WO2017062840A1 - Combination therapy for the treatment of hepatitis c virus - Google Patents

Abstract

The present invention provides a combination therapy for treating hepatitis C virus infection in a subject that includes the HCV NS3/4A protease inhibitor faldaprevir, an NS5A polymerase inhibitor, and optionally ribavirin. The combination may additionally include a non-nucleoside NS5B polymerase inhibitor (e.g., VX-222, also known as lomibuvir) and/or an inosine monophosphate dehydrogenase (IMPDH) inhibitor (e.g., VX-497, also known as merimepodib).

Description

COMBINATION THERAPY FOR THE TREATMENT OF HEPATITIS C VIRUS

CLAIM OF PRIORITY

[001] This application claims the benefit of U.S. Provisional Application number 62/239,689, filed October 9, 2015; and U.S. Provisional Application number 62/349,574, filed June 13, 2016. The entire contents of the foregoing are hereby incorporated by reference.

FIELD OF THE INVENTION

[002] The present invention relates to the treatment of hepatitis C virus

(HCV) infection. In particular, the invention provides therapeutic combinations that include hepatitis C protease inhibitor faldaprevir and a non-nucleoside NS5A polymerase inhibitor, and optionally include ribavirin, lomibuvir, and/or merimepodib. The present invention also relates to methods of using such therapeutic combinations for treating HCV infection or alleviating one or more symptoms thereof in a patient. The present invention also provides kits that include the therapeutic combinations of the invention.

BACKGROUND

[003] Chronic hepatitis C infection (CHC) is a global health problem with approximately 150 million individuals infected worldwide (approximately 3 percent of the worldwide population). In the United States over 3 million people are estimated to be infected with HCV with 70% infected with genotype 1, 16% with genotype 2, 12% genotype 3, 1% genotype 4, < 1% genotype 5, and 1% genotype 6. Globally, genotype 1 remains the most prevalent (46%), followed by genotype 3 (22%), genotype 2 (13%) and genotype 4 (13%). HCV genotype 4 is the most common variant of HCV in the Middle East and Africa, particularly Egypt. This region has the highest prevalence of HCV worldwide, with more than 90% of infections due to genotype 4. An estimated 8 to 10 million people are infected with HCV in Egypt, nearly all of whom are infected with genotype 4 HCV.

[004] Consequences of CHC infection include cirrhosis, hepatic

decompensation, liver transplantation, and hepatocellular carcinoma. CHC infection is the primary cause of death from liver disease and the leading indication for liver transplantation in the United States. With the slow progression and asymptomatic nature of early infection, it is estimated that HCV infection-related complications and mortality (e.g., death from liver failure or hepatocellular carcinoma) are expected to increase over the next two decades without intervention. However, treatment with the direct acting antivirals (DAAs) and a sustained virologic response has been shown to reduce the risk of all-cause mortality in patients with chronic hepatitis C.

[005] Combination therapies of HCV have been attempted in which DAAs target specific steps within the HCV life cycle. There are currently four classes of DAAs: protease inhibitors (Pis) that target nonstructural proteins 3/4A (NS3/4A); NS5B nucleoside polymerase inhibitors (NPIs); NS5B non-nucleoside polymerase inhibitors (NNPIs); and NS5A inhibitors. Recently, the nonstructural protein NS5B inhibitor sofosbuvir (Sovaldi®) was approved for the treatment of genotypes 1 through 4 HCV infection. For example, 12 weeks of sofosbuvir in a fixed-dose combination with the NS5A inhibitor, ledipasvir (Harvoni®), and 12 or 24 weeks of the triple fixed dose combination tablet (ombitasvir [NS5A inhibitor], paritaprevir [NS3/4A protease inhibitor], and ritonavir [cytochrome P450(CYP)3A inhibitor]) in combination with dasabuvir [non-nucleoside NS5B polymerase inhibitor] (Viekira Pak) were approved for the treatment of chronic genotype 1 HCV infection.

[006] An effective therapy for HCV must contend with the treatment of several different HCV genotypes. Of the six known major genotypes, all cause both acute and chronic hepatitis. In addition to the major genotypes, various subtypes of each major group are also known. Currently, HCV drug development has

predominantly focused on treatment of genotypes 1, 2, and 3, which as indicated above are the most common genotypes in Europe and North America.

