). As a non-limiting 55 DAAS can be administered concurrently or sequentially. For example, the patient being treated can be infected with HCV example, one DAA can be administered once daily, and the genotype 1. Such as genotype 1a or 1b. As another non other DAA can be administered twice daily. For another limiting example, the patient can be infected with HCV geno example, the two DAAs are administered once daily. For yet type 2 or 3. As yet another non-limiting example, the patient another example, the two DAAS are co-formulated in a single can be a HCV-treatment naive patient, a HCV-treatment expe 60 composition and administered concurrently (e.g., once daily). rienced patient, an interferon non-responder (e.g., a null As a non-limiting example, the patient being treated can be responder), or not a candidate for interferon treatment. In one infected with HCV genotype 1, such as genotype 1a or 1b. As example, the treatment lasts for 12 weeks, and the Subject another non-limiting example, the patient can be infected being treated is a naive patient infected with HCV genotype 1. with HCV genotype 2 or 3. As yet another non-limiting In another example, the treatment lasts for 11 weeks, and the 65 example, the patient can be a HCV-treatment naive patient, a subject being treated is a naive patient infected with HCV HCV-treatment experienced patient, an interferon non-re genotype 1. In still another example, the treatment lasts for 10 sponder (e.g., a null responder), or not a candidate for inter US 8,969,357 B2 15 16 feron treatment. In one example, the treatment lasts for 16 Such as genotype 1a or 1b. As another non-limiting example, weeks, and the Subject being treated is a naive patient infected the patient can be infected with HCV genotype 2 or 3. As yet with HCV genotype 1. In another example, the treatment lasts another non-limiting example, the patient can be a HCV for 15 weeks, and the subject being treated is a naive patient treatment naive patient, a HCV-treatment experienced infected with HCV genotype 1. In still another example, the patient, an interferon non-responder (e.g., a null responder), treatment lasts for 14 weeks, and the Subject being treated is or not a candidate for interferon treatment. In one example, a naive patient infected with HCV genotype 1. In yet another the treatment lasts for 16 weeks, and the subject being treated example, the treatment lasts for 13 weeks, and the subject is a naive patient infected with HCV genotype 1. In another being treated is a naive patient infected with HCV genotype 1. example, the treatment lasts for 15 weeks, and the subject In yet another example, the treatment lasts for 12 weeks, and 10 being treated is a naive patient infected with HCV genotype 1. the subject being treated is a naive patient infected with HCV In still another example, the treatment lasts for 14 weeks, and genotype 1. In yet another example, the treatment lasts for 12 the subject being treated is a naive patient infected with HCV weeks, and the Subject being treated is a naive patient infected genotype 1. In yet another example, the treatment lasts for 13 with HCV genotype 2. In another example, the treatment lasts weeks, and the Subject being treated is a naive patient infected for 11 weeks, and the Subject being treated is a naive patient 15 with HCV genotype 1. In yet another example, the treatment infected with HCV genotype 2. In still another example, the lasts for 12 weeks, and the Subject being treated is a naive treatment lasts for 10 weeks, and the subject being treated is patient infected with HCV genotype 1. In yet another a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 12 weeks, and the Subject example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 11 weeks, and the In yet another example, the treatment lasts for 8 weeks, and subject being treated is a naive patient infected with HCV the subject being treated is a naive patient infected with HCV genotype 2. In still another example, the treatment lasts for 10 genotype 2. In yet another example, the treatment lasts for 16 weeks, and the Subject being treated is a naive patient infected weeks, and the Subject being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment with HCV genotype 3. In another example, the treatment lasts 25 lasts for 9 weeks, and the subject being treated is a naive for 15 weeks, and the subject being treated is a naive patient patient infected with HCV genotype 2. In yet another infected with HCV genotype 3. In still another example, the example, the treatment lasts for 8 weeks, and the subject treatment lasts for 14 weeks, and the Subject being treated is being treated is a naive patient infected with HCV genotype 2. a naive patient infected with HCV genotype 3. In yet another In yet another example, the treatment lasts for 16 weeks, and example, the treatment lasts for 13 weeks, and the subject 30 the subject being treated is a naive patient infected with HCV being treated is a naive patient infected with HCV genotype 3. genotype 3. In another example, the treatment lasts for 15 In yet another example, the treatment lasts for 12 weeks, and weeks, and the subject being treated is a naive patient infected the subject being treated is a naive patient infected with HCV with HCV genotype 3. In still another example, the treatment genotype 3. In yet another example, the treatment lasts for 16 lasts for 14 weeks, and the Subject being treated is a naive weeks, and the Subject being treated is a non-responder (e.g., 35 patient infected with HCV genotype 3. In yet another a null responder) infected with HCV genotype 1. In another example, the treatment lasts for 13 weeks, and the subject example, the treatment lasts for 15 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. being treated is a non-responder (e.g., a null responder) In yet another example, the treatment lasts for 12 weeks, and infected with HCV genotype 1. In still another example, the the subject being treated is a naive patient infected with HCV treatment lasts for 14 weeks, and the Subject being treated is 40 genotype 3. In yet another example, the treatment lasts for 16 a non-responder (e.g., a null responder) infected with HCV weeks, and the Subject being treated is a non-responder (e.g., genotype 1. In yet another example, the treatment lasts for 13 a null responder) infected with HCV genotype 1. In another weeks, and the Subject being treated is a non-responder (e.g., example, the treatment lasts for 15 weeks, and the subject a null responder) infected with HCV genotype 1. In yet being treated is a non-responder (e.g., a null responder) another example, the treatment lasts for 12 weeks, and the 45 infected with HCV genotype 1. In still another example, the Subject being treated is a non-responder (e.g., a null treatment lasts for 14 weeks, and the Subject being treated is responder) infected with HCV genotype 1. a non-responder (e.g., a null responder) infected with HCV In yet another aspect, the present technology features a genotype 1. In yet another example, the treatment lasts for 13 combination of INX-189, daclatasvir and BMS-791325 for weeks, and the Subject being treated is a non-responder (e.g., use in treating HCV infection. The treatment comprises 50 a null responder) infected with HCV genotype 1. In yet administering the DAA combination to a subject infected another example, the treatment lasts for 12 weeks, and the with HCV. The duration of the treatment regimen is no more Subject being treated is a non-responder (e.g., a null than sixteen weeks (e.g., the duration being 16 weeks; or the responder) infected with HCV genotype 1. duration being 14, 12 or 10 weeks). The duration of the In yet another aspect, the present technology features a treatment regimen may also be less than 10 weeks. The treat 55 combination of PSI-7977 and GS-5885 for use in treating ment includes administering ribavirin but does not include HCV infection. The treatment comprises administering the administering interferon. The treatment may include admin DAA combination to a subject infected with HCV. The dura istering ritonavir or another CYP3A4 inhibitor (e.g., cobi tion of the treatment regimen is no more than sixteen weeks cistat) if one of the DAAS requires pharmacokinetic enhance (e.g., the duration being 16 weeks; or the duration being 14. ment. The two DAAS can be administered concurrently or 60 12 or 10 weeks). The duration of the treatment regimen may sequentially. For example, one DAA can be administered also be less than 10 weeks. The treatment includes adminis once daily, and the other DAA can be administered twice tering ribavirin but does not include administering interferon. daily. For another example, the two DAAs are administered The treatment may include administering ritonavir or another once daily. For yet another example, the two DAAs are co CYP3A4 inhibitor (e.g., cobicistat) if one of the DAAS formulated in a single composition and administered concur 65 requires pharmacokinetic enhancement. The two DAAS can rently (e.g., once daily). As a non-limiting example, the be administered concurrently or sequentially. For example, patient being treated can be infected with HCV genotype 1, one DAA can be administered once daily, and the other DAA US 8,969,357 B2 17 18 can be administered twice daily. For another example, the two can be, for example, a treatment-naïve patient. The Subject DAAS are administered once daily. For yet another example, can also be a treatment-experienced patient, or an interferon the two DAAS are co-formulated in a single composition and non-responder (e.g., a null responder). Preferably, the Subject administered concurrently (e.g., once daily). As a non-limit being treated is infected with HCV genotype 1, e.g., HCV ing example, the patient being treated can be infected with genotype 1a. As another non-limiting example, the Subject HCV genotype 1. Such as genotype 1a or 1b. As another being treatment is infected with HCV genotype 3. non-limiting example, the patient can be infected with HCV In one embodiment of this aspect of the invention, the at genotype 2 or 3. As yet another non-limiting example, the least two DAAS comprise (i) Compound 1 or a pharmaceuti patient can be a HCV-treatment naive patient, a HCV-treat cally acceptable salt thereof, and (ii) Compound 2 or a phar ment experienced patient, an interferon non-responder (e.g., a 10 null responder), or not a candidate for interferon treatment. In maceutically acceptable salt thereof, and said method further one example, the treatment lasts for 16 weeks, and the Subject comprises administering ritonavir to the Subject. Ritonavir being treated is a naive patient infected with HCV genotype 1. improves the pharmacokinetics or drug exposure of Com In another example, the treatment lasts for 15 weeks, and the pound 1. The treatment can last, for example and without subject being treated is a naive patient infected with HCV 15 limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or genotype 1. In still another example, the treatment lasts for 14 12 weeks. Preferably, the treatment lasts for 12 weeks. The weeks, and the Subject being treated is a naive patient infected treatment can also last for 8 weeks. The subject being treated with HCV genotype 1. In yet another example, the treatment can be, for example, a treatment-naïve patient. The Subject lasts for 13 weeks, and the subject being treated is a naive can also be a treatment-experienced patient, or an interferon patient infected with HCV genotype 1. In yet another non-responder (e.g., a null responder). Preferably, the Subject example, the treatment lasts for 12 weeks, and the Subject being treated is infected with HCV genotype 1, e.g., HCV being treated is a naive patient infected with HCV genotype 1. genotype 1a. As another non-limiting example, the Subject In yet another example, the treatment lasts for 12 weeks, and being treatment is infected with HCV genotype 3. the subject being treated is a naive patient infected with HCV In another embodiment of this aspect of the invention, the genotype 2. In another example, the treatment lasts for 11 25 at least two DAAS comprise (i) Compound 1 or a pharmaceu weeks, and the Subject being treated is a naive patient infected tically acceptable salt thereof, and (ii) Compound 4 or a with HCV genotype 2. In still another example, the treatment pharmaceutically acceptable salt thereof, and the method fur lasts for 10 weeks, and the subject being treated is a naive ther comprises administering ritonavir to the Subject to patient infected with HCV genotype 2. In yet another improve the pharmacokinetics or drug exposure of Com example, the treatment lasts for 9 weeks, and the subject 30 being treated is a naive patient infected with HCV genotype 2. pound 1. The treatment can last, for example and without In yet another example, the treatment lasts for 8 weeks, and limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or the subject being treated is a naive patient infected with HCV 12 weeks. Preferably, the treatment lasts for 12 weeks. The genotype 2. In yet another example, the treatment lasts for 16 treatment can also last for 8 weeks. The subject being treated weeks, and the Subject being treated is a naive patient infected 35 can be, for example, a treatment-naïve patient. The Subject with HCV genotype 3. In another example, the treatment lasts can also be a treatment-experienced patient, or an interferon for 15 weeks, and the subject being treated is a naive patient non-responder (e.g., a null responder). Preferably, the Subject infected with HCV genotype 3. In still another example, the being treated is infected with HCV genotype 1, e.g., HCV treatment lasts for 14 weeks, and the Subject being treated is genotype 1a. As another non-limiting example, the Subject a naive patient infected with HCV genotype 3. In yet another 40 being treatment is infected with HCV genotype 3. example, the treatment lasts for 13 weeks, and the subject In another embodiment of this aspect of the invention, the being treated is a naive patient infected with HCV genotype 3. at least two DAAS comprise (i) Compound 1 or a pharmaceu In yet another example, the treatment lasts for 12 weeks, and tically acceptable salt thereof, (ii) Compound 2 or a pharma the subject being treated is a naive patient infected with HCV ceutically acceptable salt thereof, and (iii) Compound 4 or a genotype 3. In yet another example, the treatment lasts for 16 45 pharmaceutically acceptable salt thereof, and the method fur weeks, and the Subject being treated is a non-responder (e.g., ther comprises administering ritonavir to the Subject to a null responder) infected with HCV genotype 1. In another improve the pharmacokinetics or drug exposure of Com example, the treatment lasts for 15 weeks, and the subject pound 1. The treatment can last, for example and without being treated is a non-responder (e.g., a null responder) limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or infected with HCV genotype 1. In still another example, the 50 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment lasts for 14 weeks, and the Subject being treated is treatment can also last for 8 weeks. The subject being treated a non-responder (e.g., a null responder) infected with HCV can be, for example, a treatment-naïve patient. The Subject genotype 1. In yet another example, the treatment lasts for 13 can also be a treatment-experienced patient, or an interferon weeks, and the Subject being treated is a non-responder (e.g., non-responder (e.g., a null responder). Preferably, the Subject a null responder) infected with HCV genotype 1. In yet 55 being treated is infected with HCV genotype 1, e.g., HCV another example, the treatment lasts for 12 weeks, and the genotype 1a. As another non-limiting example, the Subject Subject being treated is a non-responder (e.g., a null being treatment is infected with HCV genotype 3. responder) infected with HCV genotype 1. In yet another embodiment of this aspect of the invention, In another aspect, the present invention features methods the at least two DAAs comprise a HCV protease inhibitor and for treatment of HCV infection, wherein the methods com 60 a HCV polymerase inhibitor. The treatment can last, for prise administering to a Subject in need thereof at least two example and without limitation, for no more than 12 weeks, direct acting antiviral agents (DAAS) and ribavirin, and the such as 8,9, 10, 11 or 12 weeks. Preferably, the treatment lasts treatment does not include administration of interferon to the for 12 weeks. The treatment can also last for 8 weeks. The Subject. The treatment can last, for example and without Subject being treated can be, for example, a treatment-naive limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 65 patient. The Subject can also be a treatment-experienced 12 weeks. Preferably, the treatment lasts for 12 weeks. The patient, or an interferon non-responder (e.g., a null treatment can also last for 8 weeks. The subject being treated responder). Preferably, the subject being treated is infected US 8,969,357 B2 19 20 with HCV genotype 1, e.g., HCV genotype 1a. As another In yet another embodiment of this aspect of the invention, non-limiting example, the Subject being treatment is infected the at least two DAAs comprise a HCV nucleoside or nucle with HCV genotype 3. otide polymerase inhibitor and a HCV NS5A inhibitor. The In yet another embodiment of this aspect of the invention, treatment can last, for example and without limitation, for no the at least two DAAs comprise a HCV protease inhibitor and 5 more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Pref a non-nucleoside or non-nucleotide HCV polymerase inhibi erably, the treatment lasts for 12 weeks. The treatment can tor. The treatment can last, for example and without limita also last for 8 weeks. The subject being treated can be, for tion, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 example, a treatment-naïve patient. The Subject can also be a weeks. Preferably, the treatment lasts for 12 weeks. The treat treatment-experienced patient, or an interferon non-re ment can also last for 8 weeks. The Subject being treated can 10 sponder (e.g., a null responder). Preferably, the Subject being be, for example, a treatment-naïve patient. The Subject can treated is infected with HCV genotype 1, e.g., HCV genotype also be a treatment-experienced patient, oran interferon non 1a. As another non-limiting example, the Subject being treat responder (e.g., a null responder). Preferably, the Subject ment is infected with HCV genotype 3. being treated is infected with HCV genotype 1, e.g., HCV In yet another embodiment of this aspect of the invention, genotype 1a. As another non-limiting example, the Subject 15 the at least two DAAS comprise PSI-7977 and TMC-435. The being treatment is infected with HCV genotype 3. treatment can last, for example and without limitation, for no In yet another embodiment of this aspect of the invention, more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Pref the at least two DAAs comprise a HCV protease inhibitor and erably, the treatment lasts for 12 weeks. The treatment can a nucleoside or nucleotide HCV polymerase inhibitor. The also last for 8 weeks. The subject being treated can be, for treatment can last, for example and without limitation, for no example, a treatment-naïve patient. The Subject can also be a more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Pref treatment-experienced patient, or an interferon non-re erably, the treatment lasts for 12 weeks. The treatment can sponder (e.g., a null responder). Preferably, the Subject being also last for 8 weeks. The subject being treated can be, for treated is infected with HCV genotype 1, e.g., HCV genotype example, a treatment-naïve patient. The Subject can also be a 1a. As another non-limiting example, the Subject being treat treatment-experienced patient, or an interferon non-re 25 ment is infected with HCV genotype 3. sponder (e.g., a null responder). Preferably, the Subject being In yet another embodiment of this aspect of the invention, treated is infected with HCV genotype 1, e.g., HCV genotype the at least two DAAs comprise PSI-7977 and daclatasvir. 1a. As another non-limiting example, the Subject being treat The treatment can last, for example and without limitation, ment is infected with HCV genotype 3. for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. In yet another embodiment of this aspect of the invention, 30 Preferably, the treatment lasts for 12 weeks. The treatment the at least two DAAs comprise a HCV protease inhibitor and can also last for 8 weeks. The subject being treated can be, for a HCV NS5A inhibitor. The treatment can last, for example example, a treatment-naïve patient. The subject can also be a and without limitation, for no more than 12 weeks, such as 8, treatment-experienced patient, or an interferon non-re 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 sponder (e.g., a null responder). Preferably, the Subject being weeks. The treatment can also last for 8 weeks. The subject 35 treated is infected with HCV genotype 1, e.g., HCV genotype being treated can be, for example, a treatment-naïve patient. 1a. As another non-limiting example, the Subject being treat The Subject can also be a treatment-experienced patient, oran ment is infected with HCV genotype 3. interferon non-responder (e.g., a null responder). Preferably, In yet another embodiment of this aspect of the invention, the subject being treated is infected with HCV genotype 1, the at least two DAAS comprise PSI-7977 and GS-5885. The e.g., HCV genotype 1a. As another non-limiting example, the 40 treatment can last, for example and without limitation, for no subject being treatment is infected with HCV genotype 3. more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Pref In yet another embodiment of this aspect of the invention, erably, the treatment lasts for 12 weeks. The treatment can the at least two DAAs comprise a HCV polymerase inhibitor also last for 8 weeks. The subject being treated can be, for and a HCV NS5A inhibitor. The treatment can last, for example, a treatment-naïve patient. The Subject can also be a example and without limitation, for no more than 12 weeks, 45 treatment-experienced patient, or an interferon non-re such as 8,9, 10, 11 or 12 weeks. Preferably, the treatment lasts sponder (e.g., a null responder). Preferably, the Subject being for 12 weeks. The treatment can also last for 8 weeks. The treated is infected with HCV genotype 1, e.g., HCV genotype Subject being treated can be, for example, a treatment-naive 1a. As another non-limiting example, the Subject being treat patient. The Subject can also be a treatment-experienced ment is infected with HCV genotype 3. patient, or an interferon non-responder (e.g., a null 50 In yet another embodiment of this aspect of the invention, responder). Preferably, the subject being treated is infected the at least two DAAs comprise mericitabine and danoprevir. with HCV genotype 1, e.g., HCV genotype 1a. As another The treatment can last, for example and without limitation, non-limiting example, the Subject being treatment is infected for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. with HCV genotype 3. Preferably, the treatment lasts for 12 weeks. The treatment In yet another embodiment of this aspect of the invention, 55 can also last for 8 weeks. The subject being treated can be, for the at least two DAAs comprise a HCV non-nucleoside or example, a treatment-naïve patient. The Subject can also be a non-nucleotide polymerase inhibitor and a HCV NS5A treatment-experienced patient, or an interferon non-re inhibitor. The treatment can last, for example and without sponder (e.g., a null responder). Preferably, the Subject being limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or treated is infected with HCV genotype 1, e.g., HCV genotype 12 weeks. Preferably, the treatment lasts for 12 weeks. The 60 1a. As another non-limiting example, the Subject being treat treatment can also last for 8 weeks. The subject being treated ment is infected with HCV genotype 3. can be, for example, a treatment-naïve patient. The Subject In yet another embodiment of this aspect of the invention, can also be a treatment-experienced patient, or an interferon the at least two DAAs comprise BMS-790052 and BMS non-responder (e.g., a null responder). Preferably, the Subject 650032. The treatment can last, for example and without being treated is infected with HCV genotype 1, e.g., HCV 65 limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or genotype 1a. As another non-limiting example, the Subject 12 weeks. Preferably, the treatment lasts for 12 weeks. The being treatment is infected with HCV genotype 3. treatment can also last for 8 weeks. The subject being treated US 8,969,357 B2 21 22 can be, for example, a treatment-naïve patient. The Subject FIG. 2 is a contour plot showing concentrations at which can also be a treatment-experienced patient, or an interferon Compound 1 and Compound 2 exhibited Syngeristic, addi non-responder (e.g., a null responder). Preferably, the Subject tive, or antagonistic interactions in the genotype 1b HCV being treated is infected with HCV genotype 1, e.g., HCV replicon assay. genotype 1b. As a non-limiting example, the Subject being FIG. 3 is a 3-D surface plot illustrating deviations from treatment is infected with HCV genotype 1a. As another expected inhibitory effects from varying concentrations of non-limiting example, the Subject being treatment is infected Compound 1 and compound 4 in a genotype 1b HCV replicon with HCV genotype 3. assay. In yet another embodiment of this aspect of the invention, FIG. 4 is a contour plot showing concentrations at which the at least two DAAs comprise INX-189, daclatasvir and 10 Compound 1 and compound 4 exhibited Syngeristic, additive, BMS-791325. The treatment can last, for example and with or antagonistic interactions in the genotype 1b HCV replicon out limitation, for no more than 12 weeks, such as 8, 9, 10, 11 assay. or 12 weeks. Preferably, the treatment lasts for 12 weeks. The FIG. 5A is a bar graph showing the percentage of cells treatment can also last for 8 weeks. The subject being treated containing HCV genotype 1a replicon constructs Surviving can be, for example, a treatment-naïve patient. The Subject 15 after three weeks of exposure to therapeutic agent 1, thera can also be a treatment-experienced patient, or an interferon peutic agent 2, therapeutic agent 4, or a combination of some non-responder (e.g., a null responder). Preferably, the Subject or all of those therapeutic agents in the presence of G418. being treated is infected with HCV genotype 1, e.g., HCV FIG. 5B is another bar graph showing the percentage of genotype 1a. As another non-limiting example, the Subject surviving 1a-H77 replicon cells grown in the presence of being treatment is infected with HCV genotype 3. G418, and two or three DAA combinations, for approxi In yet another aspect, the present invention features meth mately three weeks. ods for treatment of a treatment-naive subject with HCV FIG. 5C depicts the effect of Compound 1, Compound 2 genotype 1 infection, wherein the method comprises admin and a combination thereof in long-term HCV RNA reduction istering to said patient PSI-7977 and ribavirin, and the treat assays in 1a-H77 replicon cell lines. ment does not include administration of interferon to the 25 FIG. 5D demonstrates the effect of Compound 1, Com Subject. The treatment can last, for example and without pound 2 and a combination thereof in long-term HCV RNA limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or reduction assays in 1b-Con1 replicon cell lines. 12 weeks. Preferably, the treatment lasts for 12 weeks. The FIG. 6A shows the predicted median and 90% confidence treatment can also last for 8 weeks. Preferably, the subject interval of SVR percentage for different treatment durations being treated is infected with genotype 1a. More preferably, 30 of a 2-DAA regimen withoutribavirin; the 2 DAAs include (i) the subject being treated is a naive patient infected with Compound 1 with ritonavir (Compound 1/r) and (ii) Com genotype 1. The subject being treated can also be a treatment pound 2. experienced patient or an interferon non-responder (e.g., a FIG. 6B illustrates the predicted median and 90% confi null responder), and/or is infected with HCV genotype 3. In dence interval of SVR percentage for different treatment one example, the treatment lasts for 12 weeks, and the Subject 35 durations of a 2-DAA regimen without ribavirin; the 2 DAAS being treated is a naive patient infected with genotype 1. In include (i) Compound 1 with ritonavir (Compound 1/r) and another example, the treatment lasts for 11 weeks, and the (ii) Compound 4. Subject being treated is a naive patient infected with genotype FIG. 6C depicts the predicted median and 90% confidence 1. In still another example, the treatment lasts for 10 weeks, interval of SVR percentage for different treatment durations and the subject being treated is a naive patient infected with 40 of a 3-DAA regimen withoutribavirin; the 3 DAAs include (i) genotype 1. In yet another example, the treatment lasts for 9 Compound 1 with ritonavir (Compound 1/r), (ii) Compound weeks, and the Subject being treated is a naive patient infected 2 and (iii) Compound 4. with genotype 1. In yet another example, the treatment lasts FIG. 7 shows the exposure-response model predicted ver for 8 weeks, and the subject being treated is a naive patient sus observed percentage of subjects with HCV RNA less than infected with genotype 1. The present invention also features 45 LOD over time in the clinical study described in Example 1. PSI-7977 or a pharmaceutical acceptable salt thereof for use FIG. 8 demonstrates the exposure-response model pre in any treatment described in this aspect of the invention. dicted versus observed percentage of subjects with SVR12 in A treatment regimen of the present technology generally the clinical study described in Example 2A. constitutes a complete treatment regimen, i.e., no Subsequent FIG. 9 shows the predicted median and 90% confidence interferon-containing regimen is intended. Thus, a treatment 50 interval of SVR rates for different treatment durations of a or use described herein generally does not include any Sub 2-DAA regimen containing BMS-790052 and BMS-650032. sequent interferon-containing treatment. FIG. 10 shows the predicted median of SVR rates for Other features, objects, and advantages of the present different treatment durations of a 3-DAA regimen containing invention are apparent in the detailed description that follows. Compound 1/r, Compound 4 and PSI-7977. It should be understood, however, that the detailed descrip 55 FIG. 11 shows the predicted median and 90% confidence tion, while indicating preferred embodiments of the inven interval of SVR percentage for different treatment durations tion, are given by way of illustration only, not limitation. of a 1-DAA regimen containing PSI-7977 and ribavirin. Various changes and modifications within the scope of the FIG. 12 depicts the predicted median and 90% confidence invention will become apparent to those skilled in the art from interval of SVR percentage for different treatment durations the detailed description 60 of a 2-DAA regimen containing daclatasvir (BMS-790052) 60 mg QD and PSI-7977 400 mg QD. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 13 shows the predicted median and 90% confidence interval of SVR percentage for different treatment durations FIG. 1 is a 3-D surface plot illustrating deviations from of a 2-DAA regimen containing TMC-435 150 mg QD and expected inhibitory effects from varying concentrations of 65 PSI-7977 400 mg QD. Compound 1 and Compound 2 in a genotype 1b HCV repli FIG. 14 illustrates the predicted median and 90% confi con assay. dence interval of SVR percentage for different treatment US 8,969,357 B2 23 24 durations of a 2-DAA regimen containing danoprevir 100 mg BID and mercitabine 750 mg BID. Compound 2 FIG. 15 depicts the predicted median and 90% confidence H interval of SVR percentage for different treatment durations of a 2-DAA regimen containing GS-9190 (tegobuvir) 30 mg 5 O N NHSOCH BID+GS-9451 200 mg QD--GS-588590 mg QD. FIG. 16 shows the predicted median and 90% confidence C N CO interval of SVR percentage for different treatment durations of the following DAA combo regimens: (1) GS-9451 200 mg o1 QD+GS-7977 (PSI-7977) 400 mg QD; (2) GS-5885 90 mg 10 QD+GS-7977 (PSI-7977) 400 mg QD; and (3) GS-9451 200 mg QD+GS-588590 mg QD+GS-7977 (PSI-7977) 400 mg QD. 15 Compound 2 is also known N-(6-(3-tert-butyl-5-(2,4-di DETAILED DESCRIPTION OF THE INVENTION oxo-3,4-dihydropyrimidin-1 (2H)-yl)-2-methoxyphenyl) The present methods can include administering therapeutic naphthalen-2-yl)methanesulfonamide. As described in, for example, International Publication No. WO2009/039127, agent 1 to a subject. Therapeutic agent 1 is Compound 1 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 Com pound 2 and its salts such as Solvate, hydrate, and solvent-free crystalline forms of Compound 2 and its salts. Compositions comprising therapeutic agent 2 can be prepared as described 25 in, for example, International Publication No. WO2009/ 039127 which is incorporated by reference herein. Therapeutic agent 2 may be administered as a free acid, salt or particular crystalline form of Compound 2. In some 30 embodiments, therapeutic agent 2 is administered as a sodium salt. Therapeutic agent 2 may be administered in any Suitable amount such as, for example, in doses of from about 5 mg/kg to about 30 mg/kg. As non-limiting examples, therapeutic agent 2 may be administered in a total daily dose amount of 35 from about 300 mg to about 1800 mg, or from about 400 mg to about 1600 mg. or from about 600 mg to about 1800 mg. or or a pharmaceutically acceptable salt thereof. Compound 1 is from about 800 mg to about 1600 mg or any amounts there also known as (2R,6S.13aS, 14aR, 16aS.Z) N-(cyclopropyl between. In some embodiments, the total daily dosage sulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5, 16-dioxo amount for therapeutic agent 2 is about 600 mg. In some 40 embodiments, the total daily dosage amount for therapeutic 2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a, 14, 14a, agent 2 is about 800 mg. In some embodiments, the total daily 15,16,16a-hexadecahydrocyclopropaelpyrrolo 12-a 1.4 dosage amount for therapeutic agent 2 is about 1200 mg. In diazacyclopentadecine-14a-carboxamide. Compound 1 is a Some embodiments, the total daily dosage amount for thera potent HCV protease inhibitor. The synthesis and formulation peutic agent 2 is about 1600 mg. of Compound 1 are described in U.S. Patent Application The present methods can include administering therapeutic Publication No. 2010/0144608, U.S. Provisional Application 45 agent 3 or a salt thereof to a subject. Therapeutic agent 3 is Ser. No. 61/339,964 filed on Mar. 10, 2010, and U.S. Patent Compound 3 or a salt thereof. Application Publication No. 2011/0312973 filed on Mar. 8, 2011. All of these applications are incorporated herein by reference in their entireties. Therapeutic agent 1 includes 50 Compound 3 various salts of Compound 1. Therapeutic agent 1 may be administered in any suitable amount Such as, for example, in doses of 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, therapeutic agent 1 may be admin 55 istered 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 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 60 suitable amounts there between. In preferred embodiments, ritonavir or another inhibitor of cytochrome P-450 is co-administered with therapeutic agent 1 to improve the pharmacokinetics of Compound 1. The present methods can include administering therapeutic 65 Compound 3 is also known as (E)-N-(4-(3-tert-butyl-5-(2, agent 2 to a subject. Therapeutic agent 2 is Compound 2 or a 4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-2-methoxystyryl) salt thereof. phenyl)methanesulfonamide. As described in, for example, US 8,969,357 B2 25 26 International Publication No. WO2009/039127, therapeutic ribavirin include COPEGUS(R), REBETOL(R) and RIBAS agent 3 includes various salts of Compound 3. Such as sodium PHERE(R). An exemplary pro-drug of ribavirin is taribavirin salts, potassium salts, and choline salts. Therapeutic agent 3 having the chemical name of 1-3-D-ribofuranosyl-1,2,4-tria also includes crystalline forms of Compound 3 and its salts Zole-3-carboxamidine. Ribavirin and taribavirin may be such as solvate, hydrate, and solvent-free crystalline forms of 5 administered in accordance with ribavirin and taribavirin Compound 3 and its salts. Compositions comprising thera administration well known in the art. In some embodiments, peutic agent 3 can be prepared as described in, for example, COPEGUSR) or REBETOL(R) is administered in a daily dos International Publication No. WO2009/039127 which is age amount of from about 500 mg to about 1500 mg in one incorporated by reference herein. dose or individed doses. In some embodiments, COPEGUS(R) Therapeutic agent 3 may be administered as a free acid, salt 10 or REBETOL(R) is administered in a daily dosage amount of or particular crystalline form of Compound 3. In some about 800 mg. In some embodiments, REBETOL(R) is admin embodiments, Compound 3 is administered as a potassium istered in a daily dosage amount of about 1000 mg. In some salt. Therapeutic agent 3 may be administered in any Suitable embodiments, COPEGUSR) or REBETOL(R) is administered amount Such as, for example, in doses of from about 0.5 in a daily dosage amount of about 1200 mg. In some embodi mg/kg to about 15 mg/kg or from about 1 mg/kg to about 10 15 ments, REBETOL(R) is administered in a daily dosage amount mg/kg. As non-limiting examples, therapeutic agent 3 may be of about 1400 mg. Suitable dosages ofribavirin are dependent administered in a total daily dose amount of from about 100 on the weight of the subject, for example about 1000-1200 mg to about 600 mg. In some embodiments, the total daily mg. Suitable total daily dosages of ribavirin include, but are dosage amount for therapeutic agent 3 is about 300 mg. In not limited to about 400 mg to about 1400 mg a day, alterna Some embodiments, the total daily dosage amount for thera tively about 800 mg to about 1400 mg per day, alternatively peutic agent 3 is about 320 mg. In some embodiments, the about 400 mg to about 1200 mg, alternatively about 800 mg to total daily dosage amount for therapeutic agent 3 is about 400 about 1200 mg. mg. In some embodiments, the total daily dosage amount for The current standard of care (SOC) for the treatment of therapeutic agent 3 is about 600 mg. HCV includes a course of treatment of interferon, e.g. pegy The present methods can include administering therapeutic 25 lated interferon (e.g., pegylated interferon-alpha-2a or pegy agent 4 or a salt thereof to a subject. Therapeutic agent 4 is lated interferon-alpha-2b, such as PEGASYS by Roche, or compound 4 or a salt thereof. PEG-INTRON by Schering-Plough) and the antiviral drug