[007] In addition to those used in the treatment regiments previously mentioned, numerous other DAAs have been or are being developed for treatment of HCV. In one example, faldaprevir (formerly BI-201335), a first-generation HCV NS3 / 4A protease inhibitor, has been shown to increase treatment success in HCV- infected patients. See Kanda et al., "Faldaprevir for the Treatment of Hepatitis C," International Journal of Molecular Science 2015, Vol. 16, pgs. 4985-4996. In particular, faldaprevir in combination with pegylated interferon and ribavirin, provided sustained virological response rates for patients with HCV genotype 1 (GT- 1) infection. In addition, the interferon-free combination of faldaprevir and deleobuvir (a non-nucleoside HCV NS5B polymerase inhibitor) with ribavirin was effective in the treatment of HCV GT-lb infections. Efficacy of this combination, however, fell below 50% for GT-la patients and for dual regimens that did not include ribavirin.

[008] In another example, multivalent NS5A inhibitors were described in U.S.

Patent Application Publication No. 20130115194. The heterodimeric structures so described permit an asymmetric binding mode to NS5A relative to structurally symmetric inhibitors. These compounds fall within the following generic structure:

where Am and R¹ through R¹⁰ are further described therein.

[009] Although effective in the treatment of HCV, the use of DAAs are linked to increased toxicity of treatment and the emergence of resistance. In addition, the use of combinations of direct acting agents can also result in drug-drug interactions. Neither of these deficiencies of HCV therapy can be predicted beforehand for any particular combination treatment regime. Furthermore, the efficacy of any combination for the treatment of a particular HCV genotype is also unpredictable. For example, although several oral combination regimens have demonstrated good efficacy in patients with genotype 4 HCV infection, the only approved regimen in the US for the treatment of genotype 4 HCV infection is pegylated

interferon+ribavirin+sofosbuvir.

[0010] As indicated above, there is a need for new combination therapies for the treatment of HCV, particularly those that obviate the use of interferon and are orally administered; that overcome drug-drug interactions to maintain drug efficacy whilst reducing side effects; have a reduced emergence of resistance; and have reduced treatment periods and/or and enhanced cure rates. SUMMARY OF THE INVENTION

[0011] the present invention, the antiviral activity of faldaprevir ' combination with an NS5A inhibitor described in U.S. Patent Application Publication No. 20130115194, or a combination of both of these inhibitors and ribavirin, has been found to improve cure rates and/or reduce treatment times for appropriate patients in the absence of pegylated interferon, particularly those patients infected with HCV genotype-4.

[0012] Accordingly, in a first aspect, the invention features a method for the treatment of hepatitis C virus (HCV) in a subject infected with HCV that includes administering to the subject an effective amount of Compound 1 (faldaprevir) having the structure:

(Compound 1),

or a pharmaceutically acceptable salt thereof, and an effective amount of TD-6450 (Compound 2) having the structure:

(Compound 2), or a pharmaceutically acceptable salt thereof. [0013] In some embodiments, the effective amount of compound 1 is from about 20 mg to about 250 mg, from about 25 mg to about 225 mg, from about 30 mg to about 220 mg, from about 35 mg to about 210 mg, from about 40 mg to about 200 mg, from about 45 mg to about 195 mg, from about 50 mg to about 190 mg, from about 55 mg to about 185 mg, from about 60 mg to about 180 mg, from about 60 mg to about 160 mg, from about 60 mg to about 150 mg, from about 60 mg to about 145 mg, from about 60 mg to about 140 mg, from about 60 mg to about 120 mg, from about 60 mg to about 100 mg, or from about 60 mg to about 80 mg. In some embodiments, Compound 1 is administered once daily. In some embodiments, Compound 1 is administered twice daily (e.g., in equal amounts).

[0014] In some embodiments, the effective amount of compound 1 is from 60 mg to 180 mg. For example, the effective amount of Compound 1 is 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, or 180 mg. In a further embodiment, the effective amount of Compound 1 is 120 mg. In some embodiments, the daily dose of

Compound 1 is 50-200 mg, 50-150 mg, 50-140 mg, or 50-130 mg. In yet further embodiment, Compound 1 is administered once per day. In yet further embodiment, the compound is administered twice a day (e.g., in equal amounts).

[0015] In some embodiments, the effective amount of compound 1 is from about 20 mg/day to about 250 mg/day, from about 25 mg/day to about 225 mg/day, from about 30 mg/day to about 220 mg/day, from about 35 mg/day to about 210 mg/day, from about 40 mg/day to about 200 mg/day, from about 45 mg/day to about 195 mg/day, from about 50 mg/day to about 190 mg/day, from about 55 mg/day to about 185 mg/day, from about 60 mg/day to about 180 mg/day, from about 60 mg/day to about 160 mg/day, from about 60 mg/day to about 150 mg/day, from about 60 mg/day to about 145 mg/day, from about 60 mg/day to about 140 mg/day, from about 60 mg/day to about 120 mg/day, from about 60 mg/day to about 100 mg/day, or from about 60 mg/day to about 80 mg/day. In some aspects of these embodiments, the compound 1 is administered to the subject once daily.

[0016] In one embodiment, the effective amount of compound 1 is from 60 mg/day to 180 mg/day. For example, the effective amount of Compound 1 is 60 mg/day, 80 mg/day, 100 mg/day, 120 mg/day, 140 mg/day, 160 mg/day, or 180 mg/day. In a further embodiment, the effective amount of Compound 1 is 120 mg/day. In some embodiments, the daily dose of Compound 1 is 20-250 mg/day, 25-225 mg/day, 30-220 mg/day, 40-200 mg/day, 50-200 mg/day, 50-150 mg/day, 50-140 mg/day, or 50-130 mg/day. In another further embodiment, Compound 1 is administered once per day.

[0017] In another embodiment, the effective amount of Compound 2 is from about 20 mg to about 500 mg, from about 25 mg to about 450 mg, from about 30 mg to about 425 mg, from about 35 mg to about 400 mg, from about 40 mg to about 350 mg, from about 45 mg to about 325 mg, from about 50 mg to about 300 mg, from about 55 mg to about 260 mg, from about 60 mg to about 240 mg, from about 60 mg to about 225 mg, from about 60 mg to about 200 mg, from about 60 mg to about 180 mg, from about 60 mg to about 160 mg, from about 60 mg to about 140 mg, from about 60 mg to about 120 mg, from about 60 mg to about 100 mg, or from about 60 mg to about 80 mg. In some embodiments, Compound 2 is administered once daily. In some embodiments, Compound 2 is administered twice daily (e.g., in equal amounts) .

[0018] In another embodiment, the effective amount of Compound 2 is from

60 mg to 240 mg. For example, the effective amount of Compound 2 is 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, or 240 mg. In some embodiments, the daily dose of Compound 2 is 25-500 mg, 40-400 mg, 50-200 mg, 50-150 mg, 50-140 mg, or 50-130 mg. In a further embodiment, effective amount of Compound 2 is 120 mg. In another further embodiment, effective amount of Compound 2 is 60 mg. In yet another further embodiment, Compound 2 is administered once per day. In yet another further embodiment, Compound 2 is administered twice per day (e.g., in equal amounts).

[0019] In another embodiment, the effective amount of Compound 2 is from about 20 mg/day to about 500 mg/day, from about 25 mg/day to about 450 mg/day, from about 30 mg/day to about 425 mg/day, from about 35 mg/day to about 400 mg/day, from about 40 mg/day to about 350 mg/day, from about 45 mg/day to about 325 mg/day, from about 50 mg/day to about 300 mg/day, from about 55 mg/day to about 260 mg/day, from about 60 mg/day to about 240 mg/day, from about 60 mg/day to about 225 mg/day, from about 60 mg/day to about 200 mg/day, from about 60 mg/day to about 180 mg/day, from about 60 mg/day to about 160 mg/day, from about 60 mg/day to about 140 mg/day, from about 60 mg/day to about 120 mg/day, from about 60 mg/day to about 100 mg/day, or from about 60 mg/day to about 80 mg/day. For example, the effective amount of Compound 2 is 60 mg/day, 80 mg/day, 100 mg/day, 120 mg/day, 140 mg/day, 160 mg/day, 180 mg/day, 200 mg/day, 220 mg/day, or 240 mg/day. In some embodiments, the daily dose of Compound 2 is about 25-500 mg/day, about 40-400 mg/day, about 50-200 mg/day, about 50-150 mg/day, about 50-140 mg/day, or about 50-130/mg day. In a further embodiment, effective amount of Compound 2 is about 120 mg/day. In another further embodiment, effective amount of Compound 2 is about 60 mg/day. In yet another further embodiment, Compound 2 is administered once per day.