Compound 4

N N r H O-N- - O NH N N r N Y- Y-Q O O O sar O O O

Compound 4 is also known as dimethyl (2S,2S)-1,1'-((2S, 45 ribavirin (e.g., COPEGUS by Roche, REBETOL by Scher 2S)-2,2'-(4,4'-(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2, ing-Plough, or RIBASPHERE by Three Rivers Pharmaceu 5.diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene) ticals). The treatment often lasts for 24-48 weeks, depending bis(pyrrolidine-2,1-diyl)bis(3-methyl-1-oxobutane-2,1-diyl) on hepatitis C virus genotype. Other interferons include, but dicarbamate. Compound 4 can be prepared as described in, 50 are not limited to, interferon-alpha-2a (e.g., Roferon-A by for example, U.S. Publication No. 2010/0317568, which is Roche), interferon-alpha-2b (e.g., Intron-A by Schering incorporated herein by reference. Plough), and interferon alfacon-1 (consensus interferon) Therapeutic agent 4 may be administered as a free acid, or (e.g., Infergen by Valeant). Less than 50% of patients with a salt form. Therapeutic agent 4 may be administered in any chronic HCV infection with genotype 1 virus respond to this Suitable amount Such as, for example, in doses of from about 55 therapy. Further, interferon therapy has many side effects that 0.1 mg/kg to about 200 mg/kg body weight, or from about hinder patient compliance and results in premature discon 0.25 mg/kg to about 100 mg/kg, or from about 0.3 mg/kg to tinuation of the treatment. about 30 mg/kg. As non-limiting examples, therapeutic agent The interferon/ribavirin-based treatment may be physi 4 may be administered in a total daily dose amount of from cally demanding, and can lead to temporary disability in some about 5 mg to about 300 mg. or from about 25 mg to about 200 60 cases. A substantial proportion of patients will experience a mg, or from about 25 mg to about 50 mg or any amounts there panoply of side effects ranging from a "flu-like' syndrome between. In some embodiments, the total daily dosage (the most common, experienced for a few days after the amount for therapeutic agent 4 is about 25 mg. weekly injection of interferon) to severe adverse events The at least two DAAS may also be co-administered with including anemia, cardiovascular events and psychiatric ribavirin, or a pro-drug thereof, in the same or separate phar 65 problems such as suicide or suicidal ideation. The latter are maceutical compositions. Ribavirin may include any Suitable exacerbated by the general physiological stress experienced form or formulation of ribavirin. Exemplary formulations of by the patients. Ribavirin also has a number of side effects, US 8,969,357 B2 27 28 including, anemia, high pill burden (e.g. 5-6 pills a day split In some embodiments, the amounts of the two or more BID) and teratogenicity restricting use in women of child DAAs and ribavirin, and/or the duration of the treatment bearing age. regimen of the two or more DAAs and ribavirin, are effective The present methods provide effective treatment of HCV to provide an RVR in a subject, or an EVR in a subject, or a infection without the use of interferon and for a shorter period cEVR in a subject, or an eRVR in a subject, or an absence of of time, such as a treatment duration of no more than twelve detectable virus at EOT in a subject. In some embodiments, weeks, alternatively no more than eleven weeks, alternatively the present methods comprise treating a population of Sub no more than ten weeks, alternatively no more than nine jects having HCV infection (e.g. treatment naive Subjects), weeks, alternatively no more than eight weeks, alternatively and the methods comprise administering at least two DAAS no more than seven weeks, alternatively no more than six 10 and ribavirin to the subjects for a duration of no more than 12 weeks, alternatively no more than five weeks, alternatively no weeks, or for another duration disclosed herein, wherein the more than four weeks, or alternatively, no more than three at least two DAAS and ribavirin are administered to the sub weeks. jects in amounts effective to provide an SVR (e.g., SVR after In some embodiments, the present technology provides 8 weeks post-treatment, or SVR after 24 weeks post-treat methods for treating HCV infection in a Subject comprising 15 ment) in at least about 70% of the population, alternatively at administering at least two DAAs with ribavirin in the absence least about 75% of the population, alternatively at least about of interferon for a duration of no more than twelve weeks, 80% of the population, alternatively at least about 85% of the alternatively no more than eight weeks. Put another way, the population, alternatively at least about 90% of the population, present methods exclude interferon, or the subject does not alternatively at least about 95% of the population, alterna receive interferon for the duration of the treatment. The at tively about 100% of the population. In some embodiments, least two DAAS can be co-administered or can be adminis the present methods comprise treating a population of IFN tered independently (with the same or different dosing fre experienced subjects (e.g., interferon non-responders) having quencies) and can be administered once a day, alternatively HCV infection, and the methods comprise administering at twice a day, alternatively three times a day. least two DAAs and ribavirin to the subjects for a duration of In some embodiments, the methods of treatment comprise 25 no more than 12 weeks, or for another duration disclosed daily administration of two or more DAAs, wherein a first herein, wherein the at least two DAAS and ribavirin are DAA may be administered once a day, twice a day, or three administered to the subjects in amounts effective to provide times a day, and a second DAA may be administered once a an SVR (e.g., SVR after 8 weeks post-treatment, or SVR after day, twice a day, or three times a day. In some embodiments, 24 weeks post-treatment) in at least about 50% of the popu a third DAA may be administered once a day, twice a day, or 30 lation, alternatively at least about 55% of the population, three times a day. The DAAS may be co-administered or alternatively at least about 60% of the population, alterna administered at different times or frequencies. Preferably, in tively at least about 65% of the population. In other embodi the methods, at least two DAAS and ribavirin are adminis ments, the amount of DAAS and ribavirin and the duration of tered in effective amounts to provide a desired measure of the treatment are effective to provide one or more of an SVR effectiveness in the subject. Preferably, the treatment has 35 (e.g., SVR after 8 weeks post-treatment, or SVR after 24 reduced side effects as compared with interferon-containing weeks post-treatment), an RVR, an EVR, a cFVR, an eRVR, treatmentS. oran absence of detectable virus at EOT in at least about 50% Various measures may be used to express the effectiveness of the population, alternatively at least about 55%, in at least of the present methods of HCV treatment. One such measure about 60% of the population, alternatively at least about 65% is rapid virological response (RVR), meaning that HCV is 40 of the population, alternatively at least about 70% of the undetectable in the subject after 4 weeks of treatment, for population, alternatively at least about 75% of the population, example, after 4 weeks of administration of two or more of alternatively at least about 80% of the population, alterna DAAs and ribavirin. Another measure is early virological tively at least about 85% of the population, alternatively at response (EVR), meaning that the Subject has 22 logo reduc least about 90% of the population, alternatively at least about tion in viral load after 12 weeks of treatment. Another mea 45 95% of the population, alternatively about 100% of the popu sure is complete EVR (cEVR), meaning the HCV is unde lation. For example, the present methods comprise adminis tectable in the serum of the subject after 12 weeks of tering at least two DAAS and ribavirin in amounts and for treatment. Another measure is extended RVR (eRVR), mean durations effective to provide an SVR (e.g., SVR after 8 ing achievement of RVR and cEVR, that is, HCV is undetect weeks post-treatment, or SVR after 24 weeks post-treatment) able at week 4 and 12. Another measure is the presence or 50 in a Subject. In some embodiments, the present technology absence of detectable virus at the end of therapy (EOT). provides for an SVR (e.g., SVR after 8 weeks post-treatment, Another measure is (SVR), which, as used herein, means that or SVR after 24 weeks post-treatment) in at least about 50% the virus is undetectable at the end of therapy and for at least of the population, alternatively at least about 55% of the 8 weeks after the end of therapy (SVR8); preferably, the virus population, in at least about 60% of the population, preferably is undetectable at the end of therapy and for at least 12 weeks 55 in at least about 65% of the population, preferably in at least after the end of therapy (SVR12); more preferably, the virus about 70% of the population, preferably at least about 75% of is undetectable at the end of therapy and for at least 16 weeks the patients treated by such methods herein described, more after the end of therapy (SVR16); and highly preferably, the preferably in at least 80% of the population, and highly pref virus is undetectable at the end of therapy and for at least 24 erably in at least about 90% of the patients being treated. In weeks after the end of therapy (SVR24). SVR24 is often 60 Some embodiments, a treatment of the present technology considered as a functional definition of cure; and a high rate of provides an RVR or undetectable level of HCV RNA in the SVR at less than 24 week post-treatment (e.g., SVR8 or bloodstream at four (4) weeks of treatment (preferably in SVR12) can be predictive of a high rate of SVR24. Likewise, addition to a SVR). a high rate of SVR at less than 12 week post-treatment (e.g., A DAA of the present technology includes, but is not SVR4 or SVR8) can be predictive of a high rate of SVR12. A 65 limited to, a protease inhibitor, a HCV polymerase inhibitor, high rate of EOT (e.g., at week 8 or week 12) can also be an HCV NS5A inhibitor, an HCV NS3B inhibitor, an HCV indicative of a significant rate of SVR12 or SVR24. NS4A inhibitor, an HCV NS5B inhibitor, an HCV entry US 8,969,357 B2 29 30 inhibitor, a cyclophilin inhibitor, a CD81 inhibitor, or an or 3. The treatment according to this aspect of the technology internal ribosome entry site inhibitor. The HCV polymerase may also be effective against other HCV genotypes. The inhibitor may be a nucleoside polymerase inhibitor or a non DAAs can be administered around the same time or at differ nucleoside polymerase inhibitor. The HCV polymerase ent times, and can be co-formulated in a single formulation or inhibitor may be a nucleotide polymerase inhibitor or a non formulated in different compositions. Each DAA can be nucleotide polymerase inhibitor. selected from HCV protease inhibitors, HCV polymerase In yet another example of this aspect of the technology, the inhibitors, or HCV NS5A inhibitors. For instance, the com combination of two or more DAAs comprises PSI-7977 and bination of two or more DAAS can be a combination of at least PSI-938. In yet another example, the combination of two or one HCV protease inhibitor and at least one HCV polymerase more DAAS comprises PSI-7977 and TMC-435. In yet 10 inhibitor (e.g., a combination of at least one HCV protease another example, the combination of two or more DAAS inhibitor and at least one non-nucleoside polymerase inhibi comprises BMS-790052 and BMS-650032. In yet another tor, or a combination of at least one HCV protease inhibitor example, the combination of two or more DAAS comprises and at least one nucleoside or nucleotide polymerase inhibi GS-5885, GS-9190, and GS-9451. In yet another example, tor, or a combination of at least one HCV protease inhibitor, the combination of two or more DAAs comprises BI-201335 15 at least one nucleoside or nucleotide polymerase inhibitor and and BI-207127. In yet another example, the combination of at least one non-nucleoside inhibitor). For another instance, two or more DAAs comprises telaprevir and VX-222. In the combination of two or more DAAS can be a combination another example, the combination of two or more DAAS of at least one HCV protease inhibitor and at least one HCV comprises GS-5885 and GS-9451. In yet another example, NS5A inhibitor. For still another instance, the combination of the combination of two or more DAAs includes danoprevir two or more DAAS can be a combination of at least one HCV (with ritonavir) and R7128. In yet another example, the com protease inhibitor, at least one HCV polymerase inhibitor, and bination of two or more DAAS includes PSI-7977 and BMS at least one HCV NS5A inhibitor. For another instance, the 790052 (daclatasvir). In yet another example, the combina combination of two or more DAAS can be a combination of at tion of two or more DAAS includes PSI-7977 and BMS least two HCV polymerase inhibitors (e.g., a combination of 650032 (asunaprevir). In still another example, the 25 at least two nucleoside polymerase inhibitors, or a combina combination of two or more DAAs includes PSI-7977, BMS tion of at least one nucleoside or nucleotide polymerase 650032 (asunaprevir) and BMS-790052 (daclatasvir). In inhibitor and at least one non-nucleoside or nucleotide poly another example, the combination of two or more DAAS merase inhibitor, or a combination of at least two non-nucleo includes INX-189 and BMS-790052 (daclatasvir). In yet side polymerase inhibitors). For another instance, the combi another example, the combination of two or more DAAS 30 nation of two or more DAAS can be a combination of at least includes INX-189 and BMS-650032 (asunaprevir). In still two HCV protease inhibitors. For another instance, the com another example, the combination of two or more DAAS bination of two or more DAAS can be a combination of at least includes INX-189, BMS-650032 (asunaprevir) and BMS two HCV NS5A inhibitors. For another instance, the combi 790052 (daclatasvir). nation of two or more DAAS can be a combination of at least It was unexpectedly discovered that an interferon-free 35 one HCV polymerase inhibitor and at least one NS5A inhibi treatment using a combination of two or more DAAS, together tor (e.g., a combination of at least one HCV NS5A inhibitor with ribavirin, and for a duration of no more than 12 weeks, and at least one non-nucleoside or nucleotide polymerase could achieve significant SVR. In many cases, such a treat inhibitor, or a combination of at least one HCV NS5A inhibi ment can achieve an SVR in at least about 75% of patients, tor and at least one nucleoside or nucleotide polymerase and in Some cases, such a treatment can achieve an SVR in at 40 inhibitor, or a combination of at least one HCV NS5A inhibi least about 85% of patients, and in certain cases, such a tor, at least one nucleoside or nucleotide polymerase inhibitor treatment can achieve an SVR in at least about 90% of and at least one non-nucleoside polymerase inhibitor). In one patients. It was also surprising that such a treatment could example, the combination of two or more DAAS is a combi achieve significant viral Suppression even at 4 weeks of the nation of Compound 1 (or a salt thereof) and Compound 2 (or treatment. In some embodiments, the interferon-free treat 45 a salt thereof). Compound 1 (or a salt thereof) can be co ment using a combination of two or more DAAS, together formulated with ritonavir. In another example, the combina with ribavirin, and for a duration of no more than 12 weeks, tion of two or more DAAs is a combination of Compound 1 could achieve significant SVR in interferon non-responders, (or a salt thereof) and Compound 3 (or a salt thereof). Com for example, treatment can achieve an SVR in at least about pound 1 (or a salt thereof) can be co-formulated with 50% of patients in the interferon non-responder population, 50 ritonavir. In still another example, the combination of two or preferably at least about 60% of patients in the interferon more DAAS is a combination of Compound 1 (or a salt non-responder population, more preferably at least about thereof) and Compound 4 (or a salt thereof). Compound 1 (or 65% of patients in the interferon non-responder population. a salt thereof) can be co-formulated with ritonavir. In a further Accordingly, in one aspect, the present technology features example, the combination of two or more DAAS is a combi a method of treating HCV infection, comprising administer 55 nation of Compound 1 (or a salt thereof), Compound 2 (or a ing to a patient in need thereof an effective amount of a salt thereof) and Compound 4 (or a salt thereof). Compound combination of two or more DAAs, together with an effective 1 (or a salt thereof) can be co-formulated with ritonavir. In yet amount of ribavirin. The treatment lasts 8 weeks and does not another example, the combination of two or more DAAS is a include administration of any interferon. The DAAs and rib combination of Compound 1 (or a salt thereof), Compound 3 avirin can be administered at the same or different dosing 60 (or a salt thereof) and Compound 4 (or a salt thereof). Com frequencies. The patient being treated can be a treatment pound 1 can be co-formulated with ritonavir. In yet another naive patient, a treatment experienced patient, including, but example, the combination of two or more DAAS comprises not limited to, a relapser, an interferon partial responder, an PSI-7977 and PSI-938. In yet another example, the combina interferon non-responder (e.g., a null responder), or a patient tion of two or more DAAS comprises PSI-7977 and TMC unable to take interferon. The patient may be infected with, 65 435. In yet another example, the combination of two or more for example and without limitation, HCV genotype 1. Such as DAAs comprises BMS-790052 and BMS-650032. In yet HCV genotype 1a or HCV genotype 1b; or HCV genotype 2 another example, the combination of two or more DAAS US 8,969,357 B2 31 32 comprises GS-5885, GS-9190, and GS-9451. In yet another HCV genotype 1b; or HCV genotype 2 or 3. The treatment example, the combination of two or more DAAS comprises according to this aspect of the technology can also be effec BI-201335 and BI-207127. In yet another example, the com tive against other HCV genotypes. The DAAs can be admin bination of two or more DAAs comprises telaprevir and istered around the same time or at different times, and can be VX-222. In another example, the combination of two or more co-formulated in a single formulation or formulated in differ DAAs comprises GS-5885 and GS-9451. In yet another ent compositions. Each DAA can be selected from HCV example, the combination of two or more DAAs includes protease inhibitors, HCV polymerase inhibitors, or HCV danoprevir (with ritonavir) and R7128. In yet another NS5A inhibitors. For instance, the combination of two or example, the combination of two or more DAAs includes more DAAS can be a combination of at least one HCV pro PSI-7977 and BMS-790052 (daclatasvir). In yet another 10 tease inhibitor and at least one HCV polymerase inhibitor example, the combination of two or more DAAs includes (e.g., a combination of at least one HCV protease inhibitor PSI-7977 and BMS-650032 (asunaprevir). In still another and at least one non-nucleoside polymerase inhibitor, or a example, the combination of two or more DAAs includes combination of at least one HCV protease inhibitor and at PSI-7977, BMS-650032 (asunaprevir) and BMS-790052 least one nucleoside or nucleotide polymerase inhibitor, or a (daclatasvir). In yet another example, the combination of two 15 combination of at least one HCV protease inhibitor, at least or more DAAs includes INX-189 and BMS-790052 (da one nucleoside or nucleotide polymerase inhibitor and at least clatasvir). In yet another example, the combination of two or one non-nucleoside inhibitor). For another instance, the com more DAAs includes INX-189 and BMS-650032 (asunapre bination of two or more DAAS can be a combination of at least vir). In still another example, the combination of two or more one HCV protease inhibitor and at least one HCV NS5A DAAs includes INX-189, BMS-650032 (asunaprevir) and inhibitor. For still another instance, the combination of two or BMS-790052 (daclatasvir). In still another example, the com more DAAS can be a combination of at least one HCV pro bination of two or more DAAs includes mericitabine and tease inhibitor, at least one HCV polymerase inhibitor, and at danoprevir. In still another example, the combination of two least one HCV NS5A inhibitor. For another instance, the or more DAAs includes INX-189, daclatasvir and combination of two or more DAAS can be a combination of at BMS-791325. In still another example, the combination of 25 least two HCV polymerase inhibitors (e.g., a combination of two or more DAAS includes PSI-7977 and GS-5885. In still at least two nucleoside or nucleotide polymerase inhibitors, another example, the combination of two or more DAAS or a combination of at least one nucleoside or nucleotide includes PSI-7977, Compound 1 (with ritonavir), and Com polymerase inhibitor and at least one non-nucleoside poly pound 4. In still another example, the method comprises merase inhibitor, or a combination of at least two non-nucleo administering to a patient in need thereofan effective amount 30 side polymerase inhibitors). For another instance, the combi of PSI-7977 as the sole DAA in lieu of a combination of two nation of two or more DAAS can be a combination of at least or more DAAs, together with an effective amountofribavirin. two HCV protease inhibitors. For another instance, the com In still another example, the method comprises administering bination of two or more DAAS can be a combination of at least 100 or 200 mg Compound 1 together with 100 mg ritonavir two HCV NS5A inhibitors. For another instance, the combi once daily, and 25 mg compound 4 once daily. In yet another 35 nation of two or more DAAS can be a combination of at least example, the method comprises administering 150 mg or 250 one HCV polymerase inhibitor and at least one NS5A inhibi mg Compound 1 together with 100 mg ritonavir once daily, tor (e.g., a combination of at least one HCV NS5A inhibitor and 400 mg Compound 2 twice daily. In another example, the and at least one non-nucleoside polymerase inhibitor, or a method comprises administering 150 mg Compound 1 combination of at least one HCV NS5A inhibitor and at least together with 100 mg ritonavir once daily, and 400 mg Com 40 one nucleoside or nucleotide polymerase inhibitor, or a com pound 3 once daily. In another example, the method com bination of at least one HCV NS5A inhibitor, at least one prises administering 150 mg Compound 1 together with 100 nucleoside or nucleotide polymerase inhibitor and at least one mg ritonavir once daily, and 400mg Compound 3 twice daily. non-nucleoside polymerase inhibitor). In one example, the In another example, the method comprises administering 100 combination of two or more DAAs is a combination of Com or 150 mg Compound 1 together with 100 mg ritonavir once 45 pound 1 (or a salt thereof) and Compound 2 (or a salt thereof). daily, 25 mg compound 4 once daily, and 400 mg Compound Compound 1 (or a salt thereof) can be co-formulated with 2 twice daily. In another example, the method comprises ritonavir. In another example, the combination of two or more administering 100 or 150 mg Compound 1 together with 100 DAAs is a combination of Compound 1 (or a salt thereof) and mg ritonavir once daily, 25 mg compound 4 once daily, and Compound 3 (or a salt thereof). Compound 1 (or a salt 400 mg Compound 3 twice daily. Ribavirin can be adminis 50 thereof) can be co-formulated with ritonavir. In still another tered based on patient weight, and in many cases, 1000 to example, the combination of two or more DAAS is a combi 1200 mg divided twice daily. Other DAA(s) can also be nation of Compound 1 (or a salt thereof) and Compound 4 (or included in a treatment regimen according to this aspect of the a salt thereof). Compound 1 (or a salt thereof) can be co technology. formulated with ritonavir. In a further example, the combina In another aspect, the present technology features a method 55 tion of two or more DAAs is a combination of Compound 1 of treating HCV, comprising administering to a patient in (or a salt thereof), Compound 2 (or a salt thereof) and Com need thereof an effective amount of a combination of two or pound 4 (or a salt thereof). Compound 1 (or a salt thereof) can more DAAs, together with an effective amount of ribavirin. be co-formulated with ritonavir. In yet another example, the The treatment lasts 7 weeks and does not include administra combination of two or more DAAs is a combination of Com tion of any interferon. The DAAs and ribavirin can be admin 60 pound 1 (or a salt thereof), Compound 3 (or a salt thereof) and istered at the same or different dosing frequency. The patient Compound 4 (or a salt thereof). Compound 1 (or a salt being treated can be a treatment naive patient, a treatment thereof) can be co-formulated with ritonavir. In yet another experienced patient, including, but not limited to, a relapser, example, the combination of two or more DAAS comprises an interferon partial responder, an interferon non-responder PSI-7977 and PSI-938. In yet another example, the combina (e.g., a null responder), or a patient unable to take interferon. 65 tion of two or more DAAS comprises PSI-7977 and TMC The patient can be infected with, for example and without 435. In yet another example, the combination of two or more limitation, HCV genotype 1, such as HCV genotype 1a or DAAs comprises BMS-790052 and BMS-650032. In yet US 8,969,357 B2 33 34 another example, the combination of two or more DAAS without limitation, HCV genotype 1, such as HCV genotype comprises GS-5885, GS-9190, and GS-9451. In yet another 1a or HCV genotype 1b; or HCV genotype 2 or 3. The example, the combination of two or more DAAS comprises treatment according to this aspect of the technology can also BI-201335 and BI-207127. In yet another example, the com be effective against other HCV genotypes. The DAAS can be bination of two or more DAAs comprises telaprevir and administered around the same time or at different times, and VX-222. In another example, the combination of two or more can be co-formulated in a single formulation or formulated in DAAs comprises GS-5885 and GS-9451. In yet another different compositions. Each DAA can be selected from HCV example, the combination of two or more DAAs includes protease inhibitors, HCV polymerase inhibitors, or HCV danoprevir (with ritonavir) and R7128. In yet another NS5A inhibitors. For instance, the combination of two or example, the combination of two or more DAAs includes 10 more DAAS can be a combination of at least one HCV pro PSI-7977 and BMS-790052 (daclatasvir). In yet another tease inhibitor and at least one HCV polymerase inhibitor example, the combination of two or more DAAs includes (e.g., a combination of at least one HCV protease inhibitor PSI-7977 and BMS-650032 (asunaprevir). In still another and at least one non-nucleoside polymerase inhibitor, or a example, the combination of two or more DAAs includes combination of at least one HCV protease inhibitor and at PSI-7977, BMS-650032 (asunaprevir) and BMS-790052 15 least one nucleoside or nucleotide polymerase inhibitor, or a (daclatasvir). In yet another example, the combination of two combination of at least one HCV protease inhibitor, at least or more DAAs includes INX-189 and BMS-790052 (da one nucleoside or nucleotide polymerase inhibitor and at least clatasvir). In yet another example, the combination of two or one non-nucleoside inhibitor). For another instance, the com more DAAs includes INX-189 and BMS-650032 (asunapre bination of two or more DAAS can be a combination of at least vir). In still another example, the combination of two or more one HCV protease inhibitor and at least one HCV NS5A DAAs includes INX-189, BMS-650032 (asunaprevir) and inhibitor. For still another instance, the combination of two or BMS-790052 (daclatasvir). In still another example, the com more DAAS can be a combination of at least one HCV pro bination of two or more DAAs includes mericitabine and tease inhibitor, at least one HCV polymerase inhibitor, and at danoprevir. In still another example, the combination of two least one HCV NS5A inhibitor. For another instance, the or more DAAs includes INX-189, daclatasvir and 25 combination of two or more DAAS can be a combination of at BMS-791325. In still another example, the combination of least two HCV polymerase inhibitors (e.g., a combination of two or more DAAS includes PSI-7977 and GS-5885. In still at least two nucleoside or nucleotide polymerase inhibitors, another example, the combination of two or more DAAS or a combination of at least one nucleoside or nucleotide includes PSI-7977, Compound 1 (with ritonavir), and Com polymerase inhibitor and at least one non-nucleoside poly pound 4. In still another example, the method comprises 30 merase inhibitor, or a combination of at least two non-nucleo administering to a patient in need thereofan effective amount side polymerase inhibitors). For another instance, the combi of PSI-7977 as the sole DAA in lieu of a combination of two nation of two or more DAAS can be a combination of at least or more DAAs, together with an effective amount ofribavirin. two HCV protease inhibitors. For another instance, the com In still another example, the method comprises administering bination of two or more DAAS can be a combination of at least 100 or 200 mg Compound 1 together with 100 mg ritonavir 35 two HCV NS5A inhibitors. For another instance, the combi once daily, and 25 mg compound 4 once daily. In yet another nation of two or more DAAS can be a combination of at least example, the method comprises administering 150 mg or 250 one HCV polymerase inhibitor and at least one NS5A inhibi mg Compound 1 together with 100 mg ritonavir once daily, tor (e.g., a combination of at least one HCV NS5A inhibitor and 400 mg Compound 2 twice daily. In another example, the and at least one non-nucleoside or nucleotide polymerase method comprises administering 150 mg Compound 1 40 inhibitor, or a combination of at least one HCV NS5A inhibi together with 100 mg ritonavir once daily, and 400 mg Com tor and at least one nucleoside or nucleotide polymerase pound 3 once daily. In another example, the method com inhibitor, or a combination of at least one HCV NS5A inhibi prises administering 150 mg Compound 1 together with 100 tor, at least one nucleoside or nucleotide polymerase inhibitor mg ritonavir once daily, and 400mg Compound 3 twice daily. and at least one non-nucleoside or nucleotide polymerase In another example, the method comprises administering 100 45 inhibitor). In one example, the combination of two or more or 150 mg Compound 1 together with 100 mg ritonavir once DAAs is a combination of Compound 1 (or a salt thereof) and daily, 25 mg compound 4 once daily, and 400 mg Compound Compound 2 (or a salt thereof). Compound 1 (or a salt 2 twice daily. In another example, the method comprises thereof) can be co-formulated with ritonavir. In another administering 100 or 150 mg Compound 1 together with 100 example, the combination of two or more DAAS is a combi mg ritonavir once daily, 25 mg compound 4 once daily, and 50 nation of Compound 1 (or a salt thereof) and Compound 3 (or 400 mg Compound 3 twice daily. Ribavirin can be adminis a salt thereof). Compound 1 (or a salt thereof) can be co tered based on patient weight, and in many cases, 1000 to formulated with ritonavir. In still another example, the com 1200 mg divided twice daily. Other DAA(s) can also be bination of two or more DAAs is a combination of Compound included in a treatment regimen according to this aspect of the 1 (or a salt thereof) and Compound 4 (or a salt thereof). technology. 55 Compound 1 (or a salt thereof) can be co-formulated with In yet another aspect, the present technology features a ritonavir. In a further example, the combination of two or method of treating HCV, comprising administering to a more DAAS is a combination of Compound 1 (or a salt patient in need thereof an effective amount of a combination thereof), Compound 2 (or a salt thereof) and Compound 4 (or of two or more DAAs, together with an effective amount of a salt thereof). Compound 1 (or a salt thereof) can be co ribavirin. The treatment lasts 6 weeks and does not include 60 formulated with ritonavir. In yet another example, the com administration of any interferon. The DAAs and ribavirin can bination of two or more DAAs is a combination of Compound be administered at the same or different dosing frequency. 1 (or a salt thereof), Compound 3 (or a salt thereof) and The patient being treated can be a treatment naive patient, a Compound 4 (or a salt thereof). Compound 1 (or a salt treatment experienced patient, including, but not limited to, a thereof) can be co-formulated with ritonavir. In yet another relapser, an interferon partial responder, an interferon non 65 example, the combination of two or more DAAS comprises responder (e.g., a null responder), or a patient unable to take PSI-7977 and PSI-938. In yet another example, the combina interferon. The patient can be infected with, for example and tion of two or more DAAS comprises PSI-7977 and TMC US 8,969,357 B2 35 36 435. In yet another example, the combination of two or more responder (e.g., a null responder), or a patient unable to take DAAs comprises BMS-790052 and BMS-650032. In yet interferon. The patient can be infected with, for example and another example, the combination of two or more DAAS without limitation, HCV genotype 1, such as HCV genotype comprises GS-5885, GS-9190, and GS-9451. In yet another 1a or HCV genotype 1b; or HCV genotype 2 or 3. The example, the combination of two or more DAAS comprises treatment according to this aspect of the technology can also BI-201335 and BI-207127. In yet another example, the com be effective against other HCV genotypes. The DAAS can be bination of two or more DAAs comprises telaprevir and administered around the same time or at different times, and VX-222. In another example, the combination of two or more can be co-formulated in a single formulation or formulated in DAAs comprises GS-5885 and GS-9451. In yet another different compositions. Each DAA can be selected from HCV example, the combination of two or more DAAs includes 10 protease inhibitors, HCV polymerase inhibitors, or HCV danoprevir (with ritonavir) and R7128. In yet another NS5A inhibitors. For instance, the combination of two or example, the combination of two or more DAAs includes more DAAS can be a combination of at least one HCV pro PSI-7977 and BMS-790052. In yet another example, the tease inhibitor and at least one HCV polymerase inhibitor combination of two or more DAAs includes PSI-7977 and (e.g., a combination of at least one HCV protease inhibitor BMS-650032 (asunaprevir). In still another example, the 15 and at least one non-nucleoside polymerase inhibitor, or a combination of two or more DAAs includes PSI-7977, BMS combination of at least one HCV protease inhibitor and at 650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet least one nucleoside or nucleotide polymerase inhibitor, or a another example, the combination of two or more DAAS combination of at least one HCV protease inhibitor, at least includes INX-189 and BMS-790052 (daclatasvir). In yet one nucleoside or nucleotide polymerase inhibitor and at least another example, the combination of two or more DAAS one non-nucleoside inhibitor). For another instance, the com includes INX-189 and BMS-650032 (asunaprevir). In still bination of two or more DAAS can be a combination of at least another example, the combination of two or more DAAS one HCV protease inhibitor and at least one HCV NS5A includes INX-189, BMS-650032 (asunaprevir) and BMS inhibitor. For still another instance, the combination of two or 790052 (daclatasvir). In still another example, the combina more DAAS can be a combination of at least one HCV pro tion of two or more DAAs includes mericitabine and dano 25 tease inhibitor, at least one HCV polymerase inhibitor, and at previr. In still another example, the combination of two or least one HCV NS5A inhibitor. For another instance, the more DAAs includes INX-189, daclatasvir and combination of two or more DAAS can be a combination of at BMS-791325. In still another example, the combination of least two HCV polymerase inhibitors (e.g., a combination of two or more DAAS includes PSI-7977 and GS-5885. In still at least two nucleoside polymerase inhibitors, or a combina another example, the combination of two or more DAAS 30 tion of at least one nucleoside or nucleotide polymerase includes PSI-7977, Compound 1 (with ritonavir), and Com inhibitor and at least one non-nucleoside polymerase inhibi pound 4. In still another example, the method comprises tor, or a combination of at least two non-nucleoside poly administering to a patient in need thereofan effective amount merase inhibitors). For another instance, the combination of of PSI-7977 as the sole DAA in lieu of a combination of two two or more DAAS can be a combination of at least two HCV or more DAAs, together with an effective amount ofribavirin. 