[0020] In another embodiment, an effective amount of ribavirin is

administered to the subject in addition to the administration of Compound 1 and Compound 2. In a further embodiment, the amount of ribavirin is from about 200 mg to about 4000 mg, from about 400 mg to about 3500 mg, from about 450 mg to about 3000 mg, from about 500 mg to about 2500 mg, from about 700 mg to about 2000 mg, from about 800 mg to about 1500 mg, or from about 1000 mg to about 1200 mg. In a further embodiment, the amount of ribavirin is from about 1000 mg to about 1200 mg. For example, the amount of ribavirin administered to the subject may be about 500 mg, about 700 mg, about 800 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, or about 1500 mg. In a further embodiment, the amount of ribavirin is from about 200 mg/day to about 4000 mg/day, from about 400 mg/day to about 3500 mg/day, from about 450 mg/day to about 3000 mg/day, from about 500 mg/day to about 2500 mg/day, from about 700 mg/day to about 2000 mg/day, from about 800 mg/day to about 1500 mg/day, or from about 1000 mg/day to about 1200 mg/day. In a further embodiment, the amount of ribavirin is from about 1000 mg/day to about 1200 mg/day. For example, the amount of ribavirin administered to the subject may be about 500 mg/day, about 700 mg/day, about 800 mg/day, about 1000 mg/day, about 1100 mg/day, about 1200 mg/day, about 1300 mg/day, or about 1500 mg/day. For example, the amount of ribavirin administered to subjects weighing less than 75 kg is 1000 mg and the amount of ribavirin administered to subjects weighing greater or equal to 75 kg is 1200 mg. In some embodiments, ribavirin is administered once per day. In another further embodiment, ribavirin is administered twice per day in equal amounts. [0021] In another embodiment, an effective amount of an NS5B polymerase inhibitor is administered to the subject in addition to the administration of

Compound 1 and Compound 2. In a further embodiment, the NS5B polymerase inhibitor is VX-222. In another further embodiment, the effective amount of VX-222 is about 800 mg or less. For example, the effective amount of VX-222 is about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg, about 400-800 mg, about 400-700 mg, or about 400-600 mg. In another further embodiment, the effective amount of VX-222 is about 800 mg/day or less. For example, the effective amount of VX-222 is about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, or about 800 mg/day, about 400-800 mg/day, about 400-700 mg/day, or about 400-600 mg/day. In some embodiments, VX-222 is administered once per day. In yet another further embodiment, VX-222 is administered twice per day in equal amounts.

[0022] In another embodiment, an effective amount of an IMPDH inhibitor is administered to the subject in addition to the administration of Compound 1 and Compound 2. In a further embodiment, the IMPDH inhibitor is VX-497. In another further embodiment, the effective amount of VX-497 is about 100 mg or less. For example, the effective amount of VX-222 is about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg, about 50-100 mg, about 50-90 mg, about 50-80 mg or about 60-90 mg. In another further embodiment, the effective amount of VX-497 is about 100 mg/day or less. For example, the effective amount of VX-222 is about 50 mg/day, about 60 mg/day, about 70 mg/day, about 80 mg/day, about 90 mg/day, or about 100 mg/day, about 50-100 mg/day, about 50-90 mg/day, about 50-80 mg/day or about 60-90 mg/day. In some embodiments, VX-497 is administered once per day. In yet another further embodiment, VX-497 is administered twice per day in equal amounts.

[0023] In another embodiment, multiple doses of Compound 1 and multiple doses of Compound 2, with or without ribavirin, VX-222, or VX-497, are

administered to the subject over a combination treatment period of 24 weeks or less. For example, the combination treatment period is 8 weeks, 12 weeks, or 24 weeks. In a further embodiment, the combination treatment period is 12 weeks.

[0024] In one embodiment, the hepatitis C virus is genotype 4. [0025] In another embodiment, the hepatitis C virus is genotype 1. For example, the hepatitis C virus is genotype lb or genotype la.

[0026] In yet another embodiment, the subject is a non-responder, a partial responder, a relapse responder, or a null responder to a direct acting agent against

HCV, such as an inhibitor of HCV NS3/4A protease or an inhibitor of HCV NS5B polymerase.

[0027] In another embodiment, the method of treatment does not include interferon or pegylated interferon.

[0028] In another aspect, the invention features a pharmaceutical composition that includes Compound 1 and Compound 2.

[0029] In one embodiment, the pharmaceutical composition includes 120 mg of Compound 1 and 120 mg of Compound 2.

[0030] In another embodiment, the pharmaceutical composition includes 120 mg of Compound 1 and 60 mg of Compound 2.

[0031] In yet another embodiment, the pharmaceutical composition further includes ribavirin. In one example, the composition includes from 1000 mg to 1200 mg of ribavirin.

[0032] In another aspect, the invention features a package that includes one or more pharmaceutically acceptable dosage forms containing Compound 1, or a pharmaceutically acceptable salt thereof, and one or more dosage forms of

Compound 2, or a pharmaceutically acceptable salt thereof, and instructions directing the administration of the dosage forms for the treatment of HCV infection in a patient.

[0033] In one embodiment, the dosage form of Compound 1 is 120 mg.

[0034] In another embodiment, the dosage form of Compound 2 is from 60 mg to 240 mg. For example, the dosage form of Compound 2 is 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, or 240 mg. In a further embodiment, the dosage form of Compound 2 is 60 mg. In yet another further embodiment, the dosage form of Compound 2 is 120 mg.

[0035] In another embodiment, the package also includes ribavirin. In a further embodiment, the dosage form of ribavirin is 1000 mg or 1200 mg divided into two separate and equal dosages. [0036] In another embodiment, the package also includes VX-222. In a further embodiment, the dosage form of VX-222 is 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg, with each amount divided into two separate and equal dosages.

[0037] In another embodiment, the package also includes VX-497. In a further embodiment, the dosage form of VX-497 is 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg, with each amount divided into two separate and equal dosages.

DETAILED DESCRIPTION

[0038] The present invention provides a combination therapy for the treatment for hepatitis C virus (HCV) infection in a subject that includes the hepatitis C protease inhibitor faldaprevir (Compound 1) and the non-nucleoside NS5A polymerase inhibitor TD-6450 (Compound 2).

[0039] The invention further provides methods of treating HCV infection in a subject in need thereof by administering, separately or together, faldaprevir and TD- 6450. The treatment may additionally include ribavirin, and/or a non-nucleoside NS5B polymerase inhibitor (e.g., VX-222), and/or an inosine monophosphate dehydrogenase (IMPDH) inhibitor (e.g., VX-497).

[0040] The above combination therapies can be used at any point during treatment, but can also be effective as a first line therapy, that is, for treating HCV- infected individuals who have not previously undergone antiviral therapy.

[0041] The above combination therapy of faldaprevir and TD-6450 can be administered together, for example as in a mixture in a pharmaceutical composition, or separately (e.g., simultaneously or sequentially, e.g., in separate dose forms). The pharmaceutical composition can include, in addition to the pharmaceutical agents, at least one pharmaceutically acceptable carrier.

[0042] The term "faldaprevir" (Compound 1, abbreviated as "FDV") is meant to include the free base form, pharmaceutically acceptable salt forms, solvates of either the free base or salt forms, hydrates of either the free base or salt forms, crystalline forms (including microcrystalline and nanocrystalline forms) of either the free base or salt forms, amorphous forms of either the free base or salt forms, and isotopically enriched or labeled forms of the compound N- [(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4i?)-4-({8-bromo-2-[2- (isobutyrylamino)-l,3-thiazol-4-yl]-7-methoxy-4-quinolinyl}oxy)-N-[(li?,25)-l- carboxy-2-vinylcyclopropyl]-L-prolinamide, having the following structure:

See U.S. Patent Nos. 7,585,845, 7,939,667, 8,067,438, 8,232,293, 8,362,035,

8,530,497, & 9,034,831; U.S. Patent Application Nos. 2014037719 & 2015038532; and International Patent Application Publication No. WO2014/151575. CAS Registry number of faldaprevir is 801283-95-4.