35 protease inhibitors. For another instance, the combination of In still another example, the method comprises administering two or more DAAS can be a combination of at least two HCV 100 or 200 mg Compound 1 together with 100 mg ritonavir NS5A inhibitors. For another instance, the combination of once daily, and 25 mg compound 4 once daily. In yet another two or more DAAS can be a combination of at least one HCV example, the method comprises administering 150 mg or 250 polymerase inhibitor and at least one NS5A inhibitor (e.g., a mg Compound 1 together with 100 mg ritonavir once daily, 40 combination of at least one HCV NS5A inhibitor and at least and 400 mg Compound 2 twice daily. In another example, the one non-nucleoside or nucleotide polymerase inhibitor, or a method comprises administering 150 mg Compound 1 combination of at least one HCV NS5A inhibitor and at least together with 100 mg ritonavir once daily, and 400 mg Com one nucleoside or nucleotide polymerase inhibitor, or a com pound 3 once daily. In another example, the method com bination of at least one HCV NS5A inhibitor, at least one prises administering 150 mg Compound 1 together with 100 45 nucleoside or nucleotide polymerase inhibitor and at least one mg ritonavir once daily, and 400mg Compound 3 twice daily. non-nucleoside polymerase inhibitor). In one example, the In another example, the method comprises administering 100 combination of two or more DAAs is a combination of Com or 150 mg Compound 1 together with 100 mg ritonavir once pound 1 (or a salt thereof) and Compound 2 (or a salt thereof). daily, 25 mg compound 4 once daily, and 400 mg Compound Compound 1 (or a salt thereof) can be co-formulated with 2 twice daily. In another example, the method comprises 50 ritonavir. In another example, the combination of two or more administering 100 or 150 mg Compound 1 together with 100 DAAs is a combination of Compound 1 (or a salt thereof) and mg ritonavir once daily, 25 mg compound 4 once daily, and Compound 3 (or a salt thereof). Compound 1 (or a salt 400 mg Compound 3 twice daily. Ribavirin can be adminis thereof) can be co-formulated with ritonavir. In still another tered based on patient weight, and in many cases, 1000 to example, the combination of two or more DAAS is a combi 1200 mg divided twice daily. Other DAA(s) can also be 55 nation of Compound 1 (or a salt thereof) and Compound 4 (or included in a treatment regimen according to this aspect of the a salt thereof). Compound 1 (or a salt thereof) can be co technology. formulated with ritonavir. In a further example, the combina In yet another aspect, the present technology features a tion of two or more DAAs is a combination of Compound 1 method of treating HCV, comprising administering to a (or a salt thereof), Compound 2 (or a salt thereof) and Com patient in need thereof an effective amount of a combination 60 pound 4 (or a salt thereof). Compound 1 (or a salt thereof) can of two or more DAAs, together with an effective amount of be co-formulated with ritonavir. In yet another example, the ribavirin. The treatment lasts 5 weeks and does not include combination of two or more DAAs is a combination of Com administration of any interferon. The DAAs and ribavirin can pound 1 (or a salt thereof), Compound 3 (or a salt thereof) and be administered at the same or different dosing frequency. Compound 4 (or a salt thereof). Compound 1 (or a salt The patient being treated can be a treatment naive patient, a 65 thereof) can be co-formulated with ritonavir. In yet another treatment experienced patient, including, but not limited to, a example, the combination of two or more DAAS comprises relapser, an interferon partial responder, an interferon non PSI-7977 and PSI-938. In yet another example, the combina US 8,969,357 B2 37 38 tion of two or more DAAS comprises PSI-7977 and TMC without limitation, HCV genotype 1, such as HCV genotype 435. In yet another example, the combination of two or more 1a or HCV genotype 1b; or HCV genotype 2 or 3. The DAAs comprises BMS-790052 and BMS-650032. In yet treatment according to this aspect of the technology can also another example, the combination of two or more DAAS be effective against other HCV genotypes. The DAAS can be comprises GS-5885, GS-9190, and GS-9451. In yet another administered around the same time or at different times, and example, the combination of two or more DAAS comprises can be co-formulated in a single formulation or formulated in BI-201335 and BI-207127. In yet another example, the com different compositions. Each DAA can be selected from HCV bination of two or more DAAs comprises telaprevir and protease inhibitors, HCV polymerase inhibitors, or HCV VX-222. In another example, the combination of two or more NS5A inhibitors. For instance, the combination of two or DAAs comprises GS-5885 and GS-9451. In yet another 10 more DAAS can be a combination of at least one HCV pro example, the combination of two or more DAAs includes tease inhibitor and at least one HCV polymerase inhibitor danoprevir (with ritonavir) and R7128. In yet another (e.g., a combination of at least one HCV protease inhibitor example, the combination of two or more DAAs includes and at least one non-nucleoside polymerase inhibitor, or a PSI-7977 and BMS-790052. In yet another example, the combination of at least one HCV protease inhibitor and at combination of two or more DAAs includes PSI-7977 and 15 least one nucleoside or nucleotide polymerase inhibitor, or a BMS-650032 (asunaprevir). In still another example, the combination of at least one HCV protease inhibitor, at least combination of two or more DAAs includes PSI-7977, BMS one nucleoside or nucleotide polymerase inhibitor and at least 650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet one non-nucleoside inhibitor). For another instance, the com another example, the combination of two or more DAAS bination of two or more DAAS can be a combination of at least includes INX-189 and BMS-790052 (daclatasvir). In yet one HCV protease inhibitor and at least one HCV NS5A another example, the combination of two or more DAAS inhibitor. For still another instance, the combination of two or includes INX-189 and BMS-650032 (asunaprevir). In still more DAAS can be a combination of at least one HCV pro another example, the combination of two or more DAAS tease inhibitor, at least one HCV polymerase inhibitor, and at includes INX-189, BMS-650032 (asunaprevir) and BMS least one HCV NS5A inhibitor. For another instance, the 790052 (daclatasvir). In still another example, the combina 25 combination of two or more DAAS can be a combination of at tion of two or more DAAs includes mericitabine and dano least two HCV polymerase inhibitors (e.g., a combination of previr. In still another example, the combination of two or at least two nucleoside or nucleotide polymerase inhibitors, more DAAs includes INX-189, daclatasvir and or a combination of at least one nucleoside or nucleotide BMS-791325. In still another example, the combination of polymerase inhibitor and at least one non-nucleoside poly two or more DAAS includes PSI-7977 and GS-5885. In still 30 merase inhibitor, or a combination of at least two non-nucleo another example, the method comprises administering to a side polymerase inhibitors). For another instance, the combi patientin need thereofan effective amount of PSI-7977 as the nation of two or more DAAS can be a combination of at least sole DAA in lieu of a combination of two or more DAAs, two HCV protease inhibitors. For another instance, the com together with an effective amount of ribavirin. In still another bination of two or more DAAS can be a combination of at least example, the method comprises administering 100 or 200 mg 35 two HCV NS5A inhibitors. For another instance, the combi Compound 1 together with 100 mg ritonavir once daily, and nation of two or more DAAS can be a combination of at least 25 mg compound 4 once daily. In yet another example, the one HCV polymerase inhibitor and at least one NS5A inhibi method comprises administering 150 mg or 250 mg Com tor (e.g., a combination of at least one HCV NS5A inhibitor pound 1 together with 100 mg ritonavir once daily, and 400 and at least one non-nucleoside polymerase inhibitor, or a mg Compound 2 twice daily. In another example, the method 40 combination of at least one HCV NS5A inhibitor and at least comprises administering 150 mg Compound 1 together with one nucleoside or nucleotide polymerase inhibitor, or a com 100 mg ritonavir once daily, and 400 mg Compound 3 once bination of at least one HCV NS5A inhibitor, at least one daily. In another example, the method comprises administer nucleoside or nucleotide polymerase inhibitor and at least one ing 150 mg Compound 1 together with 100 mg ritonavir once non-nucleoside polymerase inhibitor). In one example, the daily, and 400 mg Compound 3 twice daily. In another 45 combination of two or more DAAs is a combination of Com example, the method comprises administering 100 or 150 mg pound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 together with 100 mg ritonavir once daily, 25 Compound 1 (or a salt thereof) can be co-formulated with mg compound 4 once daily, and 400 mg Compound 2 twice ritonavir. In another example, the combination of two or more daily. In another example, the method comprises administer DAAs is a combination of Compound 1 (or a salt thereof) and ing 100 or 150 mg Compound 1 together with 100 mg 50 Compound 3 (or a salt thereof). Compound 1 (or a salt ritonavir once daily, 25 mg compound 4 once daily, and 400 thereof) can be co-formulated with ritonavir. In still another mg Compound 3 twice daily. Ribavirin can be administered example, the combination of two or more DAAS is a combi based on patient weight, and in many cases, 1000 to 1200 mg nation of Compound 1 (or a salt thereof) and Compound 4 (or divided twice daily. Other DAA(s) can also be included in a a salt thereof). Compound 1 (or a salt thereof) can be co treatment regimen according to this aspect of the technology. 55 formulated with ritonavir. In a further example, the combina In yet another aspect, the present technology features a tion of two or more DAAs is a combination of Compound 1 method of treating HCV, comprising administering to a (or a salt thereof), Compound 2 (or a salt thereof) and Com patient in need thereof an effective amount of a combination pound 4 (or a salt thereof). Compound 1 (or a salt thereof) can of two or more DAAs, together with an effective amount of be co-formulated with ritonavir. In yet another example, the ribavirin. The treatment lasts 4 weeks and does not include 60 combination of two or more DAAs is a combination of Com administration of any interferon. The DAAs and ribavirin can pound 1 (or a salt thereof), Compound 3 (or a salt thereof) and be administered at the same or different dosing frequency. Compound 4 (or a salt thereof). Compound 1 (or a salt The patient being treated can be a treatment naive patient, a thereof) can be co-formulated with ritonavir. In yet another treatment experienced patient, including, but not limited to, a example, the combination of two or more DAAS comprises relapser, an interferon partial responder, an interferon non 65 PSI-7977 and PSI-938. In yet another example, the combina responder (e.g., a null responder), or a patient unable to take tion of two or more DAAS comprises PSI-7977 and TMC interferon. The patient can be infected with, for example and 435. In yet another example, the combination of two or more US 8,969,357 B2 39 40 DAAs comprises BMS-790052 and BMS-650032. In yet 1a or HCV genotype 1b; or HCV genotype 2 or 3. The another example, the combination of two or more DAAS treatment according to this aspect of the technology can also comprises GS-5885, GS-9190, and GS-9451. In yet another be effective against other HCV genotypes. The DAAS can be example, the combination of two or more DAAS comprises administered around the same time or at different times, and BI-201335 and BI-207127. In yet another example, the com can be co-formulated in a single formulation or formulated in bination of two or more DAAs comprises telaprevir and different compositions. Each DAA can be selected from HCV VX-222. In another example, the combination of two or more protease inhibitors, HCV polymerase inhibitors, or HCV DAAs comprises GS-5885 and GS-9451. In yet another NS5A inhibitors. For instance, the combination of two or example, the combination of two or more DAAs includes more DAAS can be a combination of at least one HCV pro danoprevir (with ritonavir) and R7128. In yet another 10 tease inhibitor and at least one HCV polymerase inhibitor example, the combination of two or more DAAs includes (e.g., a combination of at least one HCV protease inhibitor PSI-7977 and BMS-790052. In yet another example, the and at least one non-nucleoside polymerase inhibitor, or a combination of two or more DAAs includes PSI-7977 and combination of at least one HCV protease inhibitor and at BMS-650032 (asunaprevir). In still another example, the least one nucleoside or nucleotide polymerase inhibitor, or a combination of two or more DAAs includes PSI-7977, BMS 15 combination of at least one HCV protease inhibitor, at least 650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet one nucleoside or nucleotide polymerase inhibitor and at least another example, the combination of two or more DAAS one non-nucleoside inhibitor). For another instance, the com includes INX-189 and BMS-790052 (daclatasvir). In yet bination of two or more DAAS can be a combination of at least another example, the combination of two or more DAAS one HCV protease inhibitor and at least one HCV NS5A includes INX-189 and BMS-650032 (asunaprevir). In still inhibitor. For still another instance, the combination of two or another example, the combination of two or more DAAS more DAAS can be a combination of at least one HCV pro includes INX-189, BMS-650032 (asunaprevir) and BMS tease inhibitor, at least one HCV polymerase inhibitor, and at 790052 (daclatasvir). In still another example, the combina least one HCV NS5A inhibitor. For another instance, the tion of two or more DAAs includes mericitabine and dano combination of two or more DAAS can be a combination of at previr. In still another example, the combination of two or 25 least two HCV polymerase inhibitors (e.g., a combination of more DAAs includes INX-189, daclatasvir and at least two nucleoside polymerase inhibitors, or a combina BMS-791325. In still another example, the combination of tion of at least one nucleoside or nucleotide polymerase two or more DAAS includes PSI-7977 and GS-5885. In still inhibitor and at least one non-nucleoside polymerase inhibi another example, the method comprises administering to a tor, or a combination of at least two non-nucleoside poly patient in need thereofan effective amount of PSI-7977 as the 30 merase inhibitors). For another instance, the combination of sole DAA in lieu of a combination of two or more DAAs, two or more DAAS can be a combination of at least two HCV together with an effective amount of ribavirin. In still another protease inhibitors. For another instance, the combination of example, the method comprises administering 100 or 200 mg two or more DAAS can be a combination of at least two HCV Compound 1 together with 100 mg ritonavir once daily, and NS5A inhibitors. For another instance, the combination of 25 mg compound 4 once daily. In yet another example, the 35 two or more DAAS can be a combination of at least one HCV method comprises administering 150 mg or 250 mg Com polymerase inhibitor and at least one NS5A inhibitor (e.g., a pound 1 together with 100 mg ritonavir once daily, and 400 combination of at least one HCV NS5A inhibitor and at least mg Compound 2 twice daily. In another example, the method one non-nucleoside polymerase inhibitor, or a combination of comprises administering 150 mg Compound 1 together with at least one HCV NS5A inhibitor and at least one nucleoside 100 mg ritonavir once daily, and 400 mg Compound 3 once 40 or nucleotide polymerase inhibitor, or a combination of at daily. In another example, the method comprises administer least one HCV NS5A inhibitor, at least one nucleoside or ing 150 mg Compound 1 together with 100 mg ritonavir once nucleotide polymerase inhibitor and at least one non-nucleo daily, and 400 mg Compound 3 twice daily. In another side polymerase inhibitor). In one example, the combination example, the method comprises administering 100 or 150 mg of two or more DAAs is a combination of Compound 1 (or a Compound 1 together with 100 mg ritonavir once daily, 25 45 salt thereof) and Compound 2 (or a salt thereof). Compound mg compound 4 once daily, and 400 mg Compound 2 twice 1 (or a salt thereof) can be co-formulated with ritonavir. In daily. In another example, the method comprises administer another example, the combination of two or more DAAS is a ing 100 or 150 mg Compound 1 together with 100 mg combination of Compound 1 (or a salt thereof) and Com ritonavir once daily, 25 mg compound 4 once daily, and 400 pound 3 (or a salt thereof). Compound 1 (or a salt thereof) can mg Compound 3 twice daily. Ribavirin can be administered 50 be co-formulated with ritonavir. In still another example, the based on patient weight, and in many cases, 1000 to 1200 mg combination of two or more DAAs is a combination of Com divided twice daily. Other DAA(s) can also be included in a pound 1 (or a salt thereof) and Compound 4 (or a salt thereof). treatment regimen according to this aspect of the technology. Compound 1 (or a salt thereof) can be co-formulated with In yet another aspect, the present technology features a ritonavir. In a further example, the combination of two or method of treating HCV, comprising administering to a 55 more DAAS is a combination of Compound 1 (or a salt patient in need thereof an effective amount of a combination thereof), Compound 2 (or a salt thereof) and Compound 4 (or of two or more DAAs, together with an effective amount of a salt thereof). Compound 1 (or a salt thereof) can be co ribavirin. The treatment lasts 3 weeks (or even less, depend formulated with ritonavir. In yet another example, the com ing on the patient’s condition) and does not include adminis bination of two or more DAAs is a combination of Compound tration of any interferon. The DAAs and ribavirin can be 60 1 (or a salt thereof), Compound 3 (or a salt thereof) and administered at the same or different dosing frequency. The Compound 4 (or a salt thereof). Compound 1 (or a salt patient being treated can be a treatment naive patient, a treat thereof) can be co-formulated with ritonavir. In yet another ment experienced patient, including, but not limited to, a example, the combination of two or more DAAS comprises relapser, an interferon partial responder, an interferon non PSI-7977 and PSI-938. In yet another example, the combina responder (e.g., a null responder), or a patient unable to take 65 tion of two or more DAAS comprises PSI-7977 and TMC interferon. The patient can be infected with, for example and 435. In yet another example, the combination of two or more without limitation, HCV genotype 1, such as HCV genotype DAAs comprises BMS-790052 and BMS-650032. In yet US 8,969,357 B2 41 42 another example, the combination of two or more DAAS be effective against other HCV genotypes. The DAAS can be comprises GS-5885, GS-9190, and GS-9451. In yet another administered around the same time or at different times, and example, the combination of two or more DAAS comprises can be co-formulated in a single formulation or formulated in BI-201335 and BI-207127. In yet another example, the com different compositions. Each DAA can be selected from HCV bination of two or more DAAs comprises telaprevir and protease inhibitors, HCV polymerase inhibitors, or HCV VX-222. In another example, the combination of two or more NS5A inhibitors. For instance, the combination of two or DAAs comprises GS-5885 and GS-9451. In yet another more DAAS can be a combination of at least one HCV pro example, the combination of two or more DAAs includes tease inhibitor and at least one HCV polymerase inhibitor danoprevir (with ritonavir) and R7128. In yet another (e.g., a combination of at least one HCV protease inhibitor example, the combination of two or more DAAs includes 10 and at least one non-nucleoside polymerase inhibitor, or a PSI-7977 and BMS-790052. In yet another example, the combination of at least one HCV protease inhibitor and at combination of two or more DAAs includes PSI-7977 and least one nucleoside or nucleotide polymerase inhibitor, or a BMS-650032 (asunaprevir). In still another example, the combination of at least one HCV protease inhibitor, at least combination of two or more DAAs includes PSI-7977, BMS one nucleoside or nucleotide polymerase inhibitor and at least 650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet 15 one non-nucleoside inhibitor). For another instance, the com another example, the combination of two or more DAAS bination of two or more DAAS can be a combination of at least includes INX-189 and BMS-790052 (daclatasvir). In yet one HCV protease inhibitor and at least one HCV NS5A another example, the combination of two or more DAAS inhibitor. For still another instance, the combination of two or includes INX-189 and BMS-650032 (asunaprevir). In still more DAAS can be a combination of at least one HCV pro another example, the combination of two or more DAAS tease inhibitor, at least one HCV polymerase inhibitor, and at includes INX-189, BMS-650032 (asunaprevir) and BMS least one HCV NS5A inhibitor. For another instance, the 790052 (daclatasvir). In still another example, the combina combination of two or more DAAS can be a combination of at tion of two or more DAAs includes mericitabine and dano least two HCV polymerase inhibitors (e.g., a combination of previr. In still another example, the combination of two or at least two nucleoside polymerase inhibitors, or a combina more DAAs includes INX-189, daclatasvir and 25 tion of at least one nucleoside or nucleotide polymerase BMS-791325. In still another example, the combination of inhibitor and at least one non-nucleoside polymerase inhibi two or more DAAS includes PSI-7977 and GS-5885. In still tor, or a combination of at least two non-nucleoside poly another example, the method comprises administering to a merase inhibitors). For another instance, the combination of patient in need thereofan effective amount of PSI-7977 as the two or more DAAS can be a combination of at least two HCV sole DAA in lieu of a combination of two or more DAAs, 30 protease inhibitors. For another instance, the combination of together with an effective amount of ribavirin. In still another two or more DAAS can be a combination of at least two HCV example, the method comprises administering 100 or 200 mg NS5A inhibitors. For another instance, the combination of Compound 1 together with 100 mg ritonavir once daily, and two or more DAAS can be a combination of at least one HCV 25 mg compound 4 once daily. In yet another example, the polymerase inhibitor and at least one NS5A inhibitor (e.g., a method comprises administering 150 mg or 250 mg Com 35 combination of at least one HCV NS5A inhibitor and at least pound 1 together with 100 mg ritonavir once daily, and 400 one non-nucleoside or nucleotide polymerase inhibitor, or a mg Compound 2 twice daily. In another example, the method combination of at least one HCV NS5A inhibitor and at least comprises administering 150 mg Compound 1 together with one nucleoside or nucleotide polymerase inhibitor, or a com 100 mg ritonavir once daily, and 400 mg Compound 3 once bination of at least one HCV NS5A inhibitor, at least one daily. In another example, the method comprises administer 40 nucleoside or nucleotide polymerase inhibitor and at least one ing 150 mg Compound 1 together with 100 mg ritonavir once non-nucleoside polymerase inhibitor). In one example, the daily, and 400 mg Compound 3 twice daily. In another combination of two or more DAAs is a combination of Com example, the method comprises administering 100 or 150 mg pound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 together with 100 mg ritonavir once daily, 25 Compound 1 (or a salt thereof) can be co-formulated with mg compound 4 once daily, and 400 mg Compound 2 twice 45 ritonavir. daily. In another example, the method comprises administer In another example, the combination of two or more DAAS ing 100 or 150 mg Compound 1 together with 100 mg is a combination of Compound 1 (or a salt thereof) and Com ritonavir once daily, 25 mg compound 4 once daily, and 400 pound 3 (or a salt thereof). Compound 1 (or a salt thereof) can mg Compound 3 twice daily. Ribavirin can be administered be co-formulated with ritonavir. In still another example, the based on patient weight, and in many cases, 1000 to 1200 mg 50 combination of two or more DAAs is a combination of Com divided twice daily. Other DAA(s) can also be included in a pound 1 (or a salt thereof) and Compound 4 (or a salt thereof). treatment regimen according to this aspect of the technology. Compound 1 (or a salt thereof) can be co-formulated with In yet another aspect, the present technology features a ritonavir. In a further example, the combination of two or method of treating HCV, comprising administering to a more DAAS is a combination of Compound 1 (or a salt patient in need thereof an effective amount of a combination 55 thereof), Compound 2 (or a salt thereof) and Compound 4 (or of two or more DAAs, together with an effective amount of a salt thereof). Compound 1 (or a salt thereof) can be co ribavirin. The treatment lasts 24 weeks and does not include formulated with ritonavir. In yet another example, the com administration of any interferon. The DAAs and ribavirin can bination of two or more DAAs is a combination of Compound be administered at the same or different dosing frequency. 1 (or a salt thereof), Compound 3 (or a salt thereof) and The patient being treated can be a treatment naive patient, a 60 Compound 4 (or a salt thereof). Compound 1 (or a salt treatment experienced patient, including, but not limited to, a thereof) can be co-formulated with ritonavir. In yet another relapser, an interferon partial responder, an interferon non example, the combination of two or more DAAS comprises responder (e.g., a null responder), or a patient unable to take PSI-7977 and PSI-938. In yet another example, the combina interferon. The patient can be infected with, for example and tion of two or more DAAS comprises PSI-7977 and TMC without limitation, HCV genotype 1, such as HCV genotype 65 435. In yet another example, the combination of two or more 1a or HCV genotype 1b; or HCV genotype 2 or 3. The DAAs comprises BMS-790052 and BMS-650032. In yet treatment according to this aspect of the technology can also another example, the combination of two or more DAAS US 8,969,357 B2 43 44 comprises GS-5885, GS-9190, and GS-9451. In yet another treatment according to this aspect of the technology can also example, the combination of two or more DAAS comprises be effective against other HCV genotypes. The DAAS can be BI-201335 and BI-207127. In yet another example, the com administered around the same time or at different times, and bination of two or more DAAs comprises telaprevir and can be co-formulated in a single formulation or formulated in VX-222. In another example, the combination of two or more different compositions. Each DAA can be selected from HCV DAAs comprises GS-5885 and GS-9451. In yet another protease inhibitors, HCV polymerase inhibitors, or HCV example, the combination of two or more DAAs includes NS5A inhibitors. For instance, the combination of two or danoprevir (with ritonavir) and R7128. In yet another more DAAS can be a combination of at least one HCV pro example, the combination of two or more DAAs includes tease inhibitor and at least one HCV polymerase inhibitor PSI-7977 and BMS-790052. In yet another example, the 10 (e.g., a combination of at least one HCV protease inhibitor combination of two or more DAAs includes PSI-7977 and and at least one non-nucleoside polymerase inhibitor, or a BMS-650032 (asunaprevir). In still another example, the combination of at least one HCV protease inhibitor and at combination of two or more DAAs includes PSI-7977, BMS least one nucleoside or nucleotide polymerase inhibitor, or a 650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet combination of at least one HCV protease inhibitor, at least another example, the combination of two or more DAAS 15 one nucleoside or nucleotide polymerase inhibitor and at least includes INX-189 and BMS-790052 (daclatasvir). In yet one non-nucleoside inhibitor). For another instance, the com another example, the combination of two or more DAAS bination of two or more DAAS can be a combination of at least includes INX-189 and BMS-650032 (asunaprevir). In still one HCV protease inhibitor and at least one HCV NS5A another example, the combination of two or more DAAS inhibitor. For still another instance, the combination of two or includes INX-189, BMS-650032 (asunaprevir) and BMS more DAAS can be a combination of at least one HCV pro 790052 (daclatasvir). In still another example, the combina tease inhibitor, at least one HCV polymerase inhibitor, and at tion of two or more DAAs includes mericitabine and dano least one HCV NS5A inhibitor. For another instance, the previr. In still another example, the combination of two or combination of two or more DAAS can be a combination of at more DAAs includes INX-189, daclatasvir and least two HCV polymerase inhibitors (e.g., a combination of BMS-791325. In still another example, the combination of 25 at least two nucleoside polymerase inhibitors, or a combina two or more DAAS includes PSI-7977 and GS-5885. In still tion of at least one nucleoside or nucleotide polymerase another example, the method comprises administering to a inhibitor and at least one non-nucleoside polymerase inhibi patient in need thereofan effective amount of PSI-7977 as the tor, or a combination of at least two non-nucleoside poly sole DAA in lieu of a combination of two or more DAAs, merase inhibitors). For another instance, the combination of together with an effective amount of ribavirin. In still another 30 two or more DAAS can be a combination of at least two HCV example, the method comprises administering 100 or 200 mg protease inhibitors. For another instance, the combination of Compound 1 together with 100 mg ritonavir once daily, and two or more DAAS can be a combination of at least two HCV 25 mg compound 4 once daily. In yet another example, the NS5A inhibitors. For another instance, the combination of method comprises administering 150 mg or 250 mg Com two or more DAAS can be a combination of at least one HCV pound 1 together with 100 mg ritonavir once daily, and 400 35 polymerase inhibitor and at least one NS5A inhibitor (e.g., a mg Compound 2 twice daily. In another example, the method combination of at least one HCV NS5A inhibitor and at least comprises administering 150 mg Compound 1 together with one non-nucleoside or nucleotide polymerase inhibitor, or a 100 mg ritonavir once daily, and 400 mg Compound 3 once combination of at least one HCV NS5A inhibitor and at least daily. In another example, the method comprises administer one nucleoside or nucleotide polymerase inhibitor, or a com ing 150 mg Compound 1 together with 100 mg ritonavir once 40 bination of at least one HCV NS5A inhibitor, at least one daily, and 400 mg Compound 3 twice daily. In another nucleoside or nucleotide polymerase inhibitor and at least one example, the method comprises administering 100 or 150 mg non-nucleoside polymerase inhibitor). In one example, the Compound 1 together with 100 mg ritonavir once daily, 25 combination of two or more DAAs is a combination of Com mg compound 4 once daily, and 400 mg Compound 2 twice pound 1 (or a salt thereof) and Compound 2 (or a salt thereof). daily. In another example, the method comprises administer 45 Compound 1 (or a salt thereof) can be co-formulated with ing 100 or 150 mg Compound 1 together with 100 mg ritonavir. In another example, the combination of two or more ritonavir once daily, 25 mg compound 4 once daily, and 400 DAAs is a combination of Compound 1 (or a salt thereof) and mg Compound 3 twice daily. Ribavirin can be administered Compound 3 (or a salt thereof). Compound 1 (or a salt based on patient weight, and in many cases, 1000 to 1200 mg thereof) can be co-formulated with ritonavir. In still another divided twice daily. Other DAA(s) can also be included in a 50 example, the combination of two or more DAAS is a combi treatment regimen according to this aspect of the technology. nation of Compound 1 (or a salt thereof) and Compound 4 (or In yet another aspect, the present technology features a a salt thereof). Compound 1 (or a salt thereof) can be co method of treating HCV, comprising administering to a formulated with ritonavir. In a further example, the combina patient in need thereof an effective amount of a combination tion of two or more DAAs is a combination of Compound 1 of two or more DAAs, together with an effective amount of 55 (or a salt thereof), Compound 2 (or a salt thereof) and Com ribavirin. The treatment lasts from 13 to 23 weeks (e.g., the pound 4 (or a salt thereof). Compound 1 (or a salt thereof) can duration of the treatment is selected from 13, 14, 15, 16, 17, be co-formulated with ritonavir. In yet another example, the 18, 19, 20, 21, 22 or 23 weeks) and does not include admin combination of two or more DAAs is a combination of Com istration of any interferon. The DAAs and ribavirin can be pound 1 (or a salt thereof), Compound 3 (or a salt thereof) and administered at the same or different dosing frequency. The 60 Compound 4 (or a salt thereof). Compound 1 (or a salt patient being treated can be a treatment naive patient, a treat thereof) can be co-formulated with ritonavir. In yet another ment experienced patient, including, but not limited to, a example, the combination of two or more DAAS comprises relapser, an interferon partial responder, an interferon non PSI-7977 and PSI-938. In yet another example, the combina responder (e.g., a null responder), or a patient unable to take tion of two or more DAAS comprises PSI-7977 and TMC interferon. The patient can be infected with, for example and 65 435. In yet another example, the combination of two or more without limitation, HCV genotype 1, such as HCV genotype DAAs comprises BMS-790052 and BMS-650032. In yet 1a or HCV genotype 1b; or HCV genotype 2 or 3. The another example, the combination of two or more DAAS US 8,969,357 B2 45 46 comprises GS-5885, GS-9190, and GS-9451. In yet another administered around the same time or at different times, and example, the combination of two or more DAAS comprises can be co-formulated in a single formulation or formulated in BI-201335 and BI-207127. In yet another example, the com different compositions. Each DAA can be selected from HCV bination of two or more DAAs comprises telaprevir and protease inhibitors, HCV polymerase inhibitors, or HCV VX-222. In another example, the combination of two or more NS5A inhibitors. For instance, the combination of two or DAAs comprises GS-5885 and GS-9451. In yet another more DAAS can be a combination of at least one HCV pro example, the combination of two or more DAAs includes tease inhibitor and at least one HCV polymerase inhibitor danoprevir (with ritonavir) and R7128. In yet another (e.g., a combination of at least one HCV protease inhibitor example, the combination of two or more DAAs includes and at least one non-nucleoside polymerase inhibitor, or a PSI-7977 and BMS-790052. In yet another example, the 10 combination of at least one HCV protease inhibitor and at combination of two or more DAAs includes PSI-7977 and least one nucleoside or nucleotide polymerase inhibitor, or a BMS-650032 (asunaprevir). In still another example, the combination of at least one HCV protease inhibitor, at least combination of two or more DAAs includes PSI-7977, BMS one nucleoside or nucleotide polymerase inhibitor and at least 650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet one non-nucleoside inhibitor). For another instance, the com another example, the combination of two or more DAAS 15 bination of two or more DAAS can be a combination of at least includes INX-189 and BMS-790052 (daclatasvir). In yet one HCV protease inhibitor and at least one HCV NS5A another example, the combination of two or more DAAS inhibitor. For still another instance, the combination of two or includes INX-189 and BMS-650032 (asunaprevir). In still more DAAS can be a combination of at least one HCV pro another example, the combination of two or more DAAS tease inhibitor, at least one HCV polymerase inhibitor, and at includes INX-189, BMS-650032 (asunaprevir) and BMS least one HCV NS5A inhibitor. For another instance, the 790052 (daclatasvir). In still another example, the combina combination of two or more DAAS can be a combination of at tion of two or more DAAs includes mericitabine and dano least two HCV polymerase inhibitors (e.g., a combination of previr. In still another example, the combination of two or at least two nucleoside polymerase inhibitors, or a combina more DAAs includes INX-189, daclatasvir and tion of at least one nucleoside or nucleotide polymerase BMS-791325. In still another example, the combination of 25 inhibitor and at least one non-nucleoside polymerase inhibi two or more DAAS includes PSI-7977 and GS-5885. In still tor, or a combination of at least two non-nucleoside poly another example, the method comprises administering to a merase inhibitors). For another instance, the combination of patient in need thereofan effective amount of PSI-7977 as the two or more DAAS can be a combination of at least two HCV sole DAA in lieu of a combination of two or more DAAs, protease inhibitors. For another instance, the combination of together with an effective amount of ribavirin. In still another 30 two or more DAAS can be a combination of at least two HCV example, the method comprises administering 100 or 200 mg NS5A inhibitors. For another instance, the combination of Compound 1 together with 100 mg ritonavir once daily, and two or more DAAS can be a combination of at least one HCV 25 mg compound 4 once daily. In yet another example, the polymerase inhibitor and at least one NS5A inhibitor (e.g., a method comprises administering 150 mg or 250 mg Com combination of at least one HCV NS5A inhibitor and at least pound 1 together with 100 mg ritonavir once daily, and 400 35 one non-nucleoside polymerase inhibitor, or a combination of mg Compound 2 twice daily. In another example, the method at least one HCV NS5A inhibitor and at least one nucleoside comprises administering 150 mg Compound 1 together with or nucleotide polymerase inhibitor, or a combination of at 100 mg ritonavir once daily, and 400 mg Compound 3 once least one HCV NS5A inhibitor, at least one nucleoside or daily. In another example, the method comprises administer nucleotide polymerase inhibitor and at least one non-nucleo ing 150 mg Compound 1 together with 100 mg ritonavir once 40 side inhibitor). In one example, the combination of two or daily, and 400 mg Compound 3 twice daily. In another more DAAS is a combination of Compound 1 (or a salt example, the method comprises administering 100 or 150 mg thereof) and Compound 2 (or a salt thereof). Compound 1 (or Compound 1 together with 100 mg ritonavir once daily, 25 a salt thereof) can be co-formulated with ritonavir. In another mg compound 4 once daily, and 400 mg Compound 2 twice example, the combination of two or more DAAS is a combi daily. In another example, the method comprises administer 45 nation of Compound 1 (or a salt thereof) and Compound 3 (or ing 100 or 150 mg Compound 1 together with 100 mg a salt thereof). Compound 1 (or a salt thereof) can be co ritonavir once daily, 25 mg compound 4 once daily, and 400 formulated with ritonavir. In still another example, the com mg Compound 3 twice daily. Ribavirin can be administered bination of two or more DAAs is a combination of Compound based on patient weight, and in many cases, 1000 to 1200 mg 1 (or a salt thereof) and Compound 4 (or a salt thereof). divided twice daily. Other DAA(s) can also be included in a 50 Compound 1 (or a salt thereof) can be co-formulated with treatment regimen according to this aspect of the technology. ritonavir. In a further example, the combination of two or In yet another aspect, the present technology features a more DAAS is a combination of Compound 1 (or a salt method of treating HCV, comprising administering to a thereof), Compound 2 (or a salt thereof) and Compound 4 (or patient in need thereof an effective amount of a combination a salt thereof). Compound 1 (or a salt thereof) can be co of two or more DAAs, together with an effective amount of 55 formulated with ritonavir. In yet another example, the com ribavirin. The treatment lasts 12 weeks and does not include bination of two or more DAAs is a combination of Compound administration of any interferon. The DAAs and ribavirin can 1 (or a salt thereof), Compound 3 (or a salt thereof) and be administered at the same or different dosing frequency. Compound 4 (or a salt thereof). Compound 1 (or a salt The patient being treated can be a treatment naive patient, a thereof) can be co-formulated with ritonavir. In yet another treatment experienced patient, including, but not limited to, a 60 example, the combination of two or more DAAS comprises relapser, an interferon partial responder, an interferon non PSI-7977 and PSI-938. In yet another example, the combina responder (e.g., a null responder), or a patient unable to take tion of two or more DAAS comprises PSI-7977 and TMC interferon. The patient can be infected with, for example and 435. In yet another example, the combination of two or more without limitation, HCV genotype 1, such as HCV genotype DAAs comprises BMS-790052 and BMS-650032. In yet 1a or HCV genotype 1b; or HCV genotype 2 or 3. The 65 another example, the combination of two or more DAAS treatment according to this aspect of the technology can also comprises GS-5885, GS-9190, and GS-9451. In yet another be effective against other HCV genotypes. The DAAS can be example, the combination of two or more DAAS comprises US 8,969,357 B2 47 48 BI-201335 and BI-207127. In yet another example, the com different compositions. Each DAA can be selected from HCV bination of two or more DAAs comprises telaprevir and protease inhibitors, HCV polymerase inhibitors, or HCV VX-222. In another example, the combination of two or more NS5A inhibitors. For instance, the combination of two or DAAs comprises GS-5885 and GS-9451. In yet another more DAAS can be a combination of at least one HCV pro example, the combination of two or more DAAs includes tease inhibitor and at least one HCV polymerase inhibitor danoprevir (with ritonavir) and R7128. In yet another (e.g., a combination of at least one HCV protease inhibitor example, the combination of two or more DAAs includes and at least one non-nucleoside polymerase inhibitor, or a PSI-7977 and BMS-790052 (daclatasvir). In yet another combination of at least one HCV protease inhibitor and at example, the combination of two or more DAAs includes least one nucleoside or nucleotide polymerase inhibitor, or a PSI-7977 and BMS-650032 (asunaprevir). In still another 10 combination of at least one HCV protease inhibitor, at least example, the combination of two or more DAAs includes one nucleoside or nucleotide polymerase inhibitor and at least PSI-7977, BMS-650032 (asunaprevir) and BMS-790052 one non-nucleoside inhibitor). For another instance, the com (daclatasvir). In yet another example, the combination of two bination of two or more DAAS can be a combination of at least or more DAAs includes INX-189 and BMS-790052 (da one HCV protease inhibitor and at least one HCV NS5A clatasvir). In yet another example, the combination of two or 15 inhibitor. For still another instance, the combination of two or more DAAs includes INX-189 and BMS-650032 (asunapre more DAAS can be a combination of at least one HCV pro vir). In still another example, the combination of two or more tease inhibitor, at least one HCV polymerase inhibitor, and at DAAs includes INX-189, BMS-650032 (asunaprevir) and least one HCV NS5A inhibitor. For another instance, the BMS-790052 (daclatasvir). In still another example, the com combination of two or more DAAS can be a combination of at bination of two or more DAAs includes mericitabine and least two HCV polymerase inhibitors (e.g., a combination of danoprevir. In still another example, the combination of two at least two nucleoside polymerase inhibitors, or a combina or more DAAs includes INX-189, daclatasvir and tion of at least one nucleoside or nucleotide polymerase BMS-791325. In still another example, the combination of inhibitor and at least one non-nucleoside polymerase inhibi two or more DAAS includes PSI-7977 and GS-5885. In still tor, or a combination of at least two non-nucleoside poly another example, the method comprises administering to a 25 merase inhibitors). For another instance, the combination of patient in need thereofan effective amount of PSI-7977 as the two or more DAAS can be a combination of at least two HCV sole DAA in lieu of a combination of two or more DAAs, protease inhibitors. For another instance, the combination of together with an effective amount of ribavirin. In still another two or more DAAS can be a combination of at least two HCV example, the method comprises administering 100 or 200 mg NS5A inhibitors. For another instance, the combination of Compound 1 together with 100 mg ritonavir once daily, and 30 two or more DAAS can be a combination of at least one HCV 25 mg compound 4 once daily. In yet another example, the polymerase inhibitor and at least one NS5A inhibitor (e.g., a method comprises administering 150 mg or 250 mg Com combination of at least one HCV NS5A inhibitor and at least pound 1 together with 100 mg ritonavir once daily, and 400 one non-nucleoside polymerase inhibitor, or a combination of mg Compound 2 twice daily. In another example, the method at least one HCV NS5A inhibitor and at least one nucleoside comprises administering 150 mg Compound 1 together with 35 or nucleotide polymerase inhibitor, or a combination of at 100 mg ritonavir once daily, and 400 mg Compound 3 once least one HCV NS5A inhibitor, at least one nucleoside or daily. In another example, the method comprises administer nucleotide polymerase inhibitor and at least one non-nucleo ing 150 mg Compound 1 together with 100 mg ritonavir once side polymerase inhibitor). In one example, the combination daily, and 400 mg Compound 3 twice daily. In another of two or more DAAs is a combination of Compound 1 (or a example, the method comprises administering 100 or 150 mg 40 salt thereof) and Compound 2 (or a salt thereof). Compound Compound 1 together with 100 mg ritonavir once daily, 25 1 (or a salt thereof) can be co-formulated with ritonavir. In mg compound 4 once daily, and 400 mg Compound 2 twice another example, the combination of two or more DAAS is a daily. In another example, the method comprises administer combination of Compound 1 (or a salt thereof) and Com ing 100 or 150 mg Compound 1 together with 100 mg pound 3 (or a salt thereof). Compound 1 (or a salt thereof) can ritonavir once daily, 25 mg compound 4 once daily, and 400 45 be co-formulated with ritonavir. In still another example, the mg Compound 3 twice daily. Ribavirin can be administered combination of two or more DAAs is a combination of Com based on patient weight, and in many cases, 1000 to 1200 mg pound 1 (or a salt thereof) and Compound 4 (or a salt thereof). divided twice daily. Other DAA(s) can also be included in a Compound 1 (or a salt thereof) can be co-formulated with treatment regimen according to this aspect of the technology. ritonavir. In a further example, the combination of two or In yet another aspect, the present technology features a 50 more DAAS is a combination of Compound 1 (or a salt method of treating HCV, comprising administering to a thereof), Compound 2 (or a salt thereof) and Compound 4 (or patient in need thereof an effective amount of a combination a salt thereof). Compound 1 (or a salt thereof) can be co of two or more DAAs, together with an effective amount of formulated with ritonavir. In yet another example, the com ribavirin. The treatment lasts 11 weeks and does not include bination of two or more DAAs is a combination of Compound administration of any interferon. The DAAs and ribavirin can 55 1 (or a salt thereof), Compound 3 (or a salt thereof) and be administered at the same or different dosing frequency. Compound 4 (or a salt thereof). Compound 1 (or a salt The patient being treated can be a treatment naive patient, a thereof) can be co-formulated with ritonavir. In yet another treatment experienced patient, including, but not limited to, a example, the combination of two or more DAAS comprises relapser, an interferon partial responder, an interferon non PSI-7977 and PSI-938. In yet another example, the combina responder (e.g., a null responder), or a patient unable to take 60 tion of two or more DAAS comprises PSI-7977 and TMC interferon. The patient can be infected with, for example and 435. In yet another example, the combination of two or more without limitation, HCV genotype 1, such as HCV genotype DAAs comprises BMS-790052 and BMS-650032. In yet 1a or HCV genotype 1b; or HCV genotype 2 or 3. The another example, the combination of two or more DAAS treatment according to this aspect of the technology can also comprises GS-5885, GS-9190, and GS-9451. In yet another be effective against other HCV genotypes. The DAAS can be 65 example, the combination of two or more DAAS comprises administered around the same time or at different times, and BI-201335 and BI-207127. In yet another example, the com can be co-formulated in a single formulation or formulated in bination of two or more DAAs comprises telaprevir and US 8,969,357 B2 49 50 VX-222. In another example, the combination of two or more NS5A inhibitors. For instance, the combination of two or DAAs comprises GS-5885 and GS-9451. In yet another more DAAS can be a combination of at least one HCV pro example, the combination of two or more DAAs includes tease inhibitor and at least one HCV polymerase inhibitor danoprevir (with ritonavir) and R7128. In yet another (e.g., a combination of at least one HCV protease inhibitor example, the combination of two or more DAAs includes and at least one non-nucleoside polymerase inhibitor, or a PSI-7977 and BMS-790052. In yet another example, the combination of at least one HCV protease inhibitor and at combination of two or more DAAs includes PSI-7977 and least one nucleoside or nucleotide polymerase inhibitor, or a BMS-650032 (asunaprevir). In still another example, the combination of at least one HCV protease inhibitor, at least combination of two or more DAAs includes PSI-7977, BMS one nucleoside or nucleotide polymerase inhibitor and at least 650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet 10 one non-nucleoside inhibitor). For another instance, the com another example, the combination of two or more DAAS bination of two or more DAAS can be a combination of at least includes INX-189 and BMS-790052 (daclatasvir). In yet one HCV protease inhibitor and at least one HCV NS5A another example, the combination of two or more DAAS inhibitor. For still another instance, the combination of two or includes INX-189 and BMS-650032 (asunaprevir). In still more DAAS can be a combination of at least one HCV pro another example, the combination of two or more DAAS 15 tease inhibitor, at least one HCV polymerase inhibitor, and at includes INX-189, BMS-650032 (asunaprevir) and BMS least one HCV NS5A inhibitor. For another instance, the 790052 (daclatasvir). In still another example, the combina combination of two or more DAAS can be a combination of at tion of two or more DAAs includes mericitabine and dano least two HCV polymerase inhibitors (e.g., a combination of previr. In still another example, the combination of two or at least two nucleoside polymerase inhibitors, or a combina more DAAs includes INX-189, daclatasvir and tion of at least one nucleoside or nucleotide polymerase BMS-791325. In still another example, the combination of inhibitor and at least one non-nucleoside polymerase inhibi two or more DAAS includes PSI-7977 and GS-5885. In still tor, or a combination of at least two non-nucleoside poly another example, the method comprises administering to a merase inhibitors). For another instance, the combination of patient in need thereofan effective amount of PSI-7977 as the two or more DAAS can be a combination of at least two HCV sole DAA in lieu of a combination of two or more DAAs, 25 protease inhibitors. For another instance, the combination of together with an effective amount of ribavirin. In still another two or more DAAS can be a combination of at least two HCV example, the method comprises administering 100 or 200 mg NS5A inhibitors. For another instance, the combination of Compound 1 together with 100 mg ritonavir once daily, and two or more DAAS can be a combination of at least one HCV 25 mg compound 4 once daily. In yet another example, the polymerase inhibitor and at least one NS5A inhibitor (e.g., a method comprises administering 150 mg or 250 mg Com 30 combination of at least one HCV NS5A inhibitor and at least pound 1 together with 100 mg ritonavir once daily, and 400 one non-nucleoside polymerase inhibitor, or a combination of mg Compound 2 twice daily. In another example, the method at least one HCV NS5A inhibitor and at least one nucleoside comprises administering 150 mg Compound 1 together with or nucleotide polymerase inhibitor, or a combination of at 100 mg ritonavir once daily, and 400 mg Compound 3 once least one HCV NS5A inhibitor, at least one nucleoside or daily. In another example, the method comprises administer 35 nucleotide polymerase inhibitor and at least one non-nucleo ing 150 mg Compound 1 together with 100 mg ritonavir once side polymerase inhibitor). In one example, the combination daily, and 400 mg Compound 3 twice daily. In another of two or more DAAs is a combination of Compound 1 (or a example, the method comprises administering 100 or 150 mg salt thereof) and Compound 2 (or a salt thereof). Compound Compound 1 together with 100 mg ritonavir once daily, 25 1 (or a salt thereof) can be co-formulated with ritonavir. In mg compound 4 once daily, and 400 mg Compound 2 twice 40 another example, the combination of two or more DAAS is a daily. In another example, the method comprises administer combination of Compound 1 (or a salt thereof) and Com ing 100 or 150 mg Compound 1 together with 100 mg pound 3 (or a salt thereof). Compound 1 (or a salt thereof) can ritonavir once daily, 25 mg compound 4 once daily, and 400 be co-formulated with ritonavir. In still another example, the mg Compound 3 twice daily. Ribavirin can be administered combination of two or more DAAs is a combination of Com based on patient weight, and in many cases, 1000 to 1200 mg 45 pound 1 (or a salt thereof) and Compound 4 (or a salt thereof). divided twice daily. Other DAA(s) can also be included in a Compound 1 (or a salt thereof) can be co-formulated with treatment regimen according to this aspect of the technology. ritonavir. In a further example, the combination of two or In yet another aspect, the present technology features a more DAAS is a combination of Compound 1 (or a salt method of treating HCV, comprising administering to a thereof), Compound 2 (or a salt thereof) and Compound 4 (or patient in need thereof an effective amount of a combination 50 a salt thereof). Compound 1 (or a salt thereof) can be co of two or more DAAs, together with an effective amount of formulated with ritonavir. In yet another example, the com ribavirin. The treatment lasts 10 weeks and does not include bination of two or more DAAs is a combination of Compound administration of any interferon. The DAAs and ribavirin can 1 (or a salt thereof), Compound 3 (or a salt thereof) and be administered at the same or different dosing frequency. Compound 4 (or a salt thereof). Compound 1 (or a salt The patient being treated can be a treatment naive patient, a 55 thereof) can be co-formulated with ritonavir. In yet another treatment experienced patient, including, but not limited to, a example, the combination of two or more DAAS comprises relapser, an interferon partial responder, an interferon non PSI-7977 and PSI-938. In yet another example, the combina responder (e.g., a null responder), or a patient unable to take tion of two or more DAAS comprises PSI-7977 and TMC interferon. The patient can be infected with, for example and 435. In yet another example, the combination of two or more without limitation, HCV genotype 1, such as HCV genotype 60 DAAs comprises BMS-790052 and BMS-650032. In yet 1a or HCV genotype 1b; or HCV genotype 2 or 3. The another example, the combination of two or more DAAS treatment according to this aspect of the technology can also comprises GS-5885, GS-9190, and GS-9451. In yet another be effective against other HCV genotypes. The DAAS can be example, the combination of two or more DAAS comprises administered around the same time or at different times, and BI-201335 and BI-207127. In yet another example, the com can be co-formulated in a single formulation or formulated in 65 bination of two or more DAAs comprises telaprevir and different compositions. Each DAA can be selected from HCV VX-222. In another example, the combination of two or more protease inhibitors, HCV polymerase inhibitors, or HCV DAAs comprises GS-5885 and GS-9451. In yet another US 8,969,357 B2 51 52 example, the combination of two or more DAAs includes tease inhibitor and at least one HCV polymerase inhibitor danoprevir (with ritonavir) and R7128. In yet another (e.g., a combination of at least one HCV protease inhibitor example, the combination of two or more DAAs includes and at least one non-nucleoside polymerase inhibitor, or a PSI-7977 and BMS-790052. In yet another example, the combination of at least one HCV protease inhibitor and at combination of two or more DAAs includes PSI-7977 and least one nucleoside or nucleotide polymerase inhibitor, or a BMS-650032 (asunaprevir). In still another example, the combination of at least one HCV protease inhibitor, at least combination of two or more DAAs includes PSI-7977, BMS one nucleoside or nucleotide polymerase inhibitor and at least 650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet one non-nucleoside inhibitor). For another instance, the com another example, the combination of two or more DAAS bination of two or more DAAS can be a combination of at least includes INX-189 and BMS-790052 (daclatasvir). In yet 10 one HCV protease inhibitor and at least one HCV NS5A another example, the combination of two or more DAAS inhibitor. For still another instance, the combination of two or includes INX-189 and BMS-650032 (asunaprevir). In still more DAAS can be a combination of at least one HCV pro another example, the combination of two or more DAAS tease inhibitor, at least one HCV polymerase inhibitor, and at includes INX-189, BMS-650032 (asunaprevir) and BMS least one HCV NS5A inhibitor. For another instance, the 790052 (daclatasvir). In still another example, the combina 15 combination of two or more DAAS can be a combination of at tion of two or more DAAs includes mericitabine and dano least two HCV polymerase inhibitors (e.g., a combination of previr. In still another example, the combination of two or at least two nucleoside polymerase inhibitors, or a combina more DAAs includes INX-189, daclatasvir and tion of at least one nucleoside or nucleotide polymerase BMS-791325. In still another example, the combination of inhibitor and at least one non-nucleoside or nucleotide poly two or more DAAS includes PSI-7977 and GS-5885. In still merase inhibitor, or a combination of at least two non-nucleo another example, the method comprises administering to a side polymerase inhibitors). For another instance, the combi patient in need thereofan effective amount of PSI-7977 as the nation of two or more DAAS can be a combination of at least sole DAA in lieu of a combination of two or more DAAs, two HCV protease inhibitors. For another instance, the com together with an effective amount of ribavirin. In still another bination of two or more DAAS can be a combination of at least example, the method comprises administering 100 or 200 mg 25 two HCV NS5A inhibitors. For another instance, the combi Compound 1 together with 100 mg ritonavir once daily, and nation of two or more DAAS can be a combination of at least 25 mg compound 4 once daily. In yet another example, the one HCV polymerase inhibitor and at least one NS5A inhibi method comprises administering 150 mg or 250 mg Com tor (e.g., a combination of at least one HCV NS5A inhibitor pound 1 together with 100 mg ritonavir once daily, and 400 and at least one non-nucleoside polymerase inhibitor, or a mg Compound 2 twice daily. In another example, the method 30 combination of at least one HCV NS5A inhibitor and at least comprises administering 150 mg Compound 1 together with one nucleoside or nucleotide polymerase inhibitor, or a com 100 mg ritonavir once daily, and 400 mg Compound 3 once bination of at least one HCV NS5A inhibitor, at least one daily. In another example, the method comprises administer nucleoside or nucleotide polymerase inhibitor and at least one ing 150 mg Compound 1 together with 100 mg ritonavir once non-nucleoside polymerase inhibitor). In one example, the daily, and 400 mg Compound 3 twice daily. In another 35 combination of two or more DAAs is a combination of Com example, the method comprises administering 100 or 150 mg pound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 together with 100 mg ritonavir once daily, 25 Compound 1 (or a salt thereof) can be co-formulated with mg compound 4 once daily, and 400 mg Compound 2 twice ritonavir. In another example, the combination of two or more daily. In another example, the method comprises administer DAAs is a combination of Compound 1 (or a salt thereof) and ing 100 or 150 mg Compound 1 together with 100 mg 40 Compound 3 (or a salt thereof). Compound 1 (or a salt ritonavir once daily, 25 mg compound 4 once daily, and 400 thereof) can be co-formulated with ritonavir. In still another mg Compound 3 twice daily. Ribavirin can be administered example, the combination of two or more DAAS is a combi based on patient weight, and in many cases, 1000 to 1200 mg nation of Compound 1 (or a salt thereof) and Compound 4 (or divided twice daily. Other DAA(s) can also be included in a a salt thereof). Compound 1 (or a salt thereof) can be co treatment regimen according to this aspect of the technology. 45 formulated with ritonavir. In a further example, the combina In yet another aspect, the present technology features a tion of two or more DAAs is a combination of Compound 1 method of treating HCV, comprising administering to a (or a salt thereof), Compound 2 (or a salt thereof) and Com patient in need thereof an effective amount of a combination pound 4 (or a salt thereof). Compound 1 (or a salt thereof) can of two or more DAAs, together with an effective amount of be co-formulated with ritonavir. In yet another example, the ribavirin. The treatment lasts 9 weeks and does not include 50 combination of two or more DAAs is a combination of Com administration of any interferon. The DAAs and ribavirin can pound 1 (or a salt thereof), Compound 3 (or a salt thereof) and be administered at the same or different dosing frequency. Compound 4 (or a salt thereof). Compound 1 (or a salt The patient being treated can be an interferon naive patient, a thereof) can be co-formulated with ritonavir. In yet another treatment experienced patient, including, but not limited to, a example, the combination of two or more DAAS comprises relapser, an interferon partial responder, an interferon non 55 PSI-7977 and PSI-938. In yet another example, the combina responder (e.g., a null responder), or a patient unable to take tion of two or more DAAS comprises PSI-7977 and TMC interferon. The patient can be infected with, for example and 435. In yet another example, the combination of two or more without limitation, HCV genotype 1, such as HCV genotype DAAs comprises BMS-790052 and BMS-650032. In yet 1a or HCV genotype 1b; or HCV genotype 2 or 3. The another example, the combination of two or more DAAS treatment according to this aspect of the technology can also 60 comprises GS-5885, GS-9190, and GS-9451. In yet another be effective against other HCV genotypes. The DAAS can be example, the combination of two or more DAAS comprises administered around the same time or at different times, and BI-201335 and BI-207127. In yet another example, the com can be co-formulated in a single formulation or formulated in bination of two or more DAAs comprises telaprevir and different compositions. Each DAA can be selected from HCV VX-222. In another example, the combination of two or more protease inhibitors, HCV polymerase inhibitors, or HCV 65 DAAs comprises GS-5885 and GS-9451. In yet another NS5A inhibitors. For instance, the combination of two or example, the combination of two or more DAAs includes more DAAS can be a combination of at least one HCV pro danoprevir (with ritonavir) and R7128. In yet another US 8,969,357 B2 53 54 example, the combination of two or more DAAs includes patient. Treatment experienced patients include interferon PSI-7977 and BMS-790052. In yet another example, the non-responders, partial responders (patients whose HCV combination of two or more DAAs includes PSI-7977 and RNA levels declined but never became undetectable), and BMS-650032 (asunaprevir). In still another example, the relapsers (patients who achieved undetectable levels of HCV combination of two or more DAAs includes PSI-7977, BMS RNA during therapy but rebound). Methods of the present 650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet technology may also be used to treat patients who are not another example, the combination of two or more DAAS candidates for interferon treatment. Patients who are not can includes INX-189 and BMS-790052 (daclatasvir). In yet didates for interferon treatment include, but are not limited to, another example, the combination of two or more DAAS one or more of the following groups: patients intolerant to includes INX-189 and BMS-650032 (asunaprevir). In still 10 interferon, patients who refuse to take interferon treatment, another example, the combination of two or more DAAS patients with medical conditions which preclude them from includes INX-189, BMS-650032 (asunaprevir) and BMS taking interferon, and patients who have an increased risk of 790052 (daclatasvir). In still another example, the combina side effects or infection by taking interferon. tion of two or more DAAs includes mericitabine and dano In some embodiments, a cytochrome P-450 inhibitor, e.g. previr. In still another example, the combination of two or 15 ritonavir, is administered either in the same or separate phar more DAAs includes INX-189, daclatasvir and maceutical composition with the protease inhibitor (e.g. BMS-791325. In still another example, the combination of Compound 1 (or a pharmaceutically acceptable salt thereof)) two or more DAAS includes PSI-7977 and GS-5885. In still to improve the pharmacokinetics. A cytochrome P450 inhibi another example, the method comprises administering to a tor reduces the metabolism of some protease inhibitors, such patient in need thereofan effective amount of PSI-7977 as the as Compound 1, thereby improving the pharmacokinetics and sole DAA in lieu of a combination of two or more DAAs, bioavailability of the protease inhibitor, for example Com together with an effective amount of ribavirin. In still another pound 1. More preferably, Compound 1 (or a pharmaceuti example, the method comprises administering 100 or 200 mg cally acceptable salt thereof) is co-formulated with ritonavir Compound 1 together with 100 mg ritonavir once daily, and in the same dosage form. Other cytochrome P450 inhibitors, 25 mg compound 4 once daily. In yet another example, the 25 Such as cobicistat, may also be administered in lieu of method comprises administering 150 mg or 250 mg Com ritonavir, to enhance the pharmacokinetics of Compound 1 pound 1 together with 100 mg ritonavir once daily, and 400 (or a pharmaceutically acceptable salt thereof). mg Compound 2 twice daily. In another example, the method Inhibitors of cytochrome P450, such as ritonavir, may be comprises administering 150 mg Compound 1 together with co-administered with the DAAs, either sequentially or simul 100 mg ritonavir once daily, and 400 mg Compound 3 once 30 taneously, in the same or different compositions. In some daily. In another example, the method comprises administer embodiments, the cytochrome P450 inhibitors are adminis ing 150 mg Compound 1 together with 100 mg ritonavir once tered in order to improve the pharmacokinetics of at least one daily, and 400 mg Compound 3 twice daily. In another of the DAAs. Not to be bound by anytheory, but a cytochrome example, the method comprises administering 100 or 150 mg P450 inhibitor may also reduce the development of resistant Compound 1 together with 100 mg ritonavir once daily, 25 35 strains of HCV when co-administered with a DAA, thus mg compound 4 once daily, and 400 mg Compound 2 twice providing the effectiveness in a shorter treatment. In some daily. In another example, the method comprises administer embodiments, ritonavir is co-administered with therapeutic ing 100 or 150 mg Compound 1 together with 100 mg agent 1. In some embodiments, ritonavir is co-administered ritonavir once daily, 25 mg compound 4 once daily, and 400 with therapeutic agent 1 in the same compositions. mg Compound 3 twice daily. Ribavirin can be administered 40 In some embodiments, the present technology provides a based on patient weight, and in many cases, 1000 to 1200 mg method of treating HCV infection comprising administering divided twice daily. Other DAA(s) can also be included in a at least one protease inhibitor and at least one HCV poly treatment regimen according to this aspect of the technology. merase inhibitor with ribavirin in a course of treatment of no In another embodiment, the present technology provides more than, or less than, eight weeks in the absence of inter interferon-free treatment comprising administering daily two 45 feron. In some embodiments, the HCV polymerase inhibitor DAAs with ribavirin, where the two DAAs include a HCV is Compound 1 (or a pharmaceutically acceptable salt polymerase inhibitor, for example PSI-7977 and a NS5A thereof). inhibitor, for example BMS-790052 for a duration of no more In some embodiments, the present technology provides a than twelve weeks (e.g., no more than eleven weeks), prefer method of treating HCV infection without using interferon, ably no more than eight weeks. 50 the method comprising administering at least two DAAS and In some embodiments, the present technology provides a ribavirin to a patient in need of such treatment, wherein the at method of treating Hepatitis C virus infection in a subject least two DAAs include at least one protease inhibitor and at comprising administering daily a HCV protease inhibitor and least one HCV polymerase inhibitor. In some embodiments, a HCV polymerase inhibitor to the subject in the absence of the at least two DAAs includes therapeutic agent 1 with at interferon for a duration of no more than twelve weeks, pref 55 least one HCV polymerase inhibitor. In some embodiments, erably no more than eight weeks. In some embodiments, the HCV polymerase inhibitor is at least one non-nucleoside ritonavir (or an equivalent thereof) is co-administered with polymerase inhibitor. In some embodiments, the non-nucleo one or more protease inhibitors to improve the pharmacoki side polymerase inhibitor is therapeutic agent 2 ortherapeutic netics of the protease inhibitor(s). The treatment further com agent 3 or a combination thereof. prises administering ribavirin to the patient. In some embodi 60 In some embodiments, the present technology provides a ments, the HCV polymerase inhibitor is at least one method of treating HCV infection without using interferon, nucleoside or nucleotide polymerase inhibitor or at least one the method comprising administering a HCV protease inhibi non-nucleoside polymerase inhibitor. In some embodiments, tor, preferably therapeutic agent 1, with at least one HCV both a nucleoside or nucleotide polymerase inhibitors and a NS5A inhibitor to a patient in need of such treatment. In some non-nucleoside polymerase inhibitor may be administered. 