[0043] The term "TD-6450" (Compound 2) is meant to include the free base form, pharmaceutically acceptable salt forms, solvates of either the free base or salt forms, hydrates of either the free base or salt forms, crystalline forms (including microcrystalline and nanocrystalline forms), amorphous forms, and isotopically enriched or labeled forms of the compound methyl [(5)-2-((25,45)-2-{4-(5'-chloro- 4'-({6-[(i?)-4-(2,2-dimethylproprionyl)-2-methyl-piperazinyl-l-yl]-pyridine-3- carbonyl}-amino)-2'-(trifluoromethoxy-biphenyl-4-yl]-l /-imidazol-2-yl)-4-methyl- pyrrolidin-l-yl)-2-oxo-l-(tetrahydropyran-4-yl)-ethyl]-carbamic acid methyl ester, havin the following structure:

See International Patent Application Publication No. WO 2013/067267. CAS Registry number of TD-6450 is 1433284-89-9.

[0044] The term "ribavirin" is meant to include the free base form, pharmaceutically acceptable salt forms, solvates of either the free base or salt forms, hydrates of either the free base or salt forms, crystalline forms (including microcrystalline and nanocrystalline forms) of either the free base or salt forms, amorphous forms of either the free base or salt forms, and isotopically enriched or labeled forms of the compound l-[(2i?,3i?,4S,5i?)-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl]-l//-l,2,4-triazole-3-carboxamide, having the following structure:

Ribavirin is commercially available as while opaque gelatin capsules and is known by the trade name REBETOL®. CAS Registry number of ribavirin is 36791-04-5.

[0045] The term "VX-222" is meant to include the free base form,

pharmaceutically acceptable salt forms, solvates of either the free base or salt forms, hydrates of either the free base or salt forms, crystalline forms (including microcrystalline and nanocrystalline forms) of either the free base or salt forms, amorphous forms of either the free base or salt forms, and isotopically enriched or labeled forms of the compound 5-(3,3-dimethyl-l-butyn-l-yl)-3-[(cis-4- hydroxycyclohexyl) [(trans-4-methylcyclohexyl)carbonyl] amino] -2 - thiophenecarboxylic acid, having the following structure:

VX-222 is also called lomibuvir and is described in U.S. Patent No. 8,269,014. CAS Registry number of VX-222 is 1026785-55-6. [0046] The term "VX-497" is meant to include the free base form,

pharmaceutically acceptable salt forms, solvates of either the free base or salt forms, hydrates of either the free base or salt forms, crystalline forms (including microcrystalline and nanocrystalline forms) of either the free base or salt forms, amorphous forms of either the free base or salt forms, and isotopically enriched or labeled forms of the compound (S)-tetrahydrofuran-3-yl-3-(3-(3-methoxy-4- (oxazol-5-yl)phenyl)ureido)benzyl carbamate, having the following structure:

VX-497 is also called merimepodib and is described in U.S. Patent No. 5,807,876. CAS Registry number of VX-497 is 198821-22-6.

[0047] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The present invention also includes compositions comprising pharmaceutically acceptable salts of the compounds described herein. As used herein,

"pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of compounds used in compositions of the present invention include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. In some embodiments, acids commonly employed to form

pharmaceutically acceptable salts of the compounds disclosed herein include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4- dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate,

dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene -1 -sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid. In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds disclosed herein include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri- alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Cl-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl) amine or tri-(2-hydroxyethyl)amine; N-methyl-D- glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like. The pharmaceutically acceptable salts of compounds used in compositions of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington: The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press, 2012. Pharmaceutically acceptable solvates are also described therein.