65 embodiments, the NS5A inhibitor is therapeutic agent 4. The methods of the present technology as described herein In some embodiments of the present technology, a method may be used to treata naive patient or a treatment experienced of treating HCV infection without using interferon, the US 8,969,357 B2 55 56 method comprises administering at least three DAAS and Non-limiting examples of suitable cyclophilin inhibitors ribavirinto a subject for no more than 8 weeks without admin includealisporovir (Novartis & Debiopharm), NM-811 (No istering interferon. The at least three DAAs can be at least one vartis), SCY-635 (Scynexis), or a combination thereof. protease inhibitor, at least one HCV polymerase inhibitor, and Non-limiting examples of suitable HCV entry inhibitors at least one NS5A inhibitors. In a preferred embodiment, the 5 include ITX-4520 (iTherx), ITX-5061 (iTherx), or a combi at least one protease inhibitor is therapeutic agent 1, the at nation thereof. least one polymerase inhibitor is therapeutic agent 2 or thera Specific examples of other DAA agents that are suitable for peutic agent 3, and the at least one NS5A inhibitor is thera the present methods include, but are not limited to, AP-H005, peutic agent 4. A-831 (Arrow Therapeutics) (NS5A inhibitor), A-689 (Ar Preferred HCV protease inhibitors include, but are not 10 row Therapeutics) (NS5A inhibitor), INX08.189 (Inhibitex) limited to, therapeutic agent 1, telaprevir (Vertex), boceprevir (polymerase inhibitor), ITMN-191 (Intermune/Roche) (NS3/ (Merck), BI-201335 (Boehringer Ingelheim), GS-9451 4A Protease inhibitor), VBY-376 (Protease Inhibitor) (Vi (Gilead), and BMS-650032 (BMS). Other suitable protease robay), ACH-1625 (Achillion, Protease inhibitor), IDX136 inhibitors include, but are not limited to, ACH-1095 (Achil (Idenix, Protease Inhibitor), IDX316 (Idenix, Protease inhibi lion), ACH-1625 (Achillion), ACH-2684 (Achillion), AVL 15 tor), VX-813 (Vertex), SCH 900518 (Schering-Plough), 181 (Avila), AVL-192 (Avila), BMS-650032 (BMS), dano TMC-435 (Tibotec), ITMN-191 (Intermune, Roche), previr (RG7227/ITMN-191, Roche), GS-9132 (Gilead), MK-7009 (Merck), IDX-PI (Novartis), R7128 (Roche), GS-9256 (Gilead), IDX-136 (Idenix), IDX-316 (Idenix), PF-868554 (Pfizer) (non-nucleoside polymerase inhibitor), IDX-320 (Idenix), MK-5172 (Merck), narlaprevir (Schering PF-4878691 (Pfizer), IDX-184 (Idenix), IDX-375 (Idenix, Plough Corp), PHX-1766 (Phenomix), TMC-435 (Tibotec), NS5B polymerase inhibitor), PPI-461 (Presidio), BILB-1941 vaniprevir (MK-7009, Merck), VBY708 (Virobay), VX-500 (Boehringer Ingelheim), GS-9190 (Gilead), BMS-790052 (Vertex), VX-813 (Vertex), VX-985 (Vertex), or a combina (BMS), CTS-1027 (Conatus), GS-9620 (Gilead), tion thereof. PF-4878691 (Pfizer), RO5303253 (Roche), ALS-2200 (Alios Preferred non-nucleoside HCV polymerase inhibitors for BioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), use in the present technology include, but are not limited to, 25 GSK62336805 (GlaxoSmithKline), or any combinations therapeutic agent 2, therapeutic agent 3, GS-9190 (Gilead), thereof. BI-207127 (Boehringer Ingelheim), and VX-222 (VCH-222) In some embodiments, the present technology features (Vertex & ViraChem). Preferred nucleotide HCV polymerase methods for treating patients with genotype 1. Such as 1a or inhibitors include, but are not limited to, PSI-7977 (Pharmas 1b, HCV infection. The methods comprise administering to set), and PSI-938 (Pharmasset). Other suitable and non-lim 30 such a patient a combination of at least 2 DAAs and ribavirin iting examples of suitable HCV polymerase inhibitors for no more than 12 weeks, preferably no more than 8 weeks, include ANA-598 (Anadys), BI-207127 (Boehringer Ingel wherein the treatment does not include administration of heim), BILB-1941 (Boehringer Ingelheim), BMS-791325 interferon. Patients with genotype 1, such as 1a or 1b, infec (BMS), filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), tion can be treated with a combination of at least 2 DAAS GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck), 35 without interferon where the at least two DAAs include thera tegobuvir, TMC-647055 (Tibotec), VCH-759 (Vertex & peutic agent 1 and therapeutic agent 2 with ribavirin. Thera ViraChem), VCH-916 (ViraChem), VX-759 (Vertex), peutic agent 1 and therapeutic agent 2 with ribavirin can be GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (Idenix), administered in therapeutically effective amounts to provide INX-189 (Inhibitex), MK-0608 (Merck), RG7128 (Roche), a SVR (for example, a SVR8, SVR12, SVR16, or SVR24) TMC64912 (Medivir), GSK625433 (GlaxoSmithKline), 40 after a treatment duration of no more than 12 weeks (e.g., the BCX-4678 (BioCryst), ALS-2200 (Alios BioPharma/Ver duration being 12 weeks), preferably no more than 8 weeks tex), ALS-2158 (Alios BioPharma/Vertex), or a combination (e.g., the duration being 8 weeks). The patients may be treat thereof. A polymerase inhibitor may be a nucleoside poly ment naive patients or treatment experienced HCV patients. merase inhibitor, such as GS-6620 (Gilead), IDX-102 The treatment duration can be no more than 12 weeks, includ (Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608 45 ing but not limited to, no more than 11 weeks, no more than 10 (Merck), PSI-7977 (Pharmasset), PSI-938 (Pharmasset), weeks, no more than 9 weeks, but preferably no more than 8 RG7128 (Roche), TMC64912 (Medivir), ALS-2200 (Alios weeks, no more than 7 weeks, no more than 6 weeks, no more BioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), than 5 weeks, no more than t 4 weeks, or no more than 3 or a combination therefore. A polymerase inhibitor may also weeks, e.g., the duration being 12 weeks, or the duration be a non-nucleoside polymerase inhibitor, Such as 50 being 8 weeks. The total daily dosage of therapeutic agent 1 PF-00868554 (Pfizer), ANA-598 (Anadys), BI-207127 (Boe can be, but is not limited to, for example, about 100 mg, about hiringer Ingelheim), BILB-1941 (Boehringer Ingelheim), 110 mg, about 120 mg, about 125 mg, about 130 mg, about BMS-791325 (BMS), filibuvir, GL59728 (Glaxo), GL60667 140 mg, about 150 mg, about 160 mg, about 170 mg, about (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 180 mg, about 190 mg, about 200 mg, about 210 mg, about (Merck), tegobuvir, TMC-647055 (Tibotec), VCH-759 (Ver 55 220 mg, about 230 mg, about 240 mg, about 250 mg, about tex & ViraChem), VCH-916 (ViraChem), VX-222 (VCH 260 mg, about 270 mg. or about 300 mg. Therapeutic agent 2 222) (Vertex & ViraChem), VX-759 (Vertex), or a combina can be administered with therapeutic agent 1 in any of the tion thereof. dosages of therapeutic agent 1 described above. The total Preferred NS5A inhibitors include, but are not limited to, daily dosage of therapeutic agent 2 can be, but is not limited therapeutic agent 4, BMS-790052 (BMS) and GS-5885 60 to, for example, about 400 mg, about 500 mg, about 600 mg. (Gilead). Non-limiting examples of suitable NS5A inhibitors about 700 mg, about 800 mg, about 900 mg, about 1000 mg. include GSK62336805 (GlaxoSmithKline), ACH-2928 about 1500 mg. or 1800 mg. Suitably, ribavirin may be (Achillion), AZD2836 (Astra-Zeneca), AZD7295 (Astra-Ze administered in connection with therapeutic agent 1 and neca), BMS-790052 (BMS), BMS-824393 (BMS), GS-5885 therapeutic agent 2 at any of the dosages described above. (Gilead), PPI-1301 (Presidio), PPI-461 (Presidio) A-831 (Ar 65 Suitable total daily dosages of ribavirin can be based on the row Therapeutics), A-689 (Arrow Therapeutics) or a combi weight of the patient and include, but are not limited to, from nation thereof. about 800 mg to about 1200 mg, including, for example, US 8,969,357 B2 57 58 about 1000 mg per day for a patient <75 kg or about 1200 mg infected with HCV genotype 3a. The treatment according to per day for a patient a 75 kg. In some embodiments, ritonavir this aspect of the technology can also be effective against can be either co-administered or administered separately with other HCV genotypes. The treatment duration can be for no therapeutic agent 1. Suitable dosages of ritonavir include, but more than 12 weeks, preferably no more than 8 weeks, includ are not limited to, from about 50 mg to about 400 mg per day, ing but not limited to, no more than 11 weeks, no more than 10 preferably about 100 mg per day. weeks, no more than 9 weeks, but preferably no more than 8 In some embodiments, the present technology features weeks, no more than 7 weeks, no more than 6 weeks, no more methods for treating patients with genotype 2 or 3 HCV than 5 weeks, no more than 4 weeks, or no more than 3 weeks, infection. The methods comprise administering to Such a e.g., the duration being 12 weeks, or the duration being 8 patient a combination of at least 2 DAAs and ribavirin for no 10 weeks. Therapeutic agent 1 and therapeutic agent 2 can be more than 12 weeks (e.g., the duration being 12 weeks), administered in therapeutically effective amounts to provide preferably no more than 8 weeks (e.g., the duration being 8 a SVR (for example, a SVR8, SVR12, SVR 16, or SVR 24) weeks), wherein the treatment does not include administra after treatment duration of no more than 12 weeks, preferably tion of interferon. Patients with genotype 2 or 3 HCV infec no more than 8 weeks. The total daily dosage of therapeutic tion can be treated with a combination of at least 2 DAAS 15 agent 1 can be, but is not limited to, for example, about 100 without interferon where the at least two DAAs include thera mg, about 110 mg, about 120 mg, about 125 mg, about 130 peutic agent 1 and therapeutic agent 2 with ribavirin. Thera mg, about 140 mg, about 150 mg, about 160 mg, about 170 peutic agent 1 and therapeutic agent 2 can be administered in mg, about 180 mg, about 190 mg, about 200 mg, about 210 therapeutically effective amounts to provide a SVR (for mg, about 220 mg, about 230 mg, about 240 mg, about 250 example, a SVR8, SVR12, SVR16, or SVR24) with a treat mg, about 260 mg, about 270 mg, or about 300 mg. Thera ment duration of no more than 12 weeks, preferably no more peutic agent 2 can be administered with therapeutic agent 1 in than 8 weeks. The patients may be treatment naive HCV any of the dosages described above. The total daily dosage of patients or treatment experienced HCV patients. The treat therapeutic agent 2 can be, but is not limited to, for example, ment duration can be no more than 12 weeks, including but about 400 mg, about 500 mg, about 600 mg, about 700 mg. not limited to, no more than 11 weeks, no more than 10 weeks, 25 about 800 mg, about 900 mg, about 1000 mg. Suitably, rib no more than 9 weeks, but preferably no more than 8 weeks, avirin may be administered in connection with therapeutic no more than 7 weeks, no more than 6 weeks, no more than 5 agent 1 and therapeutic agent 2 at any combination of the weeks, no more than 4 weeks, or no more than 3 weeks, e.g., dosages described above. Suitable total daily dosages of rib the duration being 12 weeks, or the duration being 8 weeks. avirin can be based on the weight of the patient and include, The total daily dosage of therapeutic agent 1 can be, but is not 30 but are not limited to, from about 800 mg to about 1200 mg. limited to, for example, about 100 mg, about 110 mg, about including, for example, about 1000 mg per day for a patient 120 mg, about 125 mg, about 130 mg, about 140 mg, about <75 kg or about 1200 mg per day for a patient 75 kg. 150 mg, about 160 mg, about 170 mg, about 180 mg, about In some embodiments, the present technology features 190 mg, about 200 mg, about 210 mg, about 220 mg, about methods for treating patients with HCV infection who are not 230 mg, about 240 mg, about 250 mg, about 260 mg, about 35 candidates for interferon treatment. The methods comprise 270 mg, about 300 mg. Therapeutic agent 2 can be adminis administering to such a patient a combination of at least 2 tered in connection with therapeutic agent 1 in any of the DAAs and ribavirin for no more than 12 weeks (e.g., the dosages described above. The total daily dosage of therapeu duration being 12 weeks), preferably no more than 8 weeks tic agent 2 can be, but is not limited to, about 400 mg, about (e.g., the duration being 8 weeks), wherein the treatment does 500 mg, about 600 mg, about 700 mg, about 800 mg, about 40 not include administration of interferon. Patients who are not 900 mg, about 1000 mg, about 1500 mg. or 1800 mg. Suit candidates for interferon treatment include, but are not lim ably, ribavirin may be administered in connection with thera ited to, one or more of the following groups: patients intoler peutic agent 1 and therapeutic agent 2 in any combination of ant to interferon, patients who refuse to take interferon treat suitable dosages described above. Suitable total daily dosages ment, patients with medical conditions which preclude them of ribavirin can be based on the weight of the patient and 45 from taking interferon, and patients who have an increased include, but are not limited to, from about 800 mg to about risk of side effects or infection by taking interferon. A non 1200 mg, including, for example, about 1000 mg per day for candidate for interferon treatment can be infected with HCV a patient <75 kg or about 1200 mg per day for a patient -75 genotype 1 or 2, for example, genotype 1a or 1b. A non kg. In some embodiments, ritonavir can be either co-admin candidate for interferon treatment can be infected with HCV istered or administered separately with therapeutic agent 1. 50 genotype 2, for example, genotype 2a or 2b. The treatment Suitable dosages of ritonavir include, from about 50 mg to according to this aspect of the technology can also be effec about 400 mg per day, preferably about 100 mg per day. tive against other HCV genotypes. In some embodiments, In some embodiments, the present technology features non-candidate for interferon treatment patients can be treated methods for treating patients with HCV infection. The meth with a combination of at least 2 DAAs without interferon and ods comprise administering to Such apatient a combination of 55 with ribavirin for a treatment duration of no more than 12 at least 2 DAAs and ribavirin for no more than 12 weeks (e.g., weeks, including but not limited to, no more than 11 weeks, the duration being 12 weeks), preferably no more than 8 no more than 10 weeks, no more than 9 weeks, but preferably weeks (e.g., the duration being 8 weeks), wherein the treat no more than 8 weeks, no more than 7 weeks, no more than 6 ment does not include administration of interferon. The com weeks, no more than 5 weeks, no more than 4 weeks, or no bination comprises therapeutic agent 1, therapeutic agent 2 60 more than 3 weeks, e.g., the duration being 12 weeks, or the and ribavirin. Suitably, the patient may be a treatment naive duration being 8 weeks. The at least two DAAs include at patient, a treatment experienced patient or an interferon non least one HCV protease inhibitor and at least one HCV poly responder. In some embodiments, the patient is infected with merase inhibitor. Suitably, the at least one HCV protease HCV genotype 1. Such as genotype 1a. In some embodiments, inhibitor can be therapeutic agent 1 and the at least one HCV the patient is infected with HCV genotype 1b. In some 65 polymerase inhibitor can be therapeutic agent 2. Therapeutic embodiments, the patient is infected with HCV genotype 2 or agent 1 and therapeutic agent 2 can be administered in thera 3. Such as 2a or 2b. In some other embodiments, the patient is peutically effective amounts to provide a SVR after a treat US 8,969,357 B2 59 60 ment duration of no more than 12 weeks, preferably no more mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg. than 8 weeks. The total daily dosage of therapeutic agent 1 about 80 mg, about 90 mg. or about 100 mg. In some embodi can be, but is not limited to, for example, about 100 mg, about ments, ritonavir can be either co-administered or adminis 110 mg, about 120 mg, about 125 mg, about 130 mg, about tered separately with therapeutic agent 1. Suitable dosages of 140 mg, about 150 mg, about 160 mg, about 170 mg, about 5 ritonavir include, from about 50 mg to about 400 mg per day, 180 mg, about 190 mg, about 200 mg, about 210 mg, about preferably about 100 mg per day. Suitably, ribavirin may be 220 mg, about 230 mg, about 240 mg, about 250 mg, about administered in connection with therapeutic agent 1, thera 260 mg, about 270 mg. or about 300 mg. Therapeutic agent 2 peutic agent 2, and therapeutic agent 4 in which therapeutic can be administered with therapeutic agent 1 with therapeutic agent 1, therapeutic agent 2, and therapeutic agent 4 are agent 1 administered at any of the dosages described above. 10 administered in any combination of the dosages described The total daily dosage of therapeutic agent 2 can be, but is not above. Suitable total daily dosages of ribavirin can be based limited to, for example, about 400 mg, about 500 mg, about on the weight of the patient and include, but are not limited to, 600 mg, about 700 mg, about 800 mg, about 900 mg, or about from about 800 mg to about 1200 mg, including, for example, 1000 mg. Suitably, ribavirin may be administered in connec about 1000 mg per day for a patient <75 kg or about 1200 mg tion with therapeutic agent 1 and therapeutic agent 2 at any of 15 per day for a patient a 75 kg. Suitably, in Some embodiments, the dosages described above. Suitable total daily dosages of the patient may be a treatment naive patient, a treatment ribavirin can be based on the weight of the patient and experienced patient, or an interferon nonresponder. include, but are not limited to, from about 800 mg to about In some embodiments, the present technology features 1200 mg, including, for example, about 1000 mg per day for methods for treating patients with genotype 1. Such as geno a patient <75 kg or about 1200 mg per day for a patient -75 type 1a or 1b, HCV infection. The methods comprise admin kg. istering to Such a patient a combination of at least 2 DAAS and In another aspect, the present technology features methods ribavirin for no more than 12 weeks (e.g., the duration being for treating patients with HCV infection. The methods com 12 weeks), preferably no more than 8 weeks (e.g., the dura prise administering to Such a patient a combination of at least tion being 8 weeks), wherein the treatment does not include 2 DAAs and ribavirin for no more than 12 weeks (e.g., the 25 administration of interferon. The combination comprises duration being 12 weeks), preferably no more than 8 weeks therapeutic agent 1, therapeutic agent 3 and ribavirin. The (e.g., the duration being 8 weeks), wherein the treatment does treatment duration may be no more than 12 weeks, including not include administration of interferon. The combination but not limited to, no more than 11 weeks, no more than 10 comprises therapeutic agent 1, therapeutic agent 2, therapeu weeks, no more than 9 weeks, but preferably no more than 8 tic agent 4 and ribavirin. In some embodiments, the patient is 30 weeks, no more than 7 weeks, no more than 6 weeks, no more infected with HCV genotype 1, such as genotype 1a. The than 5 weeks, no more than 4 weeks, or no more than 3 weeks, treatment according to this aspect of the technology can also e.g., the duration being 12 weeks, or the duration being 8 be effective against other HCV genotypes. The treatment weeks. The total daily dosage of therapeutic agent 1 can be, duration can be no more than 12 weeks, including but not but is not limited to, for example, about 100 mg, about 110 limited to, no more than 11 weeks, no more than 10 weeks, no 35 mg, about 120 mg, about 125 mg, about 130 mg, about 140 more than 9 weeks, but preferably no more than 8 weeks, no mg, about 150 mg, about 160 mg, about 170 mg, about 180 more than 7 weeks, no more than 6 weeks, no more than 5 mg, about 190 mg, about 200 mg, about 210 mg, about 220 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., mg, about 230 mg, about 240 mg, about 250 mg, about 260 the duration being 12 weeks or the duration being 8 weeks. mg, about 270 mg, or about 300 mg. Therapeutic agent 3 can Therapeutic agent 1, therapeutic agent 2, and therapeutic 40 be administered in connection with therapeutic agent 1 with agent 3 can be provided in effective amounts to provide a SVR therapeutic agent 1 being administered at any of the dosages (for example, a SVR8, SVR12, SVR16, or SVR24) after a of described above. Therapeutic agent 3 can be provided in treatment duration of no more than 12 weeks, preferably no combination with therapeutic agent 1. The total daily dosage more than 8 weeks. The total daily dosage of therapeutic of therapeutic agent 3 can be, but is not limited to, for agent 1 can be, but is not limited to, for example, about 100 45 example, about 400 mg, about 410 mg, about 420 mg, about mg, about 110 mg, about 120 mg, about 125 mg, about 130 430 mg, about 440 mg, about 450 mg, about 460 mg, about mg, about 140 mg, about 150 mg, about 160 mg, about 170 470 mg, about 480 mg, about 490 mg, about 500 mg, about mg, about 180 mg, about 190 mg, about 200 mg, about 210 510 mg, about 520 mg, about 530 mg, about 540 mg, about mg, about 220 mg, about 230 mg, about 240 mg, about 250 550 mg, about 560 mg, about 570 mg, about 580 mg, about mg, about 260 mg, about 270 mg, about 300 mg. Therapeutic 50 590 mg, about 600 mg, about 610 mg, about 620 mg, about agent 2 can be administered with therapeutic agent 1 with 630 mg, about 650 mg, about 700 mg, about 750 mg, about therapeutic agent 1 being administered in any of the dosages 800 mg, about 850 mg, about 900 mg, about 950 mg, or about described above. The total daily dosage of therapeutic agent 2 1000 mg. Ribavirin can be administered either at the same can be, but is not limited to, for example, about 400 mg, about time or at a separate time than therapeutic agent 1 and thera 500 mg, about 600 mg, about 700 mg, about 800 mg, about 55 peutic agent 3; and therapeutic agent 1 and therapeutic agent 900 mg. or about 1000 mg. Therapeutic agent 4 can be pro 3 can be administered in any of the Suitable dosages of thera vided in combination with therapeutic agent 1 and therapeutic peutic agent 1 or therapeutic agent 3 recited above. Suitable agent 2 in which therapeutic agent 1 and therapeutic agent 2 total daily dosages of ribavirin can be based on the weight of are administered in any combination of the dosages for thera the patient and include, but are not limited to, from about 800 peutic agent 1 and therapeutic agent 2 described above. 60 mg to about 1200 mg, including, for example, about 1000 mg Therapeutic agent 4 can be provided in combination with per day for a patient <75 kg or about 1200 mg per day for a therapeutic agent 1 and therapeutic agent 2 in a total daily patient a 75 kg. In some embodiments, ritonavir can be either dose of therapeutic agent 4 of an amount from about 5 mg to co-administered or administered separately with therapeutic about 350 mg, preferably about 5 mg to about 300 mg, more agent 1. Suitable dosages of ritonavir include, from about 50 preferably about 25 mg to about 200 mg. The total daily 65 mg to about 400 mg per day, preferably about 100 mg per day. dosage of therapeutic agent4 can be, but are not limited to, for In some embodiments, the present technology features example, about 20 mg, about 25 mg, about 30 mg, about 40 methods for treating patients with genotype 2 or 3. Such as US 8,969,357 B2 61 62 genotype 2a, 2b or 3a, HCV infection. The methods comprise 3. Such as 2a or 2b. In some other embodiments, the patient is administering to such a patient a combination of at least 2 infected with HCV genotype 3a. The treatment according to DAAs and ribavirin for no more than 12 weeks (e.g., the this aspect of the technology can also be effective against duration being 12 weeks), preferably no more than 8 weeks other HCV genotypes. The treatment duration can be no more (e.g., the duration being 8 weeks), wherein the treatment does 5 than 12 weeks, including but not limited to, no more than 11 not include administration of interferon. The combination weeks, no more than 10 weeks, no more than 9 weeks, but comprises therapeutic agent 1, therapeutic agent 3 and rib preferably no more than 8 weeks, no more than 7 weeks, no avirin. The treatment duration can be no more than 12 weeks, more than 6 weeks, no more than 5 weeks, no more than 4 including but not limited to, no more than 11 weeks, no more weeks, or no more than 3 weeks, e.g., the duration being 12 than 10 weeks, no more than 9 weeks, but preferably no more 10 weeks, or the duration being 8 weeks. The total daily dosage than 8 weeks, no more than 7 weeks, no more than 6 weeks, of therapeutic agent 1 can be, but is not limited to, for no more than 5 weeks, no more than 4 weeks, or no more than example, about 100 mg, about 110 mg, about 120 mg, about 3 weeks, e.g., the duration being 12 weeks, or the duration 125 mg, about 130 mg, about 140 mg, about 150 mg, about being 8 weeks. Therapeutic agent 1 and therapeutic agent 3 160 mg, about 170 mg, about 180 mg, about 190 mg, about and ribavirin can be administered in therapeutically effective 15 200 mg, about 210 mg, about 220 mg, about 230 mg, about amounts to provide a SVR (for example, a SVR8, SVR12. 240 mg, about 250 mg, about 260 mg, about 270 mg. or about SVR16 or SVR24) in a treatment duration of no more than 12 300 mg. Therapeutic agent 3 can be administered in connec weeks, preferably no more than 8 weeks. The total daily tion with therapeutic agent 1 with therapeutic agent 1 being dosage of therapeutic agent 1 can be, but is not limited to, for administered at any of the dosages described above. Thera example, about 100 mg, about 110 mg, about 120 mg, about peutic agent 3 can be provided in combination with therapeu 125 mg, about 130 mg, about 140 mg, about 150 mg, about tic agent 1. The total daily dosage of therapeutic agent 3 can 160 mg, about 170 mg, about 180 mg, about 190 mg, about be, but is not limited to, for example, about 300 mg, about 310 200 mg, about 210 mg, about 220 mg, about 230 mg, about mg, about 320 mg, about 330 mg, about 340 mg, about 350 240 mg, about 250 mg, about 260 mg, about 270 mg. or about mg, about 360 mg, about 370 mg, about 380 mg, about 390 300 mg. Therapeutic agent 3 can be administered with thera 25 mg, about 400 mg, about 410 mg, about 420 mg, about 430 peutic agent 1 with therapeutic agent 1 being administered at mg, about 440 mg, about 450 mg, about 460 mg, about 470 any of the dosages described above. Therapeutic agent 3 can mg, about 480 mg, about 490 mg, about 500 mg, about 510 be provided in combination with therapeutic agent 1. The mg, about 520 mg, about 530 mg, about 540 mg, about 550 total daily dosage of therapeutic agent 3 can be, but is not mg, about 560 mg, about 570 mg, about 580 mg, about 590 limited to, for example, about 300 mg, about 310 mg, about 30 mg, about 600 mg, about 610 mg, about 620 mg, about 630 320 mg, about 330 mg, about 340 mg, about 350 mg, about mg, about 650 mg, about 700 mg, about 750 mg, about 800 360 mg, about 370 mg, about 380 mg, about 390 mg, about mg, about 850 mg, about 900 mg, about 950 mg. or about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 1000 mg. Ribavirin can be administered either at the same 440 mg, about 450 mg, about 460 mg, about 470 mg, about time or at a separate time than therapeutic agent 1 and thera 480 mg, about 490 mg, about 500 mg, about 510 mg, about 35 peutic agent 3; and therapeutic agent 1 and therapeutic agent 520 mg, about 530 mg, about 540 mg, about 550 mg, about 3 can be administered in any combination of the suitable 560 mg, about 570 mg, about 580 mg, about 590 mg, about dosages recited above. Suitable total daily dosages of ribavi 600 mg, about 610 mg, about 620 mg, about 630 mg, about rin can be based on the weight of the patient and include, but 650 mg, about 700 mg, about 750 mg, about 800 mg, about are not limited to, from about 800 mg to about 1200 mg. 850 mg, about 900 mg, about 950 mg, or about 1000 mg. 40 including, for example, about 1000 mg per day for a patient Ribavirin can be administered either at the same time or at a <75 kg or about 1200 mg per day for a patient -75kg. In some separate time than therapeutic agent 1 and therapeutic agent embodiments, ritonavir can be either co-administered or 3; and therapeutic agent 1 and therapeutic agent 3 can be administered separately with therapeutic agent 1. Suitable administered in any combination of dosage of therapeutic dosages of ritonavir include, from about 50 mg to about 400 agent 1 or therapeutic agent 3 recited above. Suitable total 45 mg per day, preferably about 100 mg per day. daily dosages of ribavirin can be based on the weight of the In some embodiments, the present technology features patient and include, but are not limited to, from about 800 mg methods for treating patients with HCV infection who are not to about 1200 mg, including, for example, about 1000 mg per candidates for interferon treatment. The methods comprise day for a patient <75 kg or about 1200 mg per day for a patient administering to such a patient a combination of at least 2 >75 kg. In some embodiments, ritonavir can be either co 50 DAAs and ribavirin for no more than 12 weeks (e.g., the administered or administered separately with therapeutic duration being 12 weeks), preferably no more than 8 weeks agent 1. Suitable dosages of ritonavir include, from about 50 (e.g., the duration being 8 weeks), wherein the treatment does mg to about 400 mg per day, preferably about 100 mg per day. not include administration of interferon. The combination In some embodiments, the present technology features comprises therapeutic agent 1, therapeutic agent 3 and rib methods for treating patients with HCV infection. The meth 55 avirin. Patients who are not candidates for interferon treat ods comprise administering to Such apatient a combination of ment include, but are not limited to, one or more of the at least 2 DAAs and ribavirin for no more than 12 weeks (e.g., following groups: patients intolerant to interferon, patients the duration being 12 weeks), preferably no more than 8 who refuse to take interferon treatment, patients with medical weeks (e.g., the duration being 8 weeks), wherein the treat conditions which preclude them from taking interferon, and ment does not include administration of interferon. The com 60 patients who have an increased risk of side effects or infection bination comprises therapeutic agent 1, therapeutic agent 3 by taking interferon. In some embodiments, the patient is and ribavirin. Suitably, the patient may be a treatment naive infected with HCV genotype 1. Such as genotype 1a. In some patient, a treatment experienced patient or an interferon non embodiments, the patient is infected with HCV genotype 1b. responder. In some embodiments, the patient is infected with In some other embodiments, the patient is infected with HCV HCV genotype 1. Such as genotype 1a. In some embodiments, 65 genotype 2 or 3. Such as 2a or 2b. In some other embodiments, the patient is infected with HCV genotype 1b. In some other the patient is infected with HCV genotype 3a. The treatment embodiments, the patient is infected with HCV genotype 2 or according to this aspect of the technology can also be effec US 8,969,357 B2 63 64 tive against other HCV genotypes. The treatment duration can weeks. The total daily dosage of therapeutic agent 1 can be, be no more than 12 weeks, including but not limited to, no but is not limited to, for example, about 100 mg, about 110 more than 11 weeks, no more than 10 weeks, no more than 9 mg, about 120 mg, about 125 mg, about 130 mg, about 140 weeks, but preferably patients who are more than 8 weeks, no mg, about 150 mg, about 160 mg, about 170 mg, about 180 more than 7 weeks, no more than 6 weeks, no more than 5 mg, about 190 mg, about 200 mg, about 210 mg, about 220 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., mg, about 230 mg, about 240 mg, about 250 mg, about 260 the duration being 12 week, or the duration being 8 weeks. mg, about 270 mg, or about 300 mg. Therapeutic agent 4 can The total daily dosage of therapeutic agent 1 can be, but is not be administered in connection with therapeutic agent 1 where limited to, for example, about 100 mg, about 110 mg, about therapeutic agent 1 is administered in any of the dosages 120 mg, about 125 mg, about 130 mg, about 140 mg, about 10 described above. Therapeutic agent 4 can be provided in 150 mg, about 160 mg, about 170 mg, about 180 mg, about combination with therapeutic agent 1 in a total daily dose of 190 mg, about 200 mg, about 210 mg, about 220 mg, about therapeutic agent 4 of from about 25 mg to about 200 mg. The 230 mg, about 240 mg, about 250 mg, about 260 mg, about total daily dosage of therapeutic agent 4 can be, but is not 270 mg. or about 300 mg. Therapeutic agent 3 can be admin limited to, for example, about 20 mg, about 25 mg, about 30 istered with therapeutic agent 1 with therapeutic agent 1 15 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg. being administered at any of the dosages described above. about 75 mg, about 80 mg, about 90 mg, about 100 mg, about Therapeutic agent 3 can be provided in combination with 110 mg, about 120 mg, about 120 mg, about 130 mg, about therapeutic agent 1. The total daily dosage of therapeutic 140 mg, about 150 mg, about 160 mg, about 170 mg, about agent 3 can be, but is not limited to, for example, about 300 180 mg, about 190 mg, about 200 mg, about 210 mg, about mg, about 310 mg, about 320 mg, about 330 mg, about 340 220 mg, about 230 mg, about 240 mg, about 250 mg, about mg, about 350 mg, about 360 mg, about 370 mg, about 380 260 mg, about 270 mg, about 280 mg, about 290 mg, about mg, about 390 mg, about 400 mg, about 410 mg, about 420 300 mg, about 310 mg, about 320 mg, about 330 mg, about mg, about 430 mg, about 440 mg, about 450 mg, about 460 340 mg. or about 350 mg. In some embodiments, ritonavir mg, about 470 mg, about 480 mg, about 490 mg, about 500 can be either co-administered or administered separately with mg, about 510 mg, about 520 mg, about 530 mg, about 540 25 therapeutic agent 1. Suitable dosages of ritonavir include, mg, about 550 mg, about 560 mg, about 570 mg, about 580 from about 50 mg to about 400 mg per day, preferably about mg, about 590 mg, about 600 mg, about 610 mg, about 620 100 mg per day. In Suitable embodiments, therapeutic agent 1 mg, about 630 mg, about 650 mg, about 700 mg, about 750 and therapeutic agent 4 are administered once a day. Suitably, mg, about 800 mg, about 850 mg, about 900 mg, about 950 ribavirin may be administered in connection with therapeutic mg, or about 1000 mg. Ribavirin can be administered either at 30 agent 1 and therapeutic agent 4 where therapeutic agent 1 and the same time or at a separate time than therapeutic agent 1 therapeutic agent 4 are administered in any combination of and therapeutic agent 3; and therapeutic agent 1 and thera the suitable dosages detailed above. Suitable total daily dos peutic agent 3 can be administered in any combination of ages of ribavirin can be based on the weight of the patient and dosages of therapeutic agent 1 and therapeutic agent 3 recited include, but are not limited to, from about 800 mg to about above. Suitable total daily dosages of ribavirin can be based 35 1200 mg, including, for example, about 1000 mg per day for on the weight of the patient and include, but are not limited to, a patient <75 kg or about 1200 mg per day for a patient -75 from about 800 mg to about 1200 mg, including, for example, kg. about 1000 mg per day for a patient <75 kg or about 1200 mg In Some embodiments the present technology features per day for a patient a 75 kg. In some embodiments, ritonavir methods for treating patients with HCV infection. The meth can be either co-administered or administered separately with 40 ods comprise administering to Such apatient a combination of therapeutic agent 1. Suitable dosages of ritonavir include, at least 2 DAAs and ribavirin for no more than 12 weeks (e.g., from about 50 mg to about 400 mg per day, preferably about the duration being 12 weeks), preferably no more than 8 100 mg per day. weeks (e.g., the duration being 8 weeks), wherein the treat In some embodiments, the present technology features ment does not include administration of interferon. The com methods for treating patients with HCV genotype 1. Such as 45 bination comprises therapeutic agent 1, therapeutic agent 4 la or 1b, infection. The methods comprise administering to and ribavirin. The patients may be treatment naive patients or such a patient a combination of at least 2 DAAs and ribavirin treatment experienced patients. The treatment can be admin for no more than 12 weeks (e.g., the duration being 12 weeks), istered for a duration of no more than 12 weeks, including but preferably no more than 8 weeks (e.g., the duration being 8 not limited to, no more than 11 weeks, no more than 10 weeks, weeks), wherein the treatment does not include administra 50 no more than 9 weeks, but preferably no more than 8 weeks, tion of interferon. The combination comprises therapeutic no more than 7 weeks, no more than 6 weeks, no more than 5 agent 1, therapeutic agent 4 and ribavirin. Patients with geno weeks, no more than 4 weeks, or no more than 3 weeks, e.g., type 1a or 1b infection can be treated with a combination of at the duration being 12 weeks, or the duration being 8 weeks. least 2 DAAs without interferon in which the at least two The patient can have HCV genotype 1, such as HCV genotype DAAS include therapeutic agent 1 and therapeutic agent 4 55 1a or 1b. In other embodiments, the patient may have HCV with ribavirin. Therapeutic agent 1 and therapeutic agent 4 genotype 1b. In some embodiments, it is contemplated to treat can be administered in therapeutically effective amounts to other HCV genotypes. The total daily dosage of therapeutic provide a SVR (for example, a SVR8, SVR12, SVR16, or agent 1 can be, but is not limited to, for example, about 100 SVR24) in a treatment duration of no more than 12 weeks, mg, about 110 mg, about 120 mg, about 125 mg, about 130 preferably no more than 8 weeks. The patients may be treat 60 mg, about 140 mg, about 150 mg, about 160 mg, about 170 ment naive patients or treatment experienced patients. The mg, about 180 mg, about 190 mg, about 200 mg, about 210 treatment duration can be no more than 12 weeks, including mg, about 220 mg, about 230 mg, about 240 mg, about 250 but not limited to, no more than 11 weeks, no more than 10 mg, about 260 mg, about 270 mg, or about 300 mg. Thera weeks, no more than 9 weeks, but preferably no more than 8 peutic agent 4 can be administered in connection with thera weeks, no more than 7 weeks, no more than 6 weeks, no more 65 peutic agent 1 in any of the dosages described above. Thera than 5 weeks, no more than 4 weeks, or no more than 3 weeks, peutic agent 4 can be provided alone or in combination with e.g., the duration being 12 weeks, or the duration being 8 therapeutic agent 1. The total daily dosage of therapeutic US 8,969,357 B2 65 66 agent4 can be, but is not limited to, for example, about 15 mg. preferably about 100 mg per day. In suitable embodiments, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about therapeutic agent 1 and therapeutic agent 4 are administered 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg. once a day. about 90 mg, about 100 mg, about 110 mg, about 120 mg. In some embodiments, therapeutic agent 1 and therapeutic about 120 mg, about 130 mg, about 140 mg, about 150 mg. agent 4 are administered with ribavirin. Suitable total daily about 160 mg, about 170 mg, about 180 mg, about 190 mg. dosages of ribavirin can be based on the weight of the patient about 200 mg, about 210 mg, about 220 mg, about 230 mg. and include, but are not limited to, from about 800 mg to about about 240 mg, about 250 mg, about 260 mg, about 270 mg. 1200 mg, including, for example, about 1000 mg per day for about 280 mg, about 290 mg, about 300 mg, about 310 mg. a patient <75 kg or about 1200 mg per day for a patient -75 10 kg. about 320 mg, about 330 mg, about 340 mg. or about 350 mg. In some embodiments, the present technology features In some embodiments, ritonavir can be either co-adminis methods for treating patients with HCV infection who are not tered or administered separately with therapeutic agent 1. candidates for interferon treatment. The methods comprise Suitable dosages of ritonavir include, from about 50 mg to administering to such a patient a combination of at least 2 about 400 mg per day, preferably about 100 mg per day. In 15 DAAs and ribavirin for no more than 12 weeks (e.g., the Suitable embodiments, therapeutic agent 1 and therapeutic duration being 12 weeks), preferably no more than 8 weeks agent 4 are administered once a day. In some embodiments, (e.g., the duration being 8 weeks), wherein the treatment does therapeutic agent 1 and therapeutic agent 4 are administered not include administration of interferon. The combination with ribavirin. Suitable total daily dosages of ribavirin can be comprises therapeutic agent 1, therapeutic agent 4 and rib based on the weight of the patient and include, but are not avirin. Patients who are not candidates for interferon treat limited to, from about 800 mg to about 1200 mg, including, ment include, but are not limited to one or more of the fol for example, about 1000 mg per day for a patient <75 kg or lowing groups: patients intolerant to interferon, patients who about 1200 mg per day for a patient >75 kg. refuse to take interferon treatment, patients with medical In some embodiments, the present technology features conditions which preclude them from taking interferon, and methods for treating patients with HCV infection. The meth 25 patients who have an increased risk of side effects or infection ods comprise administering to Such apatient a combination of by taking interferon. In some embodiments, the patient is at least 2 DAAs and ribavirin for no more than 12 weeks (e.g., infected with HCV genotype 1. Such as genotype 1a. In some the duration being 12 weeks), preferably no more than 8 embodiments, the patient is infected with HCV genotype 1b. weeks (e.g., the duration being 8 weeks), wherein the treat In some other embodiments, the patient is infected with HCV ment does not include administration of interferon. The com 30 genotype 2 or 3. Such as 2a or 2b. In some other embodiments, bination comprises therapeutic agent 1, therapeutic agent 4 the patient is infected with HCV genotype 3a. The treatment and ribavirin. The patients may be treatment naive patients or according to this aspect of the technology can also be effec treatment experienced patients. The treatment can be admin tive against other HCV genotypes. Therapeutic agent 1 and istered for a duration of no more than 12 weeks, including but therapeutic agent 4 can be administered in therapeutically not limited to, no more than 11 weeks, no more than 10 weeks, 35 effective amounts to provide a SVR (for example, a SVR8, no more than 9 weeks, but preferably no more than 8 weeks, SVR12, SVR16 or SVR24) after treatment of no more than 12 no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, preferably no more than 8 weeks. The interferon non weeks, no more than 4 weeks, or no more than 3 weeks, e.g., responder patients include partial interferon responders and the duration being 12 weeks, or the duration being 8 weeks. interferon rebound patients. See GUIDANCE FOR INDUSTRY The patient can have HCV genotype 2 or 3, such as HCV 40 CHRONIC HEPATITIS CVIRUS INFECTION: DEVELOPING DIRECT-ACT genotype 2a. In some embodiments, the patient may have ING ANTIVIRAL AGENTS FORTREATMENT (FDA, September 2010, HCV genotype 2b. In other embodiments the patient may draft guidance) for the definitions of naive, partial responder, have HCV genotype 3a. The total daily dosage of therapeutic responder relapser (i.e., rebound), and null responder agent 1 can be, but is not limited to, for example, about 100 patients. The interferon non-responder patients also include mg, about 110 mg, about 120 mg, about 125 mg, about 130 45 null responder patients. The treatment can be administered mg, about 140 mg, about 150 mg, about 160 mg, about 170 for a duration of no more than 12 weeks, including but not mg, about 180 mg, about 190 mg, about 200 mg, about 210 limited to, no more than 11 weeks, no more than 10 weeks, no mg, about 220 mg, about 230 mg, about 240 mg, about 250 more than 9 weeks, but preferably no more than 8 weeks, no mg, about 260 mg, about 270 mg, or about 300 mg. Thera more than 7 weeks, no more than 6 weeks, no more than 5 peutic agent 4 can be administered in connection with thera 50 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., peutic agent 1 in which therapeutic agent 1 is administered in the duration being 12 weeks, or the duration being 8 weeks. any of the dosages described above. Therapeutic agent 4 can The total daily dosage of therapeutic agent 1 can be, but is not be provided in combination with therapeutic agent 1. The limited to, for example, about 100 mg, about 110 mg, about total daily dosage of therapeutic agent 4 can be, but is not 120 mg, about 125 mg, about 130 mg, about 140 mg, about limited to, for example, about 15 mg, about 20 mg, about 25 55 150 mg, about 160 mg, about 170 mg, about 180 mg, about mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg. 190 mg, about 200 mg, about 210 mg, about 220 mg, about about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 100 mg, about 110 mg, about 120 mg, about 120 mg, about 270 mg. or about 300 mg. Therapeutic agent 4 can be admin 130 mg, about 140 mg, about 150 mg, about 160 mg, about istered with therapeutic agent 1 where therapeutic agent 1 is 170 mg, about 180 mg, about 190 mg, about 200 mg, about 60 administered in any of the dosages described above. Thera 210 mg, about 220 mg, about 230 mg, about 240 mg, about peutic agent 4 can be provided in combination with therapeu 250 mg, about 260 mg, about 270 mg, about 280 mg, about tic agent 1. The total daily dosage of therapeutic agent 4 can 290 mg, about 300 mg, about 310 mg, about 320 mg, about be, but is not limited to, for example, about 15 mg, about 20 330 mg, about 340 mg. or about 350 mg. In some embodi mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg. ments, ritonavir can be either co-administered or adminis 65 about 60 mg, about 70 mg, about 75 mg, about 80 mg, about tered separately with therapeutic agent 1. Suitable dosages of 90 mg, about 100 mg, about 110 mg, about 120 mg, about 120 ritonavir include, from about 50 mg to about 400 mg per day, mg, about 130 mg, about 140 mg, about 150 mg, about 160 US 8,969,357 B2 67 68 mg, about 170 mg, about 180 mg, about 190 mg, about 200 about 200 mg, about 210 mg, about 220 mg, about 230 mg. mg, about 210 mg, about 220 mg, about 230 mg, about 240 about 240 mg, about 250 mg, about 260 mg, about 270 mg. mg, about 250 mg, about 260 mg, about 270 mg, about 280 about 280 mg, about 290 mg, about 300 mg, about 310 mg. mg, about 290 mg, about 300 mg, about 310 mg, about 320 about 320 mg, about 330 mg, about 340 mg. or about 350 mg. mg, about 330 mg, about 340 mg. or about 350 mg. In some In some embodiments, ritonavir can be either co-adminis embodiments, ritonavir can be either co-administered or tered or administered separately with therapeutic agent 1. administered separately with therapeutic agent 1. Suitable Suitable dosages of ritonavir include, from about 50 mg to dosages of ritonavir include, from about 50 mg to about 400 about 400 mg per day, preferably about 100 mg per day. In mg per day, preferably about 100 mg per day. In Suitable Suitable embodiments, therapeutic agent 1 and therapeutic embodiments, therapeutic agent 1 and therapeutic agent 4 are 10 agent 4 are administered once a day. Suitably, ribavirin may administered once a day. Suitably, ribavirin may be adminis be administered in connection with therapeutic agent 1 and tered in connection with therapeutic agent 1 and therapeutic therapeutic agent 4 wherein therapeutic agent 1 and therapeu agent 4 where therapeutic agent 1 and therapeutic agent 4 are tic agent 4 are administered in any combination of Suitable administered in any combination of Suitable dosages as dosages as described above. Suitable total daily dosages of described above. Suitable total daily dosages of ribavirin can 15 ribavirin can be based on the weight of the patient and be based on the weight of the patient and include, but are not include, but are not limited to, from about 800 mg to about limited to, from from about 800 mg to about 1200 mg, includ 1200 mg, including, for example, about 1000 mg per day for ing, for example, about 1000 mg per day for a patient <75 kg a patient <75 kg or about 1200 mg per day for a patient -75 or about 1200 mg per day for a patient >75 kg. kg. In some embodiments, the present technology features Accordingly, in some embodiments, the present technol methods for treating patients with HCV infection who are ogy features a method of treating HCV infection, comprising interferon non-responders (e.g., null responders). The meth administering to a patient in need thereofan effective amount ods comprise administering to Such apatient a combination of of a combination of two or more DAAs, together with an at least 2 DAAs and ribavirin for no more than 12 weeks (e.g., effective amount of ribavirin. The treatment lasts no more the duration being 12 weeks), preferably no more than 8 25 than 12 weeks, alternatively no more than 11 weeks, alterna weeks (e.g., the duration being 8 weeks), wherein the treat tively no more than 10 weeks, alternatively no more than 9 ment does not include administration of interferon. Interferon weeks, preferably no more than 8 weeks, alternatively no nonresponder patients can be treated with a combination of at more than 7 weeks, alternatively no more than 6 weeks, least 2 DAAs without interferon with ribavirin wherein the alternatively no more than 5 weeks, alternatively no more two DAAS include therapeutic agent 1 and therapeutic agent 30 than 4 weeks, alternatively no more than 3 weeks and does not 4 with ribavirin. Therapeutic agent 1 and therapeutic agent 4 include administration of any interferon. The DAAs and rib can be administered in therapeutically effective amounts to avirin can be administered at the same or different dosing provide a SVR (for example, a SVR8, SVR12, SVR16 or frequencies. The patient being treated can be an HCV-treat SVR24) after treatment duration of no more than 12 weeks, ment naive patient or HCV-treatment experienced patient, preferably no more than 8 weeks. The interferon non-re 35 including, interferon non-responders, interferon partial sponder patients include partial interferon responders and responders (patients whose HCV RNA levels declined but interferon rebound patients. The interferon nonresponder never became undetectable when treated with interferon), or patient may have HCV genotype 1, such as 1a. The interferon relapsers (patients who achieved undetectable levels of HCV nonresponder patient may have HCV genotype 1b. The inter RNA during therapy but rebound) or a patient unable to take feron nonresponder patient can have HCV genotype 2 or 3. 40 interferon. The patient can be infected with, for example and Such as HCV genotype 2a. In some embodiments, the patient without limitation, HCV genotypes 1 or 2. In some embodi may have HCV genotype 2b. In other embodiments the ments are preferably genotypes 1a or 1b. In other embodi patient may have HCV genotype 3a. In some embodiments, it ments, the HCV genotype is 2 or 3. Each DAA can be selected is contemplated to treat other HCV genotypes. The treatment from HCV protease inhibitors, HCV polymerase inhibitors, can be administered for a duration of no more than 12 weeks, 45 or HCV NS5A inhibitors. including but not limited to, no more than 11 weeks, no more For instance, the combination of two or more DAAS can be than 10 weeks, no more than 9 weeks, but preferably no more a combination of at least one HCV protease inhibitor and at than 8 weeks, no more than 7 weeks, no more than 6 weeks, least one HCV polymerase inhibitor (e.g., a combination of at no more than 5 weeks, no more than 4 weeks, or no more than least one HCV protease inhibitor and at least one non-nucleo 3 weeks, e.g., the duration being 12 weeks, or the duration 50 side polymerase inhibitor, or a combination of at least one being 8 weeks. The total daily dosage of therapeutic agent 1 HCV protease inhibitor and at least one nucleoside or nucle can be, but is not limited to, for example, about 100 mg, about otide polymerase inhibitor, or a combination of at least one 110 mg, about 120 mg, about 125 mg, about 130 mg, about HCV protease inhibitor, at least one nucleoside or nucleotide 140 mg, about 150 mg, about 160 mg, about 170 mg, about polymerase inhibitor and at least one non-nucleoside inhibi 180 mg, about 190 mg, about 200 mg, about 210 mg, about 55 tor). 220 mg, about 230 mg, about 240 mg, about 250 mg, about For another instance, the combination of two or more 260 mg, about 270 mg. or about 300 mg. Therapeutic agent 4 DAAs can be a combination of at least one HCV protease can be administered with therapeutic agent 1 wherein thera inhibitor and at least one HCV NS5A inhibitor. In an peutic agent 1 is administered in any of the dosages described example, the combination of two or more DAAS comprises above. Therapeutic agent 4 can be provided in combination 60 GS-5885 (an NS5A inhibitor), and GS-9451 (a protease with therapeutic agent 1. The total daily dosage of therapeutic inhibitor or an NS3 protease inhibitor). In some examples, agent4 can be, but is not limited to, for example, about 15 mg. GS-5885 is provided in a daily dose from about 3 mg to about about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 200 mg, alternatively from about 3 mg to about 100 mg. 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg. alternatively from about 30 mg to about 90 mg, including, but about 90 mg, about 100 mg, about 110 mg, about 120 mg. 65 not limited to, for example, about 3 mg, about 5 mg, about 10 about 120 mg, about 130 mg, about 140 mg, about 150 mg. mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg. about 160 mg, about 170 mg, about 180 mg, about 190 mg. about 40 mg, about 50 mg, about 60 mg, about 70 mg, about US 8,969,357 B2 69 70 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 TMC-435 and about 100 mg PSI-7977, alternatively about mg, about 130 mg, about 140 mg, about 150 mg, about 160 100 mg TMC-435 and about 100 mg PSI-7977, alternatively mg, about 170 mg, about 180 mg, about 190 mg. or about 200 about 150 mg TMC-435 and about 100 mg PSI-7977, and can mg. GS-9451 can be administered in combination with any of include other suitable combinations. Suitably, in some the daily dosages of GS-5885 described above. GS-9451 can 5 embodiments, ritonavir or a suitable equivalent can be added be administered in a total daily dose from about 100 mg to to the at least two DAAS comprising at least one protease about 500 mg, alternatively from about 200 mg to about 400 inhibitor, suitably in an amount from about 100 mg to about mg, including, but not limited to, for example, about 100 mg. 400 mg per day, preferably about 100 mg per day. Suitable about 150 mg, about 200 mg, about 250 mg, about 300 mg. ribavirin can be administered with the at least two DAAs, about 400 mg. or about 500 mg. Suitably examples include 10 preferably in an amount based on weight of the Subject, total daily dosages of about 30 mg. GS-5885 and about 200 mg suitably about 1000 mg or about 1200 mg per day. For GS-9451; alternatively about 60 mg GS-5885 and about 200 example, a suitable ribavirin daily treatment is weight based, mg GS-9451; alternatively about 90 mg GS-5885 and about for example, 1000 mg/day.<75 kg and 1200 mg/day 75 kg, 200 mg GS-9451. divided twice daily (BID). In alternative embodiments, the at In another instance, the present technology provides the at 15 least one protease is BI-201335 (NS3/4A protease inhibitor) least two DAAs comprise at least two HCV polymerase and the at least one HCV polymerase inhibitor is a non inhibitors. In some embodiments, the at least two HCV poly nucleoside polymerase inhibitor, e.g. BI-207127. In some merase inhibitors comprise at least one nucleoside or nucle examples, the BI-201335 is provided in a total daily dose otide analog polymerase inhibitor. In some embodiments, the from about 100 mg to about 400 mg, alternatively from about at least two HCV polymerase inhibitors comprise at least two 120 mg to about 240 mg, including about 100 mg, about 120 nucleoside or nucleotide analog polymerase inhibitors. Suit mg, about 125 mg, about 130 mg, about 140 mg, about 150 able nucleotide analog polymerase inhibitors include PSI mg, about 160 mg, about 170 mg, about 180 mg, about 190 7977 (Pharmasset) and PSI-938 (Pharmasset). Suitable daily mg, about 200 mg, about 210 mg, about 220 mg, about 230 dosages of the at least one nucleoside or nucleotide analog mg, about 240 mg, about 250 mg, about 275 mg, about 300 polymerase inhibitor include from about 100 mg to about 500 25 mg, about 320 mg, about 330 mg, about 350 mg, about 360 mg, alternatively from about 200 mg to about 400 mg, includ mg, about 370 mg, about 380 mg, or about 400 mg; and ing, but not limited to, for example, about 100 mg, about 150 BI-207127 can be administered in a total daily dose from mg, about 200 mg, about 250 mg, about 300 mg, about 350 about 300 mg to about 3600 mg, preferably from about 1200 mg, about 400 mg, about 450 mg. or about 500 mg. For mg to about 2100 mg, including, but not limited to, for example, a Suitable combination includes a total daily dose of 30 example, about 300 mg, about 400 mg, about 500 mg, about PSI-7977 of about 400 mg and a total daily of PSI-938 of 600 mg, about 700 mg, about 750 mg, about 800 mg, about about 300 mg, alternatively a total daily dose of about 200 mg 900 mg, about 1000 mg, about 1100, about 1200 mg, about PSI-7977 and a total daily dose of about 300 mg PSI-938. 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg. Suitably, ribavirin can be administered with the at least two about 1700 mg, about 1800 mg, about 1900 mg, about 2000 DAAs, preferably in an amount based on weight of the sub 35 mg, about 2100 mg, about 2200 mg, about 2400 mg, about ject, in a total daily dose of from about 400 mg to about 1400 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg. mg, suitably about 1000 mg or about 1200 mg per day. For about 3000 mg, about 3200 mg, about 3400 mg. or about 3600 example, a suitable ribavirin daily treatment is weight based, mg. Suitable examples, include, but are not limited to, a for example, 1000 mg/day.<75 kg and 1200 mg/day 75 kg, combination of a total daily dose of about 120 mg BI-201335 divided twice daily (BID). In yet another instance, the com 40 and about 1200 mg BI-207127, alternatively about 120 mg bination of two or more DAAs comprises at least one HCV BI-201335 and about 1500 mg BI-207127, alternatively protease inhibitor and at least one HCV polymerase inhibitor. about 120 mg BI-201335 and about 1800 mg BI-207127, In some embodiments, the at least one protease inhibitor is alternatively about 120 mg BI-201335 and about 2100 mg TMC-435 (Medivir) and the at least one polymerase inhibitor BI-207127, alternatively about 240 mg BI-201335 and about is a nucleotide/nucleoside analog polymerase inhibitor, for 45 1200 mg BI-207127, alternatively about 240 mg BI-201335 example PSI-7977. Suitably, the at least one protease inhibi and about 1500 mg BI-207127, alternatively about 240 mg tor, e.g. TMC-435, is provided in a total daily dosage from BI-201335 and about 1800 mg BI-207127, alternatively about 25 mg to about 250 mg, alternatively from about 25 mg about 240 mg BI-201335 and about 2100 mg BI-207127. to about 200 mg, alternatively from about 50 mg to about 200 Suitably, in some embodiments, ritonavir or a suitable mg, alternatively from about 75 mg to about 150 mg, for 50 equivalent can be added to the at least two DAAS comprising example, about 25 mg, about 50 mg, about 75 mg, about 100 at least one protease inhibitor, Suitably in an amount of about mg, about 125 mg, about 150 mg, about 175 mg, or about 200 100 mg per day. Suitably, in some embodiments, ritonavir or mg; and the at least one polymerase inhibitor (e.g. PSI-7977) a suitable equivalent can be added to the at least two DAAS is provided in a total daily dose from about 100 mg to about comprising at least one protease inhibitor, Suitable in an 500 mg, alternatively from about 200 mg to about 400 mg. 55 amount from about 100 mg to about 400 mg per day, prefer including, but not limited to, for example, about 100 mg. ably about 100 mg per day. Suitable ribavirin can be admin about 150 mg, about 200 mg, about 250 mg, about 300 mg. istered with the at least two DAAs, preferably in an amount about 350 mg, about 400 mg, about 450 mg. or about 500 mg. based on weight of the subject, suitably from about 400 mg to For example, a combination can be a total daily dosage of about 1400 mg per day, for example, about 1000 mg or about about 75 mg TMC-435 and about 400 mg PSI-7977, alterna 60 1200 mg per day. For example, a suitable ribavirin daily tively about 100 mg TMC-435 and about 400 mg PSI-7977, treatment is weight based, for example, from 400 mg to about alternatively about 150 mg TMC-435 and about 400 mg PSI 1400 mg, preferably about 1000 mg/day<75 kg and 1200 7977, alternatively about 100 mg TMC-435 and about 400 mg mg/day 75 kg, divided twice daily (BID). In yet another PSI-7977, alternatively about 75 mg TMC-435 and about 200 example, the combination of two or more DAAS comprises mg PSI-7977, alternatively about 150 mg TMC-435 and 65 telaprevir (VX-950, protease inhibitor) and VX-222 (non about 200 mg PSI-7977, alternatively about 100 mg TMC nucleoside polymerase inhibitor). In some examples, the tella 435 and about 200 mg PSI-7977, alternatively about 75 mg previr is provided in total daily doses from about 1000 mg to US 8,969,357 B2 71 72 about 2500 mg, alternatively from about 2000 mg to about 400 mg and the total daily dose of R7128 is about 200 mg. 2500 mg, including, but not limited to, for example, about alternatively, the total daily dose of the danoprevir is about 1000 mg, about 1200 mg, about 1300 mg, about 1500 mg. 1000 mg and the total daily dose of R7128 at about 200 mg. about 1700 mg, about 1800 mg, about 1900 mg, about 2000 alternatively the total daily dose of the danoprevir is about mg, about 2100 mg, about 2200 mg, about 2250 mg, about 1800 mg and the total daily dose of R7128 is about 200 mg. 2300 mg, about 2400 mg, about 2500 mg. VX-222 can be alternatively the total daily dose of the danoprevir is about administered with telaprevir in any combination with the 2000 mg and the total daily dose of R7128 is about 200 mg. dosage amounts oftelaprevir provided above. VX-222 can be alternatively the total daily dose of the danoprevir is about provided in a total daily dosage from about 100 mg to about 400 mg and the total daily dose of R7128 is about 400 mg. 1000 mg, alternatively from about 200 mg to about 800 mg. 10 alternatively, the total daily dose of the danoprevir is about including, but not limited to, for example, about 100 mg. 1000 mg and the total daily dose of R7128 is about 400 mg. about 200 mg, about 300 mg, about 400 mg, about 500 mg. alternatively the total daily dose of the danoprevir is about about 600 mg, about 700 mg, about 800 mg, about 900 mg. or 2000 mg and the total daily dose of R7128 is about 400 mg. about 1000 mg. In some examples, telaprevir can be a total alternatively the total daily dose of the danoprevir is about daily dose of about 2250 mg and VX-222 can be a total daily 15 1800 mg and the total daily dose of R7128 is about 400 mg. dose of about 100 mg, alternatively telaprevir can be a total alternatively the total daily dose of the danoprevir is about daily dose of about 2250 mg and VX-222 can be a total daily 400 mg and the total daily dose of R7128 is about 1000 mg. dose of about 200 mg, alternatively telaprevir can be a total alternatively, the total daily dose of the danoprevir is about daily dose of about 2250 mg and VX-222 can be a total daily 1000 mg and the total daily dose of R7128 is about 1000 mg. dose of about 400 mg, alternatively telaprevir can be a total alternatively the total daily dose of the danoprevir is about daily dose of about 2250 mg and VX-222 can be a total daily 2000 mg and the total daily dose of R7128 is about 1000 mg. dose of about 600 mg, alternatively telaprevir can be a total alternatively the total daily dose of the danoprevir is about daily dose of about 2250 mg and VX-222 can be a total daily 1800 mg and the total daily dose of R7128 is about 1000 mg. dose of about 800 mg, alternatively telaprevir can be a total alternatively the total daily dose of the danoprevir is about daily dose of about 1500 mg and VX-222 can be a total daily 25 400 mg and the total daily dose of R7128 is about 2000 mg. dose of about 200 mg, alternatively telaprevir can be a total alternatively, the total daily dose of the danoprevir is about daily dose of about 1500 mg and VX-222 can be a total daily 1000 mg and the total daily dose of R7128 is about 2000 mg. dose of about 400 mg, alternatively telaprevir can be a total alternatively the total daily dose of the danoprevir is about daily dose of about 1500 mg and VX-222 can be a total daily 2000 mg and the total daily dose of R7128 is about 2000 mg. dose of about 800 mg. Suitably, telaprevir can be adminis 30 alternatively the total daily dose of the danoprevir is about tered three times a day (TID), for example 3 times a day with 1800 mg and the total daily dose of R7128 is about 2000 mg. 750 mg per dose. Other suitable daily dosage of telaprevir is In suitable embodiments, danoprevir and R7128 can be 1125 mg twice a day (BID). Suitably, in some embodiments, administered with ritonavir, suitably in an amount of about ritonavir or a suitable equivalent can be added to the at least 100 mg to about 400 mg per day, preferably about 100 mg per two DAAS comprising at least one protease inhibitor, Suitably 35 day. Suitable ribavirin can be administered with the at least in an amount of about 100 mg to about 400 mg per day, two DAAs, preferably in an amount based on weight of the preferably about 100 mg per day. Suitable ribavirin can be subject, from about 400 mg to about 1400 mg, suitably about administered with the at least two DAAs, preferably in an 1000 mg or about 1200 mg per day. For example, a suitable amount based on weight of the subject, from about 400 mg to ribavirin daily treatment is weight based, for example, 1000 about 1400 mg. suitably about 1000 mg or about 1200 mg per 40 mg/day.<75 kg and 1200 mg/day-75kg, divided twice daily day. For example, a suitable ribavirin daily treatment is (BID). weight based, for example, 1000 mg/day.<75 kg and 1200 In some other instances of the present technology, the mg/day-75kg, divided twice daily (BID). combinations of two or more DAAS may be at least one In yet another example, the combination of two or more protease inhibitor and at least one NS5A inhibitor. In some DAAs includes danoprevir (protease inhibitor) and R7128 45 examples, the at least one protease inhibitor is an NS3 pro (nucleoside polymerase inhibitor). In some embodiments, tease inhibitor. In some embodiments, the at least one pro danoprevir can be administered in a total daily dosage from tease inhibitor and at least one NS5A inhibitor comprises about 100 mg to about 2000 mg, alternatively from about 200 BMS-650032 (BMS) and BMS-790052 (BMS) respectively. mg to about 1800 mg, alternatively from about 400 mg to In suitable embodiments, BMS-650032 can be administered about 1800 mg, including, but not limited to, for example, 50 in a total daily dose from about 300 mg to about 1500 mg. about 100 mg, about 200 mg, about 300 mg, about 400 mg. alternatively from about 500 mg to about 1500 mg, including, about 500 mg, about 600 mg, about 700 mg, about 800 mg. but not limited to, for example, about 300 mg, about 400 mg. about 900 mg, about 1000 mg, about 1100 mg, about 1200 about 500 mg, about 600 mg, about 700 mg, about 800 mg. mg, about 1300 mg, about 1400 mg, about 1500 mg, about about 900 mg, about 1000 mg, about 1100 mg, about 1200 1600 mg, about 1700 mg, about 1800 mg, and other amounts 55 mg, about 1300 mg, about 1400 mg, and about 1500 mg, and therebetween. R7128 can be administered in a total daily dose BMS-790052 (BMS) can have a total daily dose from about from about 100 mg to about 2000 mg, alternatively from 10 mg to about 200 mg, alternatively from about 50 mg to about 200 mg to about 2000 mg, alternatively from about about 100 mg, including, but not limited to, for example, 1000 mg to about 2000 mg, including, but not limited to, for about 10 mg, about 20 mg, about 30 mg, about 40 mg, about example, about 150 mg, about 200 mg, about 400 mg, about 60 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 500 mg, about 600 mg, about 700 mg, about 800 mg, about mg, about 150 mg, or about 200 mg. In Suitable examples, 900 mg, about 1000 mg, about 1200 mg, about 1300 mg. BMS-650032 (BMS) total daily dose is about 1200 mg and about 1400 mg, about 1500 mg, about 1600 mg, about 1700 BMS-790052 (BMS) total daily dose is about 60 mg, alter mg, about 1800 mg, about 1900 mg. or about 2000 mg. In natively BMS-650032 (BMS) total daily dose is about 300 Some examples, the total daily dose of the danoprevir is about 65 mg and BMS-790052 (BMS) total daily dose is about 60 mg. 200 mg and the total daily dose of R7128 is about 200 mg. Suitable ribavirin can be administered with the at least two alternatively the total daily doses of the danoprevir is about DAAs, preferably in an amount based on weight of the sub US 8,969,357 B2 73 74 ject, from about 400 mg to about 1400 mg. suitably about about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 1000 mg or about 1200 mg per day. For example, a suitable 110 mg, about 120 mg, about 130 mg, about 140 mg, about ribavirin daily treatment is weight based, for example, 1000 150 mg, about 160 mg, about 170 mg, about 180 mg, about mg/day<75 kg and 1200 mg/day-75kg, divided twice daily 190 mg. or about 200 mg, and GS-9190 is provided in a daily (BID). 5 dose from about 10 mg to about 100 mg, alternatively from In some other instances of the present technology, the about 30 mg to about 90 mg, including, but not limited to, for combinations of two or more DAAS may be at least one example, about 10 mg, about 20 mg, about 30 mg, about 40 nucleoside or nucleotide polymerase inhibitor, at least one mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg. protease inhibitor, and at least one NS5A inhibitor. In some about 90 mg, or about 100 mg; and GS-9451 can be admin examples, the at least one protease inhibitor is an NS3 pro 10 istered in a daily dose from about 100 mg to about 500 mg. tease inhibitor. In some embodiments, the at least one nucleo alternatively from about 200 mg to about 400 mg, including, side or nucleotide polymerase inhibitor is INX-189, the at but not limited to, about 100 mg, about 150 mg, about 200 mg. least one protease inhibitor is BMS-650032 (asunaprevir), about 250 mg, about 300 mg, about 400 mg. or about 500 mg. and the at least one NS5A inhibitor comprises is Suitably examples include about daily amounts of about 30 BMS-790052 (daclatasivr). Such embodiments are espe 15 mg GS-5885, about 60 mg GS-9190 and about 200 mg cially contemplated for treating a patient infected with HCV GS-9451; alternatively about 60 mg GS-5885, about 60 mg genotype 1. Such as genotype 1a or 1b (particularly genotype GS-9190, and about 200 mg GS-9451; alternatively about 90 1a), as well as patients infected with other HCV genotypes, mg GS-5885, about 60 mg. GS-9190, and about 200 mg such as genotypes 2 or 3. In suitable embodiments, INX-189 GS-9451. In some embodiments the GS-9190, GS-9451, and can be administered in a total daily dose from about 5 mg to GS-5885 is administered with ritonavir or a suitable equiva about 400 mg, alternatively from about 25 mg to about 200 lent, suitably in an amount of about 100 mg to about 400 mg mg, including but not limited to, for example, about 5 mg. per day, preferably about 100 mg per day. Suitable ribavirin about 10 mg, about 15 mg, about 20 mg, about 25 mg, about can be administered with the at least two DAAs, preferably in 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg. an amount based on weight of the Subject, from 400 mg to about 80 mg, about 90 mg, about 100 mg, about 110 mg. 25 about 1400 mg, suitably about 1000 mg or about 1200 mg per about 120 mg, about 125 mg, about 130 mg, about 140 mg. day. For example, a suitable ribavirin daily treatment is about 150 mg, about 160 mg, about 170 mg, about 180 mg. weight based, for example, 1000 mg/day.<75 kg and 1200 about 190 mg, about 200 mg, about 210 mg, about 220 mg. mg/day 75 kg, divided twice daily (BID). For still another about 230 mg, about 240 mg, about 250 mg, about 260 mg. instance, the combination of two or more DAAS can be a about 270 mg, or about 300 mg. In suitable embodiments, 30 combination of at least one HCV protease inhibitor, at least BMS-650032 can be administered in a total daily dose from one HCV polymerase inhibitor, and at least one HCV NS5A about 300 mg to about 1500 mg, alternatively from about 500 inhibitor. mg to about 1500 mg, including, but not limited to, for In another embodiment, the present technology provides example, about 300 mg, about 400 mg, about 500 mg, about interferon-free treatment comprising administering daily two 600 mg, about 700 mg, about 800 mg, about 900 mg, about 35 DAAs with ribavirin, where the two DAAs include a HCV 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg. polymerase inhibitor, for example PSI-7977 and a NS5A about 1400 mg, and about 1500mg, and BMS-790052 (BMS) inhibitor, for example BMS-790052 for a duration of no more can have a total daily dose from about 10 mg to about 200 mg. than eleven weeks, preferably no more than eight weeks. alternatively from about 50 mg to about 100 mg, including, PSI-7977 and BMS-790.052 are administered in an effective but not limited to, for example, about 10 mg, about 20 mg. 40 amount to provide an SVR (for example, an SVR8, SVR12. about 30 mg, about 40 mg, about 50 mg, about 60 mg, about SVR16, or SVR24) with a treatment duration of no more than 75 mg, about 100 mg, about 125 mg, about 150 mg, or about eleven weeks, no more than ten weeks, no more than nine 200 mg. In suitable examples, BMS-650032 (BMS) total weeks, no more than eight weeks, no more than seven weeks, daily dose is about 1200 mg and BMS-790052 (BMS) total no more than six weeks, no more than five weeks, no more daily dose is about 60 mg, alternatively BMS-650032 (BMS) 45 than four weeks or no more than three weeks. The patients can total daily dose is about 300 mg and BMS-790052 (BMS) be treatment naive patients or treatment experienced patients. total daily dose is about 60 mg. Suitable ribavirin can be In some embodiments, the patients can have HCV genotype administered with the at least two DAAs, preferably in an 1. Such as 1a or 1b. In some embodiments, the patients can amount based on weight of the subject, from about 400 mg to have genotype 2 or 3, such as 2a, 2b or 3a. PSI-7977 can be about 1400 mg. suitably about 1000 mg or about 1200 mg per 50 provided in a total daily dose of from about 100 mg to about day. For example, a suitable ribavirin daily treatment is 500 mg, alternatively from about 200 mg to about 400 mg. weight based, for example, 1000 mg/day.<75 kg and 1200 including, but not limited to, for example, about 100 mg. mg/day-75kg, divided twice daily (BID). about 150 mg, about 200 mg, about 250 mg, about 300 mg. For still another instance, the combination of two or more about 350 mg, about 400 mg, about 450 mg, about 500 mg. DAAs can be a combination of at least one HCV protease 55 BMS-790.052 can be administered in combination with PSI inhibitor, at least one HCV polymerase inhibitor, and at least 7977 at any daily dose of PSI-7977 provided above. BMS one HCV NS5A inhibitor. In an example, the combination of 790052 (BMS) can have a total daily dose of from about 10 two or more DAAs comprises GS-5885 (an NS5A inhibitor), mg to about 200 mg, alternatively from about 50 mg to about GS-9190 (tegobuvir, a non-nucleoside polymerase inhibitor), 100 mg, including, but not limited to, about 10 mg, about 20 and GS-9451 (a protease inhibitor or a NS3 protease inhibi 60 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg. tor). In some examples, GS-5885 is provided in a daily dose about 75 mg, about 100 mg, about 125 mg, about 150 mg. or from about 3 mg to about 200 mg, alternatively from about 3 about 200 mg. In one suitable example, PSI-7977 is admin mg to about 100 mg, alternatively from about 30 mg to about istered in a total daily dose of 400 mg and BMS-790052 is 90 mg, including, but not limited to, for example, about 3 mg, administered in a total daily dose of 60 mg. about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 65 The chemical structures of some of these HCV inhibitors mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg. as reported by numerous sources are provided below: US 8,969,357 B2 75 76

Telaprevir

H N

Br N -( O S 1. O N S. 2 Cl wO

O1. N N H

O N H O BI-2O1335 TMC-435 (TMC-435350)

V/

O)- S. * 1. V

Vaniprevir, MK-7009

BMS-650032 (Asunaprevir) Danoprevir US 8,969,357 B2 77 78 -continued

O O N1 K% i V/ ANA-598 (Setrobuvir)

O) F () GS-333126 (GS-9190 or tegobuvir)

GS-9451 Mericitabine (R-4048 or RG 7128)

HO

IDX-184

US 8,969,357 B2 81 -continued

GS-9256

H H V N N >< N O

O GS-5885

It has also been reported that BMS-791325 has the follow tion, no more than 12 weeks, no more than 11 weeks, no more ing structure: 35 than 10 weeks, no more than 9 weeks, no more than 8 weeks, alternatively no more than 7 weeks, alternatively no more

than 6 weeks, alternatively no more than 5 weeks, alterna tively no more than 4 weeks and may depend on the patients response. In any given regimen described below, the drugs 40 can be, for example and without limitation, co-formulated in a single solid dosage form when each has the same dosing frequency. For instance, two or more drugs in a regimen can be co HO formulated in amorphous forms or molecularly dispersed in a 45 matrix comprising a water-soluble polymer and optionally a Surfactant; for another instance, therapeutic agent 1 and ritonavir (RTV) are formulated in an amorphous form or See also publications at http://www1.eas 1.eu/eas12011/ molecularly dispersed in a matrix comprising a water-soluble program/Posters/Abstracté80.htm; and http://clinicaltrials 50 polymer and optionally a surfactant, and therapeutic agent 3 gov/show/NCT00664625. For GS-5885, see publications at is combined with amorphous Compound 1 and RTV in a http://www.natap.org/2011/EASL/EASL 68.htm: http:// single Solid dosage form. For yet another instance, Com www1.eas 1.eu/eas 12011/program/Posters/ pound 1 and RTV are formulated in a different dosage form Abstract1097.htm; and http://clinicaltrials.gov/ct2/show/ than that of therapeutic agent 3. NCTO1353248. 55 Any HCV inhibitor or DAA described herein encompasses TABLE 1 its suitable salt forms when it is used in therapeutic treatments Non-Limiting Examples of Interferon-free Treatment or pharmaceutical formulations. Regimens with two or more DAAS (withoutribavirin The following table lists non-limiting examples of the and with or withoutritonavir treatment regimens of the present technology. In each treat 60 Regi- Drugs Used in ment regimen, the at least two DAA with or withoutritonavir, men Treatment Suitable total daily dosages are administered daily to an HCV patient under such treat ment. Each treatment is interferon-free. Administration of 1 Therapeutic Agent 1* + 150 to 250 mg (pref. 150, 200, 250 mg) Therapeutic Agent 4 5 mg to 300 mg (pref 25 mg) ribavirin is included in each regimen. Each treatment regimen 2 Therapeutic Agent 1* + 150 to 250 mg (pref. 150, 200, 250mg) may also optionally comprise administering one or more 65 Therapeutic Agent 4+ 5 mg to 300 mg (pref 25 to 200 mg) other additional DAAS to the patient. The duration of each Therapeutic Agent 2 300 to 1800 mg (pref. 400 mg or 800 mg) treatment regimen may last, for example and without limita US 8,969,357 B2 83 84 TABLE 1-continued 300 mg (pref. 25 mg to 200 mg, more pref 25 mg); (d) Therapeutic Agent 1 at a total daily dose of 5 mg to 150 mg Non-Limiting Examples of Interferon-free Treatment (pref.5 mg, 25 mg, 50 mg, 100 mg) with ritonavir or a suitable Regimens with two or more DAAS (withoutribavirin and with or withoutritonavir equivalent, and Therapeutic Agent 2 at a total daily dose of 5 200-800 mg; (e) GS-5885 at a total daily dose of 3-200 mg Regi- Drugs Used in (pref.30-90 mg). GS-9190 at a total daily dose of 30-90 mg men Treatment Suitable total daily dosages (pref. 60 mg), and GS-9451 at a total daily dose of 100-500 3 Therapeutic Agent 1* + 150-250 mg (pref. 150 mg or 250 mg) mg (pref. 200 mg): (f) GS-5885 at a total daily dose of 3 mg Therapeutic Agent 3+ 50 mg-1000 mg (pref. 400 mg) to 200 mg (pref 30 mg, 60 mg. or 90 mg), and GS-9451 at a Therapeutic Agent 4 5 mg-300 mg (pref. 25 mg-200 mg, more 10 total daily dose of 100 mg to 500 mg (pref 200 mg); (g) pref 25 mg) 4 Therapeutic Agent 1* + 150-250 mg (150 mg, 200 mg or 250mg) BI-201335 at a total daily dose of 100 mg to 400mg (pref. 120 Therapeutic Agent 2 300-1800 mg (pref 200 mg, 800 mg) mg, 240 mg), and BI-207127 at a total daily dose of 300 mg 5 Therapeutic Agent 1* + 50 mg to 250 mg (pref. 50 mg or 250mg) to 3600mg (pref. 1200 or 1500 mg, 1800 mg or 2100mg): (h) Therapeutic Agent 3 50 mg to 1000 mg (pref. 400 mg to 800 PSI-7977 at a total daily dose of 100 mg to -500 mg (pref. mg) 15 6 PSI-7977 00 mg to 500 mg (pref. 200, 400 mg) 100, 200 mg), and TMC-435 at a total daily dose of 25 mg to PSI-938 00 mg to 500 mg (pref. 300 mg) 200 mg (pref. 75 mg, 100 mg. or 150 mg): (i) telaprevir at a 7 BMS-790OS2- Omg to 200 mg (pref. 60 mg) total daily dose of 1000 mg to 2500 mg (pref. 1500 mg or BMS-6SOO32 300 mg to 1500 mg (pref 1200 mg) 2250 mg), and VX-222 at a total daily dose of 100 mg to 800 8 GS-588S- 3 mg to 200 mg (pref. 30 mg to 90 mg) GS-9190- 30 mg to 90 mg (pref. 60 mg) mg (pref. 100 mg, 200 mg. 400 mg, 600 mg or 800 mg); () GS-94S1 00 mg to 500 mg (pref. 200 mg) INX-189 at a total daily dose of 5 mg to 400 mg (pref. 50 mg. 9 GS-588S- 3 mg to 200 mg (pref. 30 to 90 mg) 100 mg or 200 mg), and daclatasvir (BMS-790052) at a total GS-94S1 00 mg to 500 mg (pref. 200 mg) daily dose of 10 mg to 200 mg (pref. 60 mg); (k) INX-189 at O BI-2O1335- 00 mg to 400 mg (pref. 120 mg or 240 mg) a total daily dose of 5 mg to 400 mg (pref. 50 mg, 100 mg or BI-2O7127 300 mg to 3600 mg (pref 1200 mg to 200 mg), and asunaprevir (BMS-650032) at a total daily dose 2100 mg) 25 of 300 mg to 1500 mg (pref. 1200 mg); and (1) INX-189 at a 1 PSI-7977 00 mg to 500 mg (pref. 400 mg) total daily dose of 5 mg to 400 mg (pref.50 mg, 100 mg or 200 TMC-435 25 mg to 200 mg (pref. 75 mg to 150 mg) 2 telaprevir- 000 mg to 2500 mg (pref 2250mg) mg), daclatasvir (BMS-790052) at a total daily dose of 10 mg VX-222 200 mg to 800 mg to 200 mg (pref. 60 mg), and asunaprevir (BMS-650032) at a 3 Danoprevir + 00 mg to 2000 mg (pref 200 mg or total daily dose of 300 mg to 1500 mg (pref. 1200 mg). In any 400 mg) 30 of these examples, ritonavir or a suitable equivalent can be R7128 00 mg to 2000 mg (pref 200 mg, 400 mg, 1000 mg or 2000 mg) added to any one of these treatments as described and may be 4 Danoprevir 00 mg to 2000 mg (pref. 800 mg or 1000 added to any of these treatments at a daily total dosage as mg, or 1800 mg or 2000 mg) described in the present technology; preferably ritonavir is R7128 00 mg to 2000 mg (pref 200 mg, 400 co-formulated with therapeutic agent 1 or danoprevir, the mg, 1000 mg or 2000 mg) 35 5 PSI-7977 00 mg to 500 mg (pref. 400 mg) dose of ritonavir preferably is 100 mg. In these examples, daclataSvir 0-200 mg (pref. 60 mg) ribavirin preferably is used in a weight based amount from (BMS-790052) 400 mg to 1400 mg (pref. 1000 to 1200 mg). 6 PSI-7977 00 mg to 2000 mg (pref. 1800 mg or The treatments of the present technology may be effective 2000 mg) asunaprevir 300-1500 mg (pref 1200 mg) in treating HCV infection against HCV genotypes 1,2,3,4, 5, (BMS-650032) 40 6, including Subgenotypes, such as 1a, 1b, 2a, and 3a. 7 PSI-7977 00 mg to 500 mg (pref. 400 mg) In general and depending on patients’ conditions, the total daclataSvir 0-200 mg (pref. 60 mg) daily dose of the DAAs of the present technology may be (BMS-790052) asunaprevir 300-1500 mg (pref 1200 mg) administered (either as a single or divided dose) in amounts (BMS-650032) from about 0.001 mg/kg to about 200 mg/kg, or from about 45 0.001 mg/kg to about 30 mg/kg, or from about 0.001 mg/kg to *ritonavir or a suitable equivalent can be added to any one of these treatments as described and maybe added to any of these treatmentsata daily total dosage as described in the present about 30 mg/kg, or from about 0.01 mg/kg, to about 10 mg/kg technology; preferably ritonavir is co-formulated with therapeutic agent 1 or danoprevir; the (i.e. mg of the compound or salt per kg body weight), and dose of ritonavir preferably is 100 mg. Pref. = preferred **in each regimen, ribavirin preferably is used in a weight based amount from 400 mg to include any amounts or ranges there between, including, but 1400 mg (pref. 1000 to 1200 mg) not limited to increments of 0.001 mg/kg, 0.005 mg/kg, 0.01 Additional non-limiting examples of interferon-free treat 50 mg/kg, 0.05 mg/kg, and multiple factors thereof (e.g. 0.25x, ment regimens with two or more DAAs, with ribavirin and 0.5x, 1x, 2x, 3x, 5x, 10x. 100x, etc.). Suitable dosages of the with or without ritonavir or a suitable equivalent, including DAAs of the present technology include, but are not limited the following: (a) Therapeutic Agent 1 at a total daily dose of to, from about 25 mg to about 2000 mg, from about 25 mg to 5 mg to 150 mg (pref. 5 mg, 25 mg, 50 mg. or 100 mg) with about 1500 mg. from about 25 mg to about 1600 mg, from 55 about 25 mg to about 1000 mg, from about 25 mg to about 800 ritonavir or a suitable equivalent, and Therapeutic Agent 4 at mg, from about 25 mg to about 500 mg, from about 25 mg to a total daily dose of 5 mg to 150 mg (pref.5 mg, 25 mg, 50 mg. about 250 mg, from about 50 mg to about 2000 mg, from or 100 mg); (b) Therapeutic Agent 1 at a total daily dose of 5 about 50 mg to about 1500 mg. from about 50 mg to about mg to 200 mg (pref 5 mg, 25 mg, 50 mg, 100 mg) with 1600 mg, from about 50 mg to about 1000 mg, from about 50 ritonavir or a suitable equivalent, Therapeutic Agent 4 at a 60 mg to about 800 mg, from about 50 mg to about 500 mg, from total daily dose of 5 mg to 200 mg (pref. 25 mg or 100 mg), about 50 mg to about 250 mg, and include, but are not limited and Therapeutic Agent 2 at a total daily dose of 200 mg to 800 to, for example, about 25 mg, about 30 mg, about 35 mg. mg (pref. 400 mg or 800 mg); (c) Therapeutic Agent 1 at a about 40 mg, about 45 mg, about 50 mg, about 55 mg, about total daily dose of 5 mg to 150 mg (pref. 5 mg, 25 mg, 50 mg. 60 mg, about 65mg, about 70 mg, about 80 mg, about 90 mg. or 100 mg) with ritonavir or a suitable equivalent, Therapeu 65 about 95 mg, about 100 mg, about 110 mg, about 120 mg. tic Agent 3 at a total daily dose of 100 mg to 600 mg (pref. 400 about 130 mg, about 140 mg, about 150 mg, about 160 mg. mg), and Therapeutic Agent 4 at a total daily dose of 5 mg to about 165 mg, about 170 mg, about 180 mg, about 190 mg. US 8,969,357 B2 85 86 about 200 mg, about 210 mg, about 220 mg, about 230 mg. or 800 mg twice a day (BID), ritonavir at a dose of 100 mg about 250 mg, and includes any increments there between, once a day (QD), and an effective amount of ribavirin (for including increments of about 1 mg, about 2 mg, about 3 mg, example, 1000 mg or 1200 mg. or an amount based on the about 4 mg, about 5 mg, about 6 mg, about 10 mg, about 15 weight of the subject) QD, for 12 weeks. At the end of treat mg, about 20 mg, about 25, and multiples thereof (e.g. 0.25x, ment, the subject has no detectable virus. 0.5x, 1x, 2x, 3x, 5x, 10x. 100x, etc.). It will be understood, In one embodiment, a method for treating a naive subject however, that the specific dose level for any particular patient comprises administering Therapeutic agent 1 at a dose of 50 will depend upon a variety of factors including the activity of mg QD, Therapeutic agent 2 at a dose of 400 mg or 800 mg the specific compound employed, the age, body weight, gen BID, ritonavir at a dose of 100 mg QD, and an effective eral health, sex, diet, time of administration, route of admin 10 amount of ribavirin (for example, 1000 mg or 1200 mg. or an istration, rate of excretion, drug combination, and the severity amount based on the weight of the subject) QD, for 12 weeks. of the disease undergoing therapy. At the end of treatment, the subject has no detectable virus. The cytochrome P-450 inhibitor may be administered in In one embodiment, a method for treating a naive subject any Suitable amount Such as, for example, in doses of from comprises administering Therapeutic agent 1 at a dose of 250 about 0.3 mg/kg to about 2 mg/kg or from about 0.6 mg/kg to 15 mg QD, Therapeutic agent 2 at a dose of 400 mg BID, about 1.5 mg/kg. As non-limiting examples, the cytochrome ritonavir at a dose of 100 mg QD, and an effective amount of P-450 inhibitor may be administered in a total daily dose ribavirin (for example, 1000 mg or 1200 mg, or an amount amount of from about 25 mg to about 300 mg, or from about based on the weight of the subject) QD, for 12 weeks. At the 50 mg to about 250 mg. or from about 100 mg to about 200 end of treatment, the subject has no detectable virus. mg. In some embodiments, the cytochrome P-450 inhibitor is In another embodiment, a method for treating a naive Sub administered in a total daily dose of about 100 mg to about ject comprises administering Therapeutic agent 1 at a dose of 400 mg, preferably about 100 mg. In some embodiments, the 150 mg QD, Therapeutic agent 2 at a dose of 400 mg BID, cytochrome P-450 inhibitor is administered in a total daily ritonavir at a dose of 100 mg QD, and an effective amount of dose amount of about 25 mg. In some embodiments, the ribavirin (for example, 1000 mg or 1200 mg, or an amount cytochrome P-450 inhibitor is administered in a total daily 25 based on the weight of the subject) QD, for 12 weeks. At the dose amount of about 50 mg. In some embodiments, the end of treatment, the subject has no detectable virus. cytochrome P-450 inhibitor is administered in a total daily In yet another embodiment, a method for treating a dose amount of about 75 mg. In some embodiments, the peginterferon-ribavirin (P/RBV) non-responder comprises cytochrome P-450 inhibitor is administered in a total daily administering Therapeutic agent 1 at a dose of 150 mg QD. dose amount of about 100 mg. In some embodiments, the 30 Therapeutic agent 2 at a dose of 400 mg BID, ritonavir at a cytochrome P-450 inhibitor is administered in a total daily dose of 100 mg QD, and an effective amount of ribavirin (for dose amount of about 125 mg. example, 1000 mg or 1200 mg. or an amount based on the The one or more DAAS and ribavirin can be administered, weight of the subject) QD, for 12 weeks. At the end of treat for example and without limitation, concurrently or sequen ment, the subject has no detectable virus. tially, and at the same or different frequencies. For instance, 35 In yet another embodiment, a method for treating a For example, one DAA can be administered immediately peginterferon-ribavirin (P/RBV) non-responder comprises before or after the administration of another DAA. A short administering Therapeutic agent 1 at a dose of 50 mg QD. delay or time gap may exist between the administration of one Therapeutic agent 2 at a dose of 400 mg BID, ritonavir at a DAA and that of another DAA. The frequency of administra dose of 100 mg QD, and an effective amount of ribavirin (for tion may also be different. For example, a first DAA may be 40 example, 1000 mg or 1200 mg. or an amount based on the administered once a day and a second DAA may be admin weight of the subject) QD, for 12 weeks. At the end of treat istered twice or three times a day. For example, a first DAA ment, the subject has no detectable virus. with or withoutritonavir may be administered once daily, and In one embodiment, a method for treating a naive subject a second DAA may be administered twice daily. comprises administering Therapeutic agent 1 at a total daily The DAAs of the present technology can be co-formulated 45 dose of 150 mg QD, Therapeutic agent 3 at a total daily dose in a single dosage form. Non-limiting examples of Suitable of 400 mg QD, ritonavir at a dose of 100 mg QD, and an dosage forms include liquid or Solid dosage forms. For effective amount of ribavirin (for example, 1000 mg or 1200 example, a dosage form of Compound 1 as a Solid dosage mg, or an amount based on the weight of the Subject) QD, for form is described in U.S. Patent Application Publication No. 12 weeks. At the end of treatment, the subject has no detect 2011/0312973, filed Mar. 8, 2011 and entitled “Solid Com 50 able virus. positions', the entire content of which is incorporated herein In another embodiment, a method for treating a naive Sub by reference. More preferably, the dosage form is a solid ject comprises administering Therapeutic agent 1 at a total dosage form in which at least one of the DAAS is in an daily dose of 100 mg or 200 mg QD. Therapeutic agent 4 at a amorphous form, or highly preferably molecularly dispersed, total daily dose of 25 mg QD, ritonavir at a dose of 100 mg in a matrix which comprises a pharmaceutically acceptable 55 QD, and an effective amount of ribavirin (for example, 1000 water-soluble polymer and a pharmaceutically acceptable mg or 1200 mg. or an amount based on the weight of the Surfactant. The other DAAS can also be inanamorphous form subject) QD, for 12 weeks. At the end of treatment, the subject or molecularly dispersed in the matrix, or formulated in dif has no detectable virus. ferent form(s) (e.g., in a crystalline form). In yet another embodiment, a method for treating a naive The DAAs of the present technology can be formulated in 60 Subject comprises administering Therapeutic agent 1 at a total different dosage forms. It will be understood that the total daily dose of 100 mg or 150 mg QD. Therapeutic agent 2 at a daily dosage of the compounds and compositions to be total daily dose of 400 mg BID. Therapeutic agent 4 at a total administered will be decided by the attending physician daily dose of 25 mg QD, ritonavirata dose of 100 mg QD, and within the scope of Sound medical judgment. an effective amount of ribavirin (for example, 1000 mg or In one embodiment, a method for treating a naive subject 65 1200 mg, or an amount based on the weight of the subject) comprises administering Therapeutic agent 1 at a dose of 150 QD, for 12 weeks. At the end of treatment, the subject has no mg once a day (QD), therapeutic agent 2 at a dose of 400 mg detectable virus. US 8,969,357 B2 87 88 It should be understood that the above-described embodi with ritonavir), a polymerase inhibitor, and ribavirin. The ments and the following examples are given by way of illus treatment was without interferon. tration, not limitation. Various changes and modifications Subjects included 14 treatment naive subjects between the within the scope of the present invention will become appar ages of 18 and 65. One subject discontinued the study at week ent to those skilled in the art from the present description. 1.Therefore, a total of 13 subjects were under study. All of the thirteen subjects completed 12 weeks of therapy with Com EXAMPLE1 pound 1/r dosed in combination with Compound 2 and RBV. Compound 1 (150 mg QD) was dosed with 100 mg QD Use of 2-DAA Combination with Ribavirin (RBV) ritonavir, 400 mg BID Compound 2, and RBV in treatment to Treat Treatment-Naive Subjects Infected with 10 naive subjects infected with GT1 HCV. HCV Genotype 1 Group 3. Peginterferon-ribavirin (P/RBV) non-respond ers were treated with a protease inhibitor (in combination Previously untreated subjects having HCV infection were with ritonavir), a polymerase inhibitor, and ribavirin. The treated with a protease inhibitor (in combination with treatment was without interferon. ritonavir), a polymerase inhibitor, and ribavirin. The treat 15 Subjects included 17 P/RBV non-responders between the ment was without interferon. ages of 18 and 65. Subjects were treated with Compound 1/r Subjects included 11 treatment naive, non-cirrhotic HCV dosed in combination with Compound 2 and RBV for 12 genotype 1-infected subjects between the ages of 18 and 65. weeks. Compound 1 (150 mg QD) was dosed with 100 mg All subjected had IL28B CC genotype. All subjects com QD ritonavir, 400 mg BID Compound 2, and RBV in P/RBV pleted 12 weeks of therapy with Compound 1 and ritonavir non-responders infected with GT1 HCV. During the treat (Compound 1/r) dosed in combination with Compound 3 and ment, four patients had breakthroughs and discontinued the ribavirin (RBV). Compound 1 (150 mg once daily (QID)) was study before week 7. dosed with 100 mg QD ritonavir, 400 mg QD Compound 3. The baseline characteristics of the patients are shown in the and weight-based amounts of RBV (1,000-1,200 mg/day table below. dosed twice daily) in treatment naive subjects infected with 25 genotype (GT) 1 HCV. TABLE 2 HCV RNA levels were measured by TaqManassay. Five of the eleven subjects had hepatitis C ribonucleic acid (HCV Group 1 Group 2 Group 3 RNA)<25 IU/mL (i.e., below the limit of quantification) at 2 Genotype (1a1b) 17.2 11.3 16.1 weeks. Another five subjects had undetectable levels of HCV 30 IL28B: RNA at 2 weeks. At week 3, three of the eleven subjects had CC 10 5 O HCV RNA levels of less than 25 IU/mL, and eight subjects CT 7 7 11 had undetectable levels of HCV RNA. Ten of the eleven TT 2 2 5 subjects had undetectable levels of HCV RNA at 4 weeks, and Undetermined O O 1 one subject had an HCV RNA levelofless than 25 IU/mL. All 35 Median baseline HCV RNA 6.4.4.1-7.2. 6.9 (3.1-7.5 6.9 (6.0-7.8 eleven subjects had undetectable levels of HCV RNA at 5 (log IU/mL) weeks. HCV RNA levels remained undetectable in all sub jects at week 6, 7, 8, 9, 10, 11 and 12. All subjects had Results from Group 1. Ten of the nineteen subjects had undetectable levels of HCV RNA at post-treatment weeks 2 HCV RNA <25 IU/mL at 2 weeks. Another eight had unde and 4. At post-treatment weeks 8 and 12, a single subject had 40 tectable levels of HCV RNA at 2 weeks. At week 3, one detectable HCV RNA (breakthrough), and the remaining 10 Subject discontinued, four of the remaining 18 subjects had subjects did not have any detectable level of HCV RNA. HCV RNA levels of less than 25 IU/mL, and fourteen of the These remaining ten Subjects were further tested at post remaining 18 subjects had undetectable levels of HCV RNA. treatment weeks 16 and 24, and all of them had undetectable At week 4, seventeen of the remaining 18 Subjects had unde levels of HCV RNA at both timepoints. One of the remaining 45 tectable levels of HCV RNA; one subject had HCV RNA-25 ten subjects unexpectedly showed detectable HCV RNA at IU/mL. At week 5, all of the remaining 18 subjects had post-treatment week 36. undetectable levels of HCV RNA. At week 6, seventeen of the remaining 18 subjects had undetectable levels of HCV RNA, EXAMPLE 2 and one subject had HCV RNA <25 IU/mL. At weeks 7,8,9, 50 10, 11 and 12, all of the remaining 18 subjects had undetect A Use of 2-DAA Combination with Ribavirin to able levels of HCV RNA (one subject was not tested at week Treat Treatment-Naive or Non-Responder Subjects 12). At post-treatment weeks 2, 4, 8, and 12 all of the remain Infected with HCV Genotype 1 ing 18 Subjects (including the one who was not tested at week 12 during treatment) had undetectable levels of HCV RNA. Group 1. Previously untreated subjects having HCV infec 55 At post-treatment week 24, seventeen of the remaining 18 tion were treated with a protease inhibitor (in combination subjects were tested, and all of the seventeen subjects tested with ritonavir), a polymerase inhibitor, and ribavirin. The had undetectable levels of HCV RNA. At post-treatment treatment was without interferon. week 24, all of the remaining 18 subjects were tested and Subjects included 19 treatment naive subjects between the found no detectable levels of HCV RNA. ages of 18 and 65. One subject discontinued the study at week 60 Results from Group 2. Of the thirteen subjects tested, six 3. All of the remaining 18 subjects completed 12 weeks of had HCV RNA <25 IU/mL at 2 weeks. Another six subjects therapy with Compound 1/r dosed in combination with Com had undetectable levels of HCV RNA at 2 weeks. At week 3, pound 2 and RBV. Compound 1 (250 mg QD) was dosed with two subjects had HCV RNA levels of less than 25 IU/mL, and 100 mg QDritonavir, 400 mg BID Compound 2, and RBV in ten subjects had undetectable levels of HCV RNA. Eleven of treatment naive subjects infected with GT1 HCV. 65 the thirteen subjects had undetectable levels of HCV RNA at Group 2. Previously untreated subjects having HCV infec 4 weeks and two had HCV RNA <25 IU/mL. At weeks 5, 6, tion were treated with a protease inhibitor (in combination 7, 8, 9 and 10, all thirteen subjects that were tested had US 8,969,357 B2 89 90 undetectable levels of HCV RNA. One subject had detectable to last 12 weeks. The 2-DAA combination included Com levels of HCV RNA at week 11 (the remaining 12 subjects pound 1/r (200/100 mg QD) and Compound 4 (25 mg QD). had undetectable levels of HCV RNA at week 11), but HCV The weight based dosing of ribavirin ranged from 1000 to RNA levels in that subject, as well as all other subjects, were 1200 mg divided twice daily. At weeks 5, 6 and 7 of the undetectable at week 12. At post-treatment weeks 2, 4, 8 and treatment, nine of the ten subjects showed no detectable HCV 12, all thirteen subjects tested (including the one who had RNA; and the remaining one subject had HCV RNA levels of detectable levels of HCV RNA at week 11 during treatment) less than 25 IU/mL. At week 8 of the treatment, five of the had undetectable levels of HCV RNA. At post-treatment nine subjects were tested and showed no detectable HCV weeks 24, twelve of the thirteen subjects were tested and RNA. At weeks 9 and 10 of the treatment, four of the five found no detectable levels of HCV RNA. 10 subjects were further tested and found no detectable HCV Results from Group 3. Seven of the seventeen subjects RNA. At week 11, two of the four subjects were tested and tested had HCV RNA <25 IU/mL at 2 weeks. Another seven found no detectable HCV RNA. subjects had undetectable levels of HCV RNA at 2 weeks. Three subjects had detectable levels of HCV RNA at 2 weeks. Additional testing showed that all of the initial ten subjects At week 3, three subjects had HCV RNA levels of less than 25 15 at weeks 8, 9, 10 and 11 of the treatment had no detectable IU/mL, twelve subjects had undetectable levels of HCV HCV RNA. At week 12, nine of the initial ten subjects showed RNA, and two subjects had detectable levels of HCV RNA. At undetectable HCV RNA, and one had HCV RNA levels of week 4, two subjects had HCV RNA levels of less than 25 less than 25 IU/mL. At post-treatment week 2, all of the ten IU/mL, thirteen subjects had undetectable levels of HCV subjects were tested (including the one with HCV RNA levels RNA, and two subjects had detectable levels of HCV RNA. of less than 25 IU/mL at week 12 of the treatment), and all ten Sixteen subjects were tested at 5 weeks; thirteen subjects had subjects showed no detectable HCV RNA. At post-treatment undetectable levels of HCV RNA and three subjects had weeks 4 and 8, all of the ten subjects were tested and found no detectable levels of HCV RNA. Fifteen subjects were tested detectable HCV RNA. Two of the ten subjects were further at 6 weeks; twelve subjects had undetectable levels of HCV tested at post-treatment week 12 and found no detectable RNA and three subjects had detectable levels of HCV RNA. 25 HCV RNA. All thirteen subjects that were tested at 7 weeks had undetect Genotype 2 able levels of HCV RNA. Twelve of the thirteen subjects that Ten previously untreated subjects infected with HCV were tested at 8 weeks had undetectable levels of HCV RNA; genotype 2 were treated with the same regimen of this one subject had HCV RNA levels of less than 25 IU/mL. All Example. At week 4 of the treatment, all of the ten subjects ten subjects that were tested at 9 weeks had undetectable 30 were tested and showed no detectable HCV RNA. At weeks 5 levels of HCV RNA. Twelve of the thirteen subjects that were and 6 of the treatment, all of the ten subjects were tested and tested at 9 weeks had undetectable levels of HCV RNA; one found no detectable HCV RNA. At weeks 9-11 of the treat subject had detectable levels of HCV RNA. Twelve of the thirteen subjects that were tested at 10 weeks had undetect ment, all of the ten subjects were further tested, and nine of able levels of HCV RNA; one subject had detectable levels of 35 them showed no detectable HCV RNA, and one subject HCV RNA. Eleven of the twelve subjects that were tested at showed HCV RNA levels of less than 25 IU/mL. At week 12 11 weeks had undetectable levels of HCV RNA; one subject of the treatment, nine of the initial ten subjects were tested, had HCV RNA levels of less than 25 IU/mL. Ten of the twelve eight of the nine subjects found no detectable HCV RNA and subjects that were tested at week-12 of the treatment had one showed detectable HCV RNA. undetectable levels of HCV RNA; one subject had HCV RNA 40 The subject showing detectable HCV RNA at week 12 of levels of less than 25 IU/mL, and another subject had detect the treatment was confirmed breakthrough at post-treatment able levels of HCV RNA. The one subject that had HCV RNA week 2. Eight of the initial ten subjects were also tested at levels of less than 25 IU/mL at week-12 of the treatment had post-treatment week 2 and found no detectable HCV RNA; breakthrough at post-treatment week 2. At post-treatment seven of the initial ten subjects were further tested at post weeks 2 and 4, ten subjects that had undetectable HCV RNA 45 treatment week 4 and found no detectable HCV RNA; three at week-12 of the treatment were tested: eight of the ten of the initial ten subjects were further tested at post-treatment subjects had undetectable levels of HCV RNA; and the week 8 and found no detectable HCV RNA; and one of the remaining two subjects had detectable HCV RNA (break initial ten subject was further tested at post-treatment week 12 through). The eight subjects that had undetectable HCV RNA and found no detectable HCV RNA. at post-treatment weeks 2 and 4 were further test at post 50 Genotype 3 treatment weeks 8 and 12 and found no detectable HCV RNA. Similarly, ten previously untreated subjects infected with The seventeen non-responder subjects in Group 3 included HCV genotype 3 were treated with the same regimen of this 6 null responders and 11 partial responders. Three out of the Example. At week 5 of the treatment, two subjects had viral six null responders, and five out of the eleven partial respond rebound; seven of the remaining eight Subjects had no detect ers, achieved SVR12. 55 able HCV RNA; and one of the remaining eight subjects had The study also showed that IL28B host genotype appeared HCV RNA levels of less than 25 IU/mL. At week 12 of the not to have significantly impact on SVR12 in this study (in treatment, and among the eight non-breakthrough subjects, cluding Groups 1, 2 and 3). one subject was lost from the study, another showed detect able HCV RNA, and the remaining six found no detectable EXAMPLE 2B 60 HCV RNA. At post-treatment weeks 2, 4 and 8, two more Subjects had Use of 2-DAA Combination with Ribavirin to Treat Treat breakthrough, and five subjects had no detectable HCV RNA. ment-Naive Subjects Infected with Genotype 1, 2 or 3 One of the two subjects that had viral rebound at week 5 of Genotype 1 the treatment was treated with a combination of peginterferon Ten previously untreated subjects infected with HCV 65 and ribavirin (P/RBV) starting at week 12. After four weeks genotype 1 were treated with a 2-DAA combination with of the P/RBV treatment, the subject was tested and found no ribavirin. The treatment was interferon-free and was designed detectable HCV RNA. US 8,969,357 B2 91 92 EXAMPLE 2C a standard interferon/ribavirin therapy but were not respon sive (interferon null responders). Use of 2-DAA Combination with Ribavirin to Treat At weeks 6, 8, 10 and 12 of the treatment, all ten subjects Treatment-Experienced Subjects Infected with showed no detectable HCV RNA. Genotype 1 At post-treatment weeks 2, 4 and 8, all of the four subjects in the 12-week treatment regimen found no detectable HCV Six treatment-experienced subjects with HCV genotype 1 RNA; and two of the four subjects were further tested at infection were treated with a 2-DAA combination with rib post-treatment week 12 and found no detectable HCV RNA. avirin for 12 weeks. The treatment was interferon-free. The At post-treatment weeks 2, 4 and 8, the one Subject in the 2-DAA combination included Compound 1/r (200/100 mg 10 16-week treatment regimen found no detectable HCV RNA. QD) and Compound 4 (25 mg QD). The weight based dosing One of the five subjects in the 24-week treatment regimen ofribavirin ranged from 1000 to 1200 mg divided twice daily. were tested at post-treatment weeks 2 and 4 and found no These patients had previously undergone a standard inter detectable HCV RNA. feron/ribavirin therapy but were not responsive (interferon null responders). 15 EXAMPLE 3 At week 6 of the treatment, all six subjects showed no detectable HCV RNA. At week 8 of the treatment, all six Synergistic Concentrations of Compound 1 and Subjects were tested and, among them, five showed no detect Compound 2 in Genotype 1b HCV Replicon Assay able HCV RNA and one had HCV RNA levels of less than 25 IU/mL. At weeks 10 and 12 of the treatment, all six subjects Examples 3-5 are for illustration and do not limit the scope were tested and found no detectable HCV RNA. of this disclosure in any way. Not to be bound by any theory, At post-treatment weeks 2 and 4, all six Subjects were the unexpected Synergistic effects from combining different tested, one had breakthrough and the remaining five Subjects classes of HCV inhibitors (e.g., a combination of a protease found no detectable HCV RNA. At post-treatment week 8, the inhibitor (such as Compound 1) and a polymerase inhibitor five non-breakthrough subjects were further tested and found 25 (such as Compound 2), or a combination of a protease inhibi no detectable HCV RNA. tor (such as Compound 1) and a NS5A inhibitor (such as compound 4)) may contribute to the effectiveness of the EXAMPLE 2D short-duration, interferon-free therapies of the present tech nology. Use of 3-DAA Combination with Ribavirin to Treat 30 Materials: Treatment-Naive or Treatment-Experienced Subjects A replicon cell line was derived from the human hepatoma Infected with Genotype 1 cell line Huh?. It was derived from HCV genotype 1b (Con1), and is a bicistronic Subgenomic replicon, essentially similar Treatment-Naive Patients to those described in Science 285(5424): 110-3 (1999). The Six previously untreated subjects having HCV genotype 1 35 first cistron of the construct contains a firefly luciferase infection were treated with a 3-DAA combination with rib reporter and a neomycin phosphotransferase selectable avirin for 8 weeks. The treatment was interferon-free. The marker. Replicon cells were maintained in Dulbecco's Modi 3-DAA combination included Compound 1/r (150/100 mg fied Eagle Media (DMEM) containing 100 IU/ml penicillin, QD), Compound 2 (400 mg BID), and Compound 4 (25 mg 100 mg/ml streptomycin (Invitrogen), 200 mg/ml G418, an QD). The weight based dosing of ribavirin ranged from 1000 40 aminoglycoside antibiotic (Invitrogen) and 10% fetal bovine to 1200 mg divided twice daily. At week 8 of the treatment, all serum (FBS) at 37° C. and 5% CO. six subjects had no detectable HCV RNA. At post-treatment Replicon Cell Culture: weeks 2, 4, 8 and 12, all six subjects had no detectable HCV Replicon cells were seeded at a density of 5000 cells per RNA. well of a 96-well plate in 100 ul DMEM containing 5% FBS. Nine previously untreated subjects having HCV genotype 45 The following day, Compounds 1 and 2 were diluted in dim 1 infection were treated with a 3-DAA combination with ethyl sulfoxide (DMSO) to generate a 200x stock in a series ribavirin for 12 weeks. The treatment was interferon-free. of 6 two-fold dilutions. The dilution series was then further The 3-DAA combination included Compound 1/r (150/100 diluted 100-fold in the medium containing 5% FBS. mg QD or 100/100 mg QD), Compound 2 (400 mg BID), and Combination Studies: Compound 4 (25 mg QD). The weight based dosing of rib 50 Combination studies were performed to evaluate the inter avirin ranged from 1000 to 1200 mg divided twice daily. At action effects of therapeutic agent 1 and therapeutic agent 2 in week 8 of the treatment, all nine subjects had no detectable the replicon assay described above. The purpose of these HCV RNA. At week of the treatment, all nine subjects were studies was to determine whether there are doses or concen tested and found no detectable HCV RNA. At post-treatment trations of each compound where synergy or antagonism is weeks 2, 4, 8 and 12, all of the nine subjects were further 55 demonstrated with the other compound. Three experiments tested and showed no detectable HCV RNA. with three plates in each experiment were performed on three Treatment-Experienced Patients separate days. Six concentrations of Compound 1 alone and Ten treatment-experienced subjects with HCV genotype 1 six concentrations of Compound 2 alone were assayed in each infection were treated with a 3-DAA combination with rib plate. In addition, 36 combinations of concentrations of the avirin: four subjects were treated for 12-week, one subject 60 two compounds were assayed for each plate. The variable was treated for 16-week treatment, and the remaining five analyzed was the fraction of inhibition of the luciferase sig subjects were treated for 24-week treatment. The treatment nal. was interferon-free. The 3-DAA combination included Com The dilutions of each compound were combined with the pound 1/r (150/100 mg QD or 100/100 mg QD), Compound dilutions of the other compound in a checkerboard fashion. 2 (400 mg BID), and Compound 4 (25 mg QD). The weight 65 The concentrations tested were chosen to ensure that the ECso based dosing of ribavirin ranged from 1000 to 1200 mg for each compound alone is in the middle of the serial dilution divided twice daily. These patients had previously undergone range. Medium with inhibitor(s) was added to the cell culture US 8,969,357 B2 93 94 plates already containing 100 ul of DMEM with 5% FBS. The greater than 1%. By doing this, small differences of statistical cells were incubated in a tissue culture incubator at 37°C. and significance caused by very small variance could be excluded. 5% CO for three days. The inhibitor effects of compounds on Combination of Therapeutic Agent 1 and Therapeutic HCV replication were determined by measuring activity of a Agent 2: luciferase reporter gene using a Luciferase Assay System kit 5 The inhibitory effects on replicons produced by each drug (Promega) following the manufacturers instructions. Passive alone or in combination with the other at concentrations up to Lysis buffer (30 ul, Promega) was added to each well, and the ten-fold above the ECs were examined in the genotype 1b plates were incubated for 15 minutes with rocking to lyse the (Con1) replicon using a checkerboard titration pattern (two cells. Luciferin solution (100 ul, Promega) was added to each fold serial dilutions) in a standard three-day antiviral assay. well and the luciferase activity was measured using a Victor II 10 The concentrations tested were chosen to ensure that the ECso luminometer (Perkin-Elmer). To determine the ECso, the values of the compounds were in the middle of the serial luciferase inhibition data were analyzed using GraphPad dilution range. For Compound 1, concentrations ranged from Prism 4 software. Three experiments were performed with 0.031 nM to 1.0 nM. For Compound 2, concentrations ranged three replicates per experiment. The percent inhibition results from 0.125 nM to 4.0 nM. Synergy, additivity, and antago were analyzed for synergy, additivity and antagonism accord 15 nism were evaluated using the Pritchard and Shipman model. ing to the Pritchard and Shipman model (Antiviral Research Results: 14:181-206 (1990)). The results of the assay analysis are illustrated in FIGS. 1 Combination Analysis: and 2 and Table 3. In the 3-D surface plot of FIG.1, deviations Prichard and Shipman proposed a direct approach to solve from expected interactions between Compound 1 and Com this drug-drug interaction problem. The method was able to pound 2 are purely additive at concentrations associated with calculate theoretical additive effects directly from the indi a horizontal plane at 0%. Synergistic interactions between vidual dose-response curves determined in the assay. The Compound 1 and Compound 2 appear as a peak above the calculated theoretical additivity was then compared to the horizontal plane with a height corresponding to the percent experimental dose-response Surface, and Subsequently Sub above calculated additivity. Antagonistic interactions tracted to reveal any areas of aberrant interaction. The follow 25 between Compound 1 and Compound 2 appear as a pit or ing equation was used to calculate the theoretical additive trough below the horizontal plane with a negative value sig effects: nifying the percent below the calculated additivity. Synergis tic interactions appear as dark grey, additive interactions appear white, and antagonistic interactions appear as speck where Z is the total inhibition produced by the combination of 30 led. drugs X and Y, with X and Y representing the inhibition As illustrated in the 3-D surface plot of FIG. 1 and the produced by drugs X and Y alone respectively. contour plot of FIG. 2, an additive or synergistic effect exists A difference between the actual observed fraction of inhi at most of the concentrations for Compound 1 and Compound bition and the predicted value was calculated for each con 2. In particular, there is a concentration region showing Syn centration combination for each plate in each experiment to ergy at most concentrations of Compound 1 and at the lower determine whether the observed combined effect was greater to mid-range dose concentrations of Compound 2. than the theoretical additive effect Z calculated from the Table 3 below lists combinations of concentrations of equation above. For each concentration combination, the rep Compound 1 and Compound 2 with statistically significant licates (across all plates and experiments) were used to cal synergistic or antagonistic effects based on the Prichard and culate a mean difference between observed and predicted 40 Shipman model analysis. For each combination of concen fraction of inhibition, its standard error and its two-sided 95% trations, Table 3 includes the mean difference in the observed confidence interval. and predicted fraction of inhibition, the standard deviation or Synergy or antagonism for a concentration combination error of the mean difference, and the upper and lower limits of was determined based on the following 2 rules: First, the 95% the 95% confidence interval. CI of the mean difference between observed and predicted 45 According to Table 3, all of the combinations of Compound fraction of inhibition at each concentration combination is 1 and Compound 2 listed in the table have statistically sig calculated. If the lower bound of 95% CI is larger than Zero, nificant synergistic effects. then the drug combination would be considered having a The results presented in FIGS. 1 and 2 and Table 3 dem synergistic effect; if the upper bound of 95% CI is less than onstrate that the combination of therapeutic agent 1 and thera Zero, then the drug combination would be considered having 50 peutic agent 2 achieves additivity or synergy at most of the an antagonistic effect; otherwise, no significant antagonism concentration combinations of the two agents. Taken or synergy at this concentration combination. together, these in vitro replicon results suggest that therapeu Second, the synergistic orantagonistic effect must have its tic agent 2 should produce a significant antiviral effect in relative mean difference, the absolute mean difference patients when administered in combination with therapeutic divided by its corresponding observed mean inhibition, agent 1 in patients infected with HCV. TABLE 3

Mean difference in Compound Compound fraction of inhibition: Standard error Lower 95% Upper 95% 2, nM 1, nM Observed - Predicted of mean difference confidence limit confidence limit 12S 12SOO O.O6176 O.O23352 O.OO7912 O.11561 12S 2SOOO O.OS321 O.O22199 O.OO2O24 O.10440 12S SOOOO O.O1176 O.OO268O O.OOSS83 O.O1794 2SO 2SOOOc 0.06626 O.O2O630 O.O18692 O.11384 2SO SOOOO O.O1061 O.OO2677 O.OO4438 O.O1679 SOO O62SO O.O4373 O.O14897 O.O09375 O.O7808 US 8,969,357 B2 95 96 TABLE 3-continued

Mean difference in Compound Compound fraction of inhibition: Standard error Lower 95% Upper 95% 2, nM 1, nM Observed - Predicted of mean difference COinfidence limit confidence limit SOO 12SOO O.10416 0.026757 O.0424.54 O.16586 SOO 2SOOO O.O9327 O.O19859 O.047471 O.13906 SOO SOOOO O.O1422 O.OO3333 O.OO6535 O.O2191 1.OO O62SO O.O6696 O.O2O488 O.O1971S O. 11421 1.OO 12SOO O.14103 O.O21289 O.O91939 O.19013 1.OO 2SOOO O.11027 O.016762 O.O71617 O.14892 1.OO SOOOO O.O1365 O.OO2312 O.OO8315 O.O1898 2.OO O62SO O.OS974 O.007690 O.042004 O.O7747 2.OO 12SOO O.10O32 O.O11820 O.O73066 O.12758 2.OO 2SOOO 0.07117 O.OO9428 O.049428 O.09291 4.OO O312S O.O323S O.OO39SO O.O23236 O.O4145 4.OO O62SO O.OS141 O.0043.13 O.04.1470 O.06136 4.OO 12SOO O.O6572 O.OO4692 O.OS4901 O.O7654 4.OO 2SOOO O.O3452 O.OO4775 O.O23S09 O.O4SS3

EXAMPLE 4 Lysis buffer (30 ul, Promega) was added to each well, and the plates were incubated for 15 minutes with rocking to lyse the Synergistic Concentrations of Compound 1 and cells. Luciferin solution (100 ul, Promega) was added to each Compound 4 in Genotype 1b HCV Replicon Assay well and the luciferase activity was measured using a Victor II luminometer (Perkin-Elmer). To determine the ECso, the Materials: 25 luciferase inhibition data were analyzed using GraphPad The replicon cell line was derived from the human Prism 4 software. Three experiments were performed with hepatoma cell line Huh7. It was derived from HCV genotype three replicates per experiment. The percent inhibition results 1b (Con1), and is a bicistronic Subgenomic replicon, essen were analyzed for synergy, additivity and antagonism accord tially similar to those described in Science 285 (5424): 110-3 ing to the Pritchard and Shipman model (Antiviral Research (1999). The first cistron of the construct contains a firefly 30 14:181-206 (1990)). luciferase reporter and a neomycin phosphotransferase Combination Analysis: selectable marker. Replicon cells were maintained in Dulbec The Prichard and Shipman approach to calculating theo co's Modified Eagle Media (DMEM) containing 100 IU/ml retical additive effects (described in Example 3) was used for penicillin, 100 mg/ml streptomycin (Invitrogen), 200 mg/ml the present example. G418 (Invitrogen) and 10% fetal bovine serum (FBS) at 37° 35 The difference between the actual observed fraction of C. and 5% CO. inhibition and the predicted value was calculated for each Replicon Cell Culture: concentration combination for each plate in each experiment Replicon cells were seeded at a density of 5000 cells per to determine whether the observed combined effect was well of a 96-well plate in 100 ul DMEM containing 5% FBS. greater than the theoretical additive effect Z calculated from The following day, compounds were diluted in dimethyl sul 40 the Prichard and Shipman equation. For each concentration foxide (DMSO) to generate a 200x stock in a series of 6 combination, the replicates (across all plates and experi two-fold dilutions. The dilution series was then further ments) were used to calculate a mean difference between diluted 100-fold in the medium containing 5% FBS. observed and predicted fraction of inhibition, its standard Combination Studies: error and its two-sided 95% confidence interval. Combination studies were performed to evaluate the inter 45 Synergy or antagonism for a concentration combination action effects of therapeutic agent 1 and therapeutic agent 4 in was determined based on the same rules set forth in Example the replicon assay described above. The purpose of these 3. studies was to determine doses or concentrations of each Combination of Therapeutic Agent 1 and Therapeutic compound where synergy or antagonism is demonstrated Agent 4: with the other compound. Three experiments with three 50 The inhibitory effects in replicon produced by each drug plates in each experiment were performed on three separate alone or in combination with the other at concentrations up to days. Six concentrations of Compound 1 alone and six con ten-fold above the ECs were examined in the genotype 1b centrations of Compound 2 alone were assayed in each plate. (Con1) replicon using a checkerboard titration pattern (two In addition, 36 combinations of concentrations of the two fold serial dilutions) in the standard three-day antiviral assay. compounds were assayed for each plate. The variable ana 55 The concentrations tested were chosen to ensure that the ECso lyzed was the fraction of inhibition of the luciferase signal. values of the compounds were in the middle of the serial The dilutions of each compound were combined with the dilution range. For compound 4, concentrations ranged from dilutions of the other compound in a checkerboard fashion. 0.0002 nM to 0.0063 nM, and for Compound 1, concentra The concentrations tested were chosen to ensure that the ECso tions ranged from 0.023 nM to 0.75 nM. Synergy, additivity, for each compound alone is in the middle of the serial dilution 60 and antagonism were evaluated using the Pritchard and Ship range. Medium with inhibitor(s) was added to the cell culture man model. plates already containing 100 ul of DMEM with 5% FBS. The Results: cells were incubated in a tissue culture incubator at 37°C. and The results of the assay analysis are illustrated in FIGS. 3 5% CO for three days. The inhibitor effects of compounds on and 4 and Table 4. In the 3-D surface plot of FIG.3, deviations HCV replication were determined by measuring activity of a 65 from expected interactions between Compound 1 and com luciferase reporter gene using a Luciferase Assay System kit pound 4 are purely additive at concentrations associated with (Promega) following the manufacturers instructions. Passive a horizontal plane at 0%. Synergistic interactions between US 8,969,357 B2 97 98 Compound 1 and compound 4 appear as a peak above the replicon also has a firefly luciferase reporter and a neomycin horizontal plane with a height corresponding to the percent phosphotransferase (Neo) selectable marker. The two coding above calculated additivity. Antagonistic interactions regions, separated by the FMDV 2a protease, comprise the between Compound 1 and compound 4 appear as a pit or first cistron of the bicistronic replicon construct, with the trough below the horizontal plane with a negative value sig second cistron containing the HCVNS3-NS5B coding region nifying the percent below the calculated additivity. Synergis with addition of adaptive mutations E1202G, K1691R, tic interactions appear as shades of dark grey, additive inter K2040R and S2204I. This HCV replicon cell line was main actions appear white, and antagonistic interactions appear as tained in Dulbecco's modified Eagles medium (DMEM; speckled. Invitrogen) containing 10% (v/v) fetal bovine serum, 100 As illustrated in the 3-D surface plot of FIG. 3 and the 10 IU/ml penicillin, 100 ug/ml streptomycin, and 200 g/ml contour plot of FIG. 4, an additive or synergistic effect exists G418 (all from Invitrogen). 1a-H77 replicon cells (105-106) at most of the concentrations for Compound 1 and compound were plated in 150 mm cell culture plates and grown in the 4. In particular, there is a concentration region showing Syn presence of G418 (400 g/ml) and Compound 1, Compound ergy at the lower dose concentrations of compound 4 and 2, and/or compound 4 at concentrations that were either mid-range dose concentrations of Compound 1. 15 10-fold (10x) or 100-fold (100x) above the EC50 value for Table 4 below lists combinations of concentrations of the HCV genotype 1a replicon cell line. The EC50 values for Compound 1 and compound 4 with statistically significant Compound 1, Compound 2, and compound 4 used for this synergistic or antagonistic effects based on the Prichard and experiment were 0.9, 7.7, and 0.01 nM, respectively. After Shipman Model analysis. For each combination of concen three weeks of treatment, the majority of replicon cells were trations, Table 4 includes the mean difference in the observed cleared of replicon RNA and, therefore, were unable to sur and predicted fraction of inhibition, the standard deviation or vive in the G418-containing medium since the replicon RNA error of the mean difference, and the upper and lower limits of included the neo marker conferring G418 resistance. The the 95% confidence interval. cells containing resistant replicon variants Survived and According to Table 4, most of the combinations of Com formed colonies, and these colonies were stained with 1% pound 1 and compound 4 listed in the table have statistically 25 crystal violet in 10% Protocol SafeFix II reagent (Fisher significant synergistic effects. A Small amount of antagonism Scientific), and counted. As shown in FIG. 5A, the combina was observed at the lowest concentrations of Compound 1. tion of compound 4 plus either Compound 1 or Compound 2 The results presented in FIGS. 3 and 4 and Table 4 dem at either 10-fold or 100-fold above their respective EC50 onstrate that the combination of therapeutic agent 4 and thera value resulted in significantly fewer colonies than either peutic agent 1 achieves additivity at most of the concentration 30 Compound 1, Compound 2, or compound 4 alone at 10-fold combinations of the two agents and achieves synergy at cer or 100-fold above their respective EC50 value. tain concentration combinations, in particular, at low concen FIG. 5B illustrates the percentage of colonies surviving trations of therapeutic agent 4 and mid-range concentrations two vs. three DAA combinations. In colony Survival assays, of therapeutic agent 1. Taken together, these in vitro replicon 1a-H77 replicon cells were grown in the presence of a DAA results suggest that therapeutic agent 4 should produce a 35 combination and G418 for approximately three weeks, after significant antiviral effect in patients when administered in which time the cells containing resistant replicon Variants had combination with therapeutic agent 1 in patients infected with formed colonies. The cells were stained with crystal violet HCV. and counted. “Triple Combination' is either a combination of TABLE 4

Mean difference in Compound Compound fraction of inhibition: Standard error Lower 95% Upper 95% 4, nM 1, nM Observed - Predicted of mean difference confidence limit confidence limit O.OOO197 0.375OOO O.O9895 0.033975 O.O2O60 0.17729 O.OOO394 O.187SOO O.16900 O.O38934 O.07922 O.25878 O.OOO394 0.375OOO O.11401 0.027710 O.OSO11 0.17791 O.OOO788 O.187SOO O.15349 O.O38860 O.O6388 O.24310 O.OOO788 0.375OOO O.O9992 O.O27266 O.O3704 O.16279 O.OO1575 O.O23438 -O.O8326 O.027126 -O-14582 -O.O2O71 O.OO1575 O.O46875 -0.11894 O.O26099 -0.17913 -O.OS876 O.OO1575 O.187SOO O.O7958 O.O2O080 O.O3328 O.12588 O.OO31SO O.O23438 -0.10156 O.O184O6 -0.14401 -0.05912 O.OO31SO O.O46875 -O.O8091 O.O14615 -0.11462 -O.04721

EXAMPLE 5 55 Compounds 1, 2 and 4 at concentrations of 5-fold (5x) over their respective EC50 values, or a combination of Com Reduction of HCV-Infected Cells with Combinations pounds 1, 2 and 4 at concentrations of 10-fold (10x) over their of Therapeutic Agents 1, 2 and 4 respective EC50 values. FIGS. SC and 5D show the effect of a combination of In order to quantify the frequency of resistant replicon 60 Compounds 1 and 4 in long-term HCV RNA reduction assays colonies selected by therapeutic agent 1, therapeutic agent 2, in genotype 1 replicon cell lines. In long-term replicon RNA therapeutic agent 4, or various combinations of these agents, reduction assays, 106 replicon cells were plated in the the stable subgenomic replicon cell line derived from HCV absence of G418. The inhibitors at concentrations of either genotype 1a (H77; Genbank accession number AF011751) 10-fold (10x) or 100-fold (100x) over their respective ECso was utilized. The replicon construct was bicistronic and the 65 values were added, and the cells were grown to approximately cell line was generated by introducing the constructs into cell 95% confluence (4 days). At each passage, 106 cells were lines derived from the human hepatoma cell line Huh-7. The removed and frozen, and an additional 106 cells were passed US 8,969,357 B2 99 100 into another flask with fresh media and inhibitors. RNA was included single and double mutants. Specifically, the model extracted from 106 cells and HCV RNA was measured in a included 2 single mutants and one double mutant for each of Real-Time RT-PCR assay. FIGS.5C and 5D show that in both the 2-DAA combination regimens. Thus, a 2-DAA combina 1a and 1b replicon cells, the combination of Compounds 1 tion regimen (e.g., a combination of a protease inhibitor and and 4, each at 10-fold over ECs is more effective at clearing a NS5A inhibitor) included 2 single mutants and one double cells of replicon than 100-fold over ECs of either inhibitor mutant. A 3-DAA combination (e.g., a combination of a pro alone. tease inhibitor, a polymerase inhibitor and a NS5A inhibitor, Predominant resistant variants selected by Compound 1, 2, Such as a combination of a protease inhibitor, a non-nucleo or 4 in genotype 1 replicons were also determined. For Com side polymerase inhibitor (NNPI) and a NS5A inhibitor) pound 1, the predominant resistance variants in 1a-H77 rep 10 included 3 single and 2 double mutants. licons include R155K, D168A and D168V with fold resis The model has 3 components: hepatocytes (uninfected or tance of 26, 48 and 128, respectively; and the predominant target cell), infected cell and viral dynamics. The differential resistance variants in 1b-Con1 replicons include R155K, equations describing the dynamics of the 3 components areas A156T and D168V with fold resistance of 48, 9 and 190, follows: respectively. For Compound 2, the predominant resistance 15 (1) Hepatocytes (Uninfected or Target Cell) Dynamics variants in 1a-H77 replicons include C316Y.M414T, Y448C and S556G with fold resistance of 1600, 36, 980 and 15, respectively; and the predominant resistance variants in 1b-Con1 replicons include C316Y. M414T and D559G with (2) Infected Cell Dynamics fold resistance of 1400, 26 and 100, respectively. For Com (a) Infected with Wild type Virus pound 4, the predominant resistance variants in 1a-H77 rep d IWT/dt=(1-m)*B*T*VLWT-8*IWT licons include M28T, M28V. Q30R, Y93C and Y93H with (b) Infected with Polymerase Mutant Virus fold resistance of 9000, 60, 800, 1700 and 41000, respec tively; and the predominant resistance variants in 1b-Con1 d IPoly/dt=(1-m)*B*T*VLPoly-8*IPoly replicons include Y93H with fold resistance of 55. These 25 (c) Infected with Protease Mutant Virus experiments also showed that in genotype 1a, a number of variants selected by Compounds 2 or 4 conferred higher d IProt/dt=(1-m)*B*T*VLProt-8*IProt levels of resistance than those selected by Compound 1, and (d) Infected with NS5A Mutant Virus that in genotype 1b, one variant (C316Y) selected by Com pound 2 conferred a higher level of resistance than those 30 d INS5A/dt=(1-m)*B*T*VLNSSA-8*INS5A selected by either Compound 1 or Compound 4. (e) Infected with Protease-NS5A Double Mutant Virus The above examples show that the combination of two different classes of DAAS (e.g., a combination of a HCV protease inhibitor and a HCV polymerase inhibitor, or a com bination of a HCV protease inhibitor and a HCV NSSA 35 (f) Infected with Protease-Polymerase Double Mutant inhibitor, or a combination of a HCV polymerase inhibitor Virus and a HCV NSSA inhibitor) can lead to an improved resis tance barrier in patients relative to a single DAA alone, while the combination of three different classes of DAAS (e.g., a (3) Viral Dynamics combination of a HCV protease inhibitor, a HCV polymerase 40 (a) Wild Type Virus inhibitor, and a HCV NS5A inhibitor) can lead to even more significant barrier to resistance. Improvement in the barrier to resistance achieved through co-administration of multiple DAAs of different classes or with different mechanism of (b) Polymerase Mutant Virus action is expected to correlate with enhanced efficacy in 45 patients. EXAMPLE 6 (c) Protease Mutant Virus Clinical Modeling for Interferon-Free DAA 50 Combination Therapies This example describes a novel clinical model for evaluat ing optimal doses and durations of interferon-free HCV (d) NS5A Mutant Virus therapies using combinations of different DAAs. This model 55 reasonably predicted the effectiveness of numerous DAA combinations in interferon-free, short-duration therapies. A mechanistic model was used to model the relationship between DAA exposures and antiviral efficacy in HCV-in (e) NS5A and Protease Double Mutant Virus fected subjects. This model was used to conduct clinical trial 60 simulations of clinical outcomes following administration of various DAA combination regimens (e.g., specific DAA combinations and different doses of DAAS) and durations of (f) Poly and Protease Mutant Double Mutant Virus therapy. Numerous DAAs have been extensively documented to 65 select mutants following short duration of monotherapy (e.g., less than 1 week). The viral dynamic model of this Example US 8,969,357 B2 101 102 The parameters used in the above equations are described The lowest available limit of detection (LOD) of viral load in Table 5. assays is 10 IU/mL. Assuming 3 virion particles per IU, this constitutes about 0.5 million viruses in the body at LOD. TABLE 5 Hence, subjects have to be treated for significant period of 5 time after their viral load falls below the LOD to achieve cure. Viral Dynamic Parameters This duration depends on the potency of the compounds and Parameter Description the individual response to therapy. S Zero-order production of hepatocytes In order to predict the duration required for cure, a “thresh T number of Target or uninfected hepatocytes old concept was used. For simulations, an HCV-infected de first-order rate constant for the death of hepatocytes 10 subject was assumed to achieve SVR when viral load reaches B rate-constant for the infection of hepatocytes by virus 8 first-order rate constant for the death of infected less than 1 virion in the total plasma and extracellular fluid hepatocytes volume (about 15000 mL), i.e., viral load measurement of <1 n ractional reduction of the rate-constant for the infec copy/15000 mL or <0.33 IU/15000 mL. This translates to ion of hepatocytes by virus l probability of the formation of single mutants and 15 about 5 log IU/mL. CfSnoeck E et al., CLIN PHARMACOL THER. mutation back to Wild-Type 87(6):706-13 (2010), wherein based on data from patients op probability of the formation of double mutants and treated with peg-IFN and ribavirin, subjects were estimated to mutation back to single mutant o production rate of the Wild-Type virus achieve SVR when the predicted number of infected cells fell C clearance rate of the virus below 1. While such low viral loads cannot be measured Eff1, Eff2, inhibition of production of Wild Type, polymerase, experimentally, they can be simulated using the viral dynamic Eff3, Eff4 protease, and NS5A mutant, respectively model. Effs, Effs inhibition of production of polymerase-protease and NS5A-protease double mutant, respectively The model can be used to predict SVR for any combination Fit1, Fit?, fitness of polymerase, protease and NS5A mutant of DAAs, with or without interferon, and with or without Fit relative to wild type virus, respectively ribavirin. Fit-4, Fit5 fitness of polymerase-protease and NS5A-protease 25 double mutant relative to wild type virus, As non-limiting examples, various interferon-free treat respectively ment regimens using different combinations of Compound 1. IWT, IPoly, number of cells infected with wild type, polymerase, Compound 2 and/or Compound 4, with or without ribavirin, Iprot, INS5A protease and NS5A mutants, respectively IPoly-Prot, number of cells infected with polymerase-protease and were evaluated using the model of this Example. The follow INSSA-Prot NS5A-protease double mutant, respectively ing approach was used to include mutants in the model: VLWT, VLPoly, viral load for wild type virus, polymerase, protease 30 a. One single mutant per DAA VLProt, VLNS5A and NS5A mutant virus, respectively VLPoly-Prot, viral load for polymerase-protease and NS5A-protease b. One double mutant per DAA combination WLNSSA-Prot double mutant, respectively For a combination of two DAAs, e.g., a combination of Compound 1 and Compound 2, the model included one mutant resistant to Compound 1, one mutant resistant to As shown in the differential equations for viral dynamics, 35 the effect of DAA is included as an inhibition of viral load Compound 2, and one double mutant resistant to both Com production. For example, the effect of DAA(s) on production pound 1 and Compound 2. Compound 1 is coadministered or of wild type virus is given as (1-Effl)*p where Effl is the co-formulated with ritonavir (or another pharmacokinetics fraction of viral production that is inhibited. In the absence of enhancer) to improve its drug exposure. drug Effl =0 and in the presence of drug Effl takes a value 40 A double mutant to Compound 2 and Compound 4 was not between 0 and 1. Effl is described using an Emax model: included in the modeling. In the 3-DAA regimens, a Com pound 2/Compound 4 double mutant is likely wild type for Compound 1 due to the high potency and resistant profile of where Emax represents maximum inhibition, Conc is the Compound 1. Hence, the Compound 2/Compound 4 double plasma DAA concentration and ECso is the concentration that 45 mutant is not expected to affect clinical outcomes for treat inhibits viral load production by 50%. As the fold-change in ments containing Compound 1. ECso for the mutants compared to wild type virus was based Single mutants included in the model were based on on values obtained from in vitro replicon Studies, ECso was mutants observed for the individual DAAs in the Phase 1b and estimated only for wild type virus. 2a studies (e.g., clinical studies M10-351, M12-116, and For DAA combinations, the effect was assumed to be mul 50 M11-602). For double mutants with resistance to 2 DAA tiplicative and incorporated as follows: classes, the sensitivity (ECs) of double mutants to drug was (1-Effl)=(1-Eff)*(1-Eff)*(1-Eff) assumed to be a combination of the 2 single mutants. Thus, The effect of ribavirin (RBV) was added on infection rate for Compound 1 and Compound 2, the single mutants were (3 as an Emax model. In presence of ribavirin, the infection D168V and M414T, respectively, and the double mutant was 55 D168V-M414T. In this scenario, the D168V mutant would be rate decreases by a factor (1-1)) where less sensitive to Compound 1 but would be as sensitive to n-Concrypt (ECso Revi-Conerve) Compound 2 as wildtype virus. Similarly, the M414T mutant The model does not include a double mutant to the poly would be less sensitive to Compound 2 but would be as merase--NS5A inhibitors. In a 3-DAA regimens, a poly sensitive to Compound 1 as wild type virus. The double merase--NS5A double mutant is often wild type for the pro 60 mutant D168V-M414T would be less sensitive to both Com tease inhibitor. Hence, this double mutant is not expected to pound 1 and Compound 2. significantly affect clinical outcomes for a 3-DAA regimen The fold change in ECso for the mutants compared to wild simulation. On the other hand, the model can be readily type virus was based on values obtained from in vitro replicon adapted to simulate a 2-DAA regimen containing a poly studies. Since monotherapy data for Compound 4 indicated a merase inhibitor and a NS5A inhibitor by treating the poly 65 variety of mutants with different ECsos, a value of 1000x fold merase inhibitor (e.g., PSI-7977) as a protease inhibitor in the change in ECso was used for Compound 4 for modeling and model. simulations. US 8,969,357 B2 103 104 Baseline prevalence of the mutants was estimated during Addition of the 3" DAA was predicted to shorten treatment model fitting, while the mutation rate was based on the litera duration by 2 to 4 weeks as optimal durations for the 3-DAA ture values. Both baseline prevalence and mutation rate deter combination of Compound 1, Compound 2 and Compound 4 mined mutant fitness. were predicted to be 8-10 weeks. Pharmacokinetic data and viral load data from 140 treat FIGS. 6A, 6B and 6C illustrate the predictions for DAA ment-naive HCV-infected subjects were used to construct the combinations without ribavirin. The model also predicts model. For modeling, number of target cells at baseline, num similar or comparable SVR percentages for these DAA com ber of infected cells at baseline, death rate of target cells and binations when used with ribavirin. In addition, the effect of mutation rates were based on literature values. See, e.g., interferon (e.g., pegylated interferon) can also be added by Snoecket al. Supra; Rong et al. SCITRANSL MED. 2(30):30ra32 10 incorporating interferon similar to a DAA but without any (2000); Neal and Pravin, ACOP 2009 (http://2009.go resistant mutants. acop.org/sites/all/assets/webform/Lauren-Neal ACoP One of the advantages that the model provides is that it 2009.pdf): Neumann et al. SCIENCE 282(5386):103-7 (1998); allows examination of various viral parameters and its effect Shudo et al. ANTIVIRTHER. 13(7):919-26 (2008); and Dahariet on dose, duration and SVR. For example while experimen al. JTHEORBIOL. 247(2):371-81 (2007). The production rate of 15 tally determining the effect of mutants parameters is very virus and infection rate of virus were derived from other difficult if not impossible, they can be examined using the parameters in the model. All other parameters were esti model. Thus SVR in patient population that have different mated. Exposure-antiviral response modeling was performed mutants can be predicted with the model. using NONMEM 7.2. The model was used to simulate the treatment described in Clinical trial simulations were performed using Trial Example 1 which included 150/100 mg Compound Simulator version 2.2.1. Fifty subjects and 50 replicates were 1/ritonavir QD-400 mg Compound 3 QD--weight-based simulated for each treatment. A subject drop out rate from the amounts of RBV BID for 12 weeks, and the percentage of study due to any reason was assumed to be 8% over 24 weeks subjects with HCV RNA less than LOD at 2, 4, 8, 10, and 12 based on available literature on trials in subjects with HCV. weeks was summarized in FIG. 7. The mean predicted versus All simulations were conducted assuming 100% compliance. observed percentage of subjects with below LOD (“%LOD) Covariates included in the simulations were genotype 1a/1b 25 at respective weeks are shown FIG. 7.95% confidence inter status. Clinical outcomes simulated included: (1) percentage vals for the predicted data (the vertical bar at the top of each of subjects below limit of detection (LOD) of 10 IU/mL and respective predicted LOD percentage column) were also indi (2) percentage of Subjects achieving SVR. cated. As shown in FIG. 7, the model reasonably predicted the Clinical trial simulations were conducted to determine clinical outcome of 96 LOD. optimal dose and duration for SVR. Over 80 scenarios were 30 The model was also used to simulate the treatment simulated to predict the percentage of subjects with SVR described in Example 2A. The mean predicted versus following administration of various 2- and 3-DAA combina observed percentage SVR (“% SVR') after 12-week treat tions (e.g., Compound 1+Compound 2, or Compound ment are shown FIG. 8. 95% confidence intervals for the 1+Compound 4, or Compound 1+Compound 2+Compound predicted data (the vertical bar at the top of each respective 4), without RBV. at a range of doses for each DAA (e.g., 35 predicted SVR percentage column) were also indicated. As Compound 1/ritonavir at 250/100, 150/100 or 100/100 mg shown in FIG. 8, the predicted SVR percentages aligned well QD, Compound 4 at 5, 25 or 100 mg QD, and Compound 2 at with the observed SVR percentages. Simulations also predict 400 or 800 mg BID) and across a range of treatment durations that the same treatment regimen as described in Example 2A (e.g., 2. 4, 6, 8, 10, 12, 16, and 24 weeks). but without ribavirin has similar or comparable LOD percent Optimal dose and duration were predicted based on per 40 ages for different treatment durations. centage of subjects with viral load of less than -5 log IU/mL The exposure response viral dynamic model of this threshold for SVR. Selected and relevant results of simulation Example provided a quantitative method to reasonably pre for the 2- and 3-DAA combinations of Compounds 1,2 and/or dict SVR for various combination of antiviral compounds. 4 are shown in FIGS. 6A, 6B and 6C for two different doses Based on the exposure-antiviral response modeling and clini of Compound 1. FIG. 6A shows the predicted median SVR cal trial simulations, it demonstrated that (1) addition of a 3" percentage (“/6 SVR) and 90% confidence interval (the ver 45 DAA to a 2-DAA combination can reduce optimal duration of tical bar at the top of each SVR percentage column) for treatment and/or increase SVR; (2) 8-12 weeks of dosing is different treatment durations using a combination of Com the optimal duration of therapy for 2 and 3 DAA combina pound 1 and Compound 2: FIG. 6B shows the predicted tions of Compound 1/r, Compound 2 and Compound 4; and median and 90% confidence interval for different treatment (3) durations shorter than 8 weeks of interferon-free treat durations using a combination of Compound 1 and Com 50 ment have been predicted to cure a significant percent of the pound 4; and FIG. 6C shows the predicted median and 90% Subjects. confidence interval for different treatment durations using a combination of Compound 1, Compound 2 and Compound 4. EXAMPLE 7 In each simulation, RBV was included, and Compound 1 was used with 100 mg ritonavir, and the subjects are HCV geno type 1, treatment-naïve patients. SVR24 is lower than SVR12 55 Clinical Modeling for Interferon-Free DAA in some cases due to drop out; longer durations are not nec Combination Therapies Containing BMS-790052 essarily predicted to improve SVR but could result in more and BMS-650032 dropouts resulting in lower SVR. The model predicted that with 8-12 weeks of dosing at least The model described above was also used to predict the 80 to 90% subjects can achieve SVR with 2 and 3 DAA 60 SVR percentage of interferon-free treatment regimens con combinations. The model also predicted that durations taining BMS-790052 and BMS-650032 without ribavirin, shorter than 8 weeks can cure a significant number of Sub based on existing published clinical data including two Phase jects. A 2-DAA regimen was predicted to cure over 40% of 1 and one Phase 2 study of BMS-790052 and one Phase 1 and the Subjects and a 3-DAA regimen was predicted to cure one Phase 2a study of BMS-650032. FIG. 9 shows the pre about 60% of the subjects with only 6 weeks of dosing. 65 dicted median SVR percentage and 90% SVR confidence Dosing for durations of over 12 weeks was not expected to interval for different treatment durations of a 2-DAA regimen increase the percentage of subjects with SVR significantly. containing BMS-790052 (60 mg QD) and BMS-650032 (600 US 8,969,357 B2 105 106 BID) in genotype 1 naive subjects. The combination of BMS EXAMPLE 9 790052 (60 mg QD) plus BMS-650032 (600 mg BID) in genotype 1 subjects was predicted to achieve improved SVR Clinical Modeling for Interferon-Free DAA for durations of 12 weeks or greater with predicted SVR rates Combination Therapies Containing Danoprevir and of about 70% for 10 weeks of dosing. Similar regimens but 5 Mercitabine containing ribavirin, or regimens with similar dosings of BMS-790052 and BMS-650032 with or withoutribavirin, are In addition, data from one Phase 1 and one Phase 2 study of expected to achieve similar SVR rates. Danoprevir and Mercitabine were used for estimating the pharmacokinetic and viral dynamic model parameters. EXAMPLE 8 10 Ritonavir was co-administered with danoprevir to improve Clinical Modeling for Interferon-Free Therapies the pharmacokinetics of Danoprevir. Predictions for a 2-DAA Containing PSI-7977 combination with Danoprevir and Mercitabine in genotype 1 naive patients are shown in FIG. 14. The model predicts that Likewise, a 3-DAA regimen without interferon and ribavi 15 following 16 weeks of dosing with the combination of Dano rin was modeled for genotype 1 patients based on existing previr and Mercitabine without ribavirin, at least 90% of clinical data. The 3-DAA regimen contains 200/100 mg QD HCV patients can achieve SVR. Similar or better SVR rates Compound 1/r 50 mg QD Compound 4, and 400 mg QD are predicted if ribavirin is included in the regimens PSI-7977. FIG. 10 depicts the predicted median SVR rates for different treatment durations of this 3-DAA combination. EXAMPLE 10 This 3-DAA combination was predicted to have over 60% SVR in 6 weeks and over 80% SVR at duration of 8-week, Clinical Modeling for Interferon-Free DAA 10-week, 12-week or longer treatment. Similar regimens but Combination Therapies Containing Tegobuvir containing ribavirin, or regimens with similar dosings of (GS-9190), GS-9451 and GS-5885 Compound 1/r, Compound 4 and PSI-7977 with or without 25 ribavirin, are expected to achieve similar SVR rates. Data from Phase 1 and Phase 2 studies of GS-9190 (te The model can also be used to predict SVR for regimens gobuvir), GS-9451 and GS-5885 were used forestimating the containing single DAA or single DAA with ribavirin. For pharmacokinetic and viral dynamic model parameters. Pre example, the model predictions for PSI-7977+ribavirin for dictions for the combination with GS-9190 (tegobuvir), various durations for treating HCV genotype 1 treatment 30 GS-9451 and GS-5885 in genotype 1 naive patients are shown naive patients were obtained. FIG. 11 depicts the predicted in FIG. 15. The model predicts that following 12 weeks of median and 90% confidence interval of SVR percentage for dosing with the combination of GS-9190 (tegobuvir)+GS different treatment durations of Such a regimen containing 9451+GS-5885+RBV, about 70% of genotype 1 naive PSI-7977 (as the sole DAA; 400 mg QD) and ribavirin (600 patients can achieve SVR and following 24 weeks of treat mg BID). The 90% confidence interval for the predicted SVR 35 ment 80% of genotype 1 naive patients can achieve SVR. (the vertical bar at the top of each respective predicted SVR Similar or better SVR rates are expected when ribavirin is percentage column) is also indicated in FIG. 11. The predic included in the regimen. tion was based on the already published clinical data for PSI-7977. SVR rate for PSI-7977+ribavirin was predicted to EXAMPLE 11 be around 75-90% following 12 weeks of dosing, and about 40 55-75% following 8 weeks dosing, in genotype 1 subjects. Clinical Modeling for Interferon-free DAA Similar SVR percentages for genotype 1 treatment-naïve Combination Therapies Containing PSI-7977 patients are expected for similar regimens containing similar (GS-7977) PSI-7977 QD dosing (e.g., 200-600 mg QD) and weight based amounts of ribavirin (e.g., 1000 to 1200 mg divided 45 Data from Phase 1 and Phase 2 studies of GS-9451 and twice daily). GS-7977 (PSI-7977) were used forestimating the pharmaco Data from two Phase 1 and one Phase 2 study of Daclatas kinetic and viral dynamic model parameters. Predictions for vir (BMS-790052) and one Phase 1 and one Phase 2 study of the combination with GS-9451 and GS-7977 (PSI-7977) in PSI-7977 were used for estimating the pharmacokinetic and genotype 1 naive patients are shown in FIG. 16. viral dynamic model parameters. Predictions for a 2-DAA 50 Data from Phase 1 and Phase 2 studies of GS-5885 and combination with Daclatasvir (BMS-790052) and PSI-7977 GS-7977 (PSI-7977) were used forestimating the pharmaco in genotype 1 naive patients are shown in FIG. 12. The model kinetic and viral dynamic model parameters. Predictions for predicted that following 10-12 weeks of dosing with the the combination with GS-5885 and GS-7977 (PSI-7977) in combination of Daclatasvir and PSI-7977 without ribavirin, genotype 1 naive patients are shown in FIG. 16. at least 90% of HCV genotype 1 naive patients can achieve 55 Data from Phase 1 and Phase 2 studies of GS-9451, SVR. Similar or better SVR rates are predicted if ribavirin is GS-5885 and GS-7977 (PSI-7977) were used for estimating included in the regimens. the pharmacokinetic and viral dynamic model parameters. Similarly, data from one Phase 1a study of TMC-435 and Predictions for the combination with GS-9451, GS-5885 and one Phase 1 and one Phase 2 study of PSI-7977 were used for GS-7977 (PSI-7977) in genotype 1 naive patients are shown estimating the pharmacokinetic and viral dynamic model 60 in FIG. 16. parameters. Predictions for a 2-DAA combination with the The model predicts that following 12 weeks of dosing with TMC-435 and PSI-7977 in genotype 1 naive patients are the combination of GS-9451 and GS-7977 (PSI-7977), or the shown in FIG. 13. The model predicts that following 10-12 combination of GS-5885 and GS-7977 (PSI-7977), or the weeks of dosing with the combination of TMC-435 and PSI combination of GS-9451, GS-5885 and GS-7977 (PSI-7977), 7977 without ribavirin, at least 90% of HCV patients can 65 at least 90% of genotype 1 naive patients can achieve SVR. achieve SVR. Similar or better SVR rates are predicted if Similar or better SVR rates are expected when ribavirin is ribavirin is included in the regimens. included in these regimens. US 8,969,357 B2 107 108 The foregoing description of the present invention pro- Compound 4 vides illustration and description, but is not intended to be exhaustive or to limit the invention to the precise one dis closed. Modifications and variations are possible in light of the above teachings or may be acquired from practice of the 5 invention. Thus, it is noted that the scope of the invention is defined by the claims and their equivalents. What is claimed is: H 1. A method of treatment for HCV, comprising administer- -O H N N ing at least two direct acting antiviral agents (DAAS) and 10 y-N ribavirin to a patient infected with HCV genotype 1, wherein O Y-Q O said treatment lasts for 8 or 12 weeks and does not include O administration of interferon to said patient, wherein said at -\ least two DAAS comprise Compound 1 15

2O -

and PSI-7977, and wherein Compound 1 is administered with ritonavir. 2. The method of claim 1, wherein said patient is a treat 30 ment-naïve patient.