Advantages of the combination therapy of the present invention

[0048] There are several enzymes and transporters that are particularly important in the metabolism of many drug substances, including faldaprevir and TD- 6450. The most important enzymes and transporters are Cytochrome P450 3A4 (CYP3A4) and P -glycoprotein (Pgp), respectively. Pgp acts as a transporter that pumps drugs from intestinal epithelium back into the intestinal lumen, or from liver cells back into bile ducts. Accordingly a first drug (Drug 1) that is affected by Pgp (a substrate of Pgp) may have lower drug concentration levels and reduced efficacy. If a second drug (Drug 2) is given with Drug 1 and Drug 2 inhibits Pgp, this inhibition may result in higher concentration levels of Drug 1 with a concomitant greater chance of toxicity. Alternatively, if Drug 2 induces Pgp, the increased level of transport may result in lower concentration levels of Drug 1 with a concomitant risk of decreased efficacy. In another example of drug metabolism, CYP3A4 is an enzyme that oxidizes drugs so that they can be degraded and eliminated from the body, and is found mostly in the liver and intestine. A first drug that is a substrate of CYP3A4 may have its concentration levels decreased by a second drug that induces CYP3A4 (risk of decreased efficacy) or have its levels increased by a second drug that inhibits CYP3A4 (increased risk of toxicity).

[0049] In addition to PgP and CYP3A4, there are many other enzymes and transporters that can affect drug levels. When two or more drugs with well- characterized efficacy and toxicity are combined and the drugs have minimal or well-understood effects on metabolic enzymes and transporter proteins, the dose of the drugs can often be selected without the need to devise and test multiple doses. Both faldaprevir and TD-6450, however, have complex interactions with transporter proteins and enzymes. Faldaprevir, for example, is primarily metabolized by CYP3A4 and is also an inhibitor and inactivator of CYP3A4. Faldaprevir is also a substrate of Pgp and other transporter proteins and also may inhibit Pgp. TD-6450 exhibits a concentration-dependent induction of CYP3A4, could be a substrate of Pgp, and is an inhibitor of Pgp. As a result, a significant risk could be foreseen because these drugs may interact with each other in a way that would affect the efficacy and toxicity of both.

[0050] Given the potential for a significant interaction between the faldaprevir and TD-6450, a clinical pharmacology computer-modeling program was designed to assess the effect each drug would have on the other and the resulting change in drug concentration levels. The modeling results were inconclusive and only suggested that co-administration of faldaprevir and TD-6450 would increase the drug levels of TD-6450 by two-fold to four-fold yet only modestly increase intracellular faldaprevir levels. In view of the potential four-fold increase in TD- 6450 levels upon co -administration with faldaprevir and because of the complexities of the potential interactions between these two drugs, the combination therapy of the present invention advantageously provides optimal amounts of faldaprevir and TD-6450 for administration such that patients would not be harmed by TD-6450 levels that were too low (inadequate efficacy) or too high (risk of toxicity) .

Methods of Treatment

[0051] The present invention relates to methods for treating an HCV infection in a person that include administering to the person, separately or together, therapeutically effective amounts of faldaprevir (Compound 1) and TD-6450 (Compound 2).

[0052] According to further embodiments of the invention, there are provided methods for treating an HCV infection in a person that include

administering to the person, separately or together, therapeutically effective amounts of faldaprevir (Compound 1), TD-6450 (Compound 2), and ribavirin.

[0053] According to further embodiments of the invention, there are provided methods for treating an HCV infection in a person that include

administering to the person, separately or together, therapeutically effective amounts of faldaprevir (Compound 1), TD-6450 (Compound 2), and lomibuvir (VX- 222). Lomibuvir, a thiophene-2-carboxylic acid derivative, is an orally administered selective nonnucleoside inhibitor of the hepatitis C virus (HCV) NS5B RNA- dependent RNA polymerase. In phase 1 and 2 clinical studies, VX-222 demonstrated effective antiviral efficacy, with substantial reductions in plasma HCV RNA in patients chronically infected with genotype 1 HCV.

[0054] According to further embodiments of the invention, there are provided methods for treating an HCV infection in a person that include

administering to the person, separately or together, therapeutically effective amounts of faldaprevir (Compound 1), TD-6450 (Compound 2), and merimepodib (VX-497). Merimepodib is an orally administered inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C when combined with pegylated interferon-alfa 2 a and ribavirin.

[0055] According to further embodiments of the invention, there are provided methods for treating an HCV infection in a person that include

administering to the person, separately or together, therapeutically effective amounts of faldaprevir (Compound 1), TD-6450 (Compound 2), ribavirin and lomibuvir (VX-222).

[0056] According to further embodiments of the invention, there are provided methods for treating an HCV infection in a person that include

administering to the person, separately or together, therapeutically effective amounts of faldaprevir (Compound 1), TD-6450 (Compound 2), ribavirin and merimepodib (VX-497).

[0057] According to further embodiments of the invention, there are provided methods for treating an HCV infection in a person that include

administering to the person, separately or together, therapeutically effective amounts of faldaprevir (Compound 1), TD-6450 (Compound 2), lomibuvir (VX-222) and merimepodib (VX-497).

[0058] According to further embodiments of the invention, there are provided methods for treating an HCV infection in a person that include

administering to the person, separately or together, therapeutically effective amounts of faldaprevir (Compound 1), TD-6450 (Compound 2), ribavirin, lomibuvir (VX-222) and merimepodib (VX-497).

[0059] The compositions according to the invention are administered in a solid dosage form. According to an embodiment, the solid dosage form is administered orally. According to another embodiment, the methods according to the invention are carried out according to a dosage regimen wherein a solid dosage form of faldaprevir and TD-6450, separately or together, is administered no more than once per day.

[0060] According to an embodiment of methods of the invention, the compositions according to the invention are administered as a first line therapy for treatment of HCV, i.e., the method comprises treating an HCV infection in a person who has not previously received antiviral therapy. In one example, the

compositions according to the invention are administered as a first line therapy for treatment of HCV genotype 4.

[0061] As used herein, the term "person" or "patient" or "subject" used interchangeably, refers to a human, or to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates.

[0062] In some embodiments, the target patient population is subjects infected with HCV genotype 1, la, lb, 2, 3, 4, 5 or 6. In some embodiments, the target patient population is subjects infected with HCV genotype 1. In some embodiments, the target patient population is subjects infected with HCV genotype lb. In some embodiments, the target patient population is subjects infected with HCV genotype 4. In some embodiments, the target patient population is treatment-naive noncirrhotic subjects infected with HCV genotype 4. In some embodiments, the target patient population is treatment-naive noncirrhotic subjects infected with HCV genotype 1. In some embodiments, the target patient population is treatment-naive noncirrhotic subjects infected with HCV genotype lb.

[0063] As used herein, the phrase "therapeutically effective amount" refers to the amount of a pharmaceutical composition of the invention, or of an individual compound in a pharmaceutical composition of the invention, that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (i) inhibiting HCV in a person who is experiencing or displaying the pathology or symptomotology related to HCV infection (i.e., arresting further development of the pathology and/or

symptomotology) such as stabilizing viral load; (ii) ameliorating the disease; for example, ameliorating an HCV-related disease, condition or disorder in a person who is experiencing or displaying the pathology or symptomotology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomotology) such as lowering viral load in the case of a viral infection; (iii) preventing HCV infection or a disease associated with HCV infection; for example, treatment with compositions of the invention may be carried out to substantially reduce the risk of HCV infection following an actual or potential exposure to HCV (e.g., a needle-stick injury involving blood or body fluids from an individual known to be infected with HCV) when the patient does not yet experience or display the pathology or symptomotology of HCV infection or of a HCV-related disease; and (iv) preventing mother-to-child transmission of HCV during pregnancy, labor and delivery or cesarean section procedure.

[0064] In some embodiments, the treatment is associated with less nausea than conventional HCV therapy. In some embodiments, the treatment is associated with only mild and infrequent adverse events (e.g., adverse events such as diarrhea and/ or vomiting).

Pharmaceutical Formulations and Dosage Forms

[0065] The combinations of compounds in the pharmaceutical compositions of the invention may conveniently be presented for use in the form of a

pharmaceutical formulation and thus pharmaceutical formulations comprising a combination of compounds as defined above together with a pharmaceutically acceptable carrier therefore comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical

formulations. These pharmaceutical compositions can be prepared in a manner well known in the pharmaceutical art.

[0066] In making the compositions of the invention, the active ingredients are typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.

When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, capsules, powders, suspensions, emulsions, solutions, or soft and hard gelatin capsules.

[0067] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The

compositions of the invention can be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

[0068] In preparing a formulation, the active compounds can be milled, separately or together, to provide the appropriate particle size prior to combining with the other ingredients. If an active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. Substantially insoluble compounds can also be dispersed in a spray-dried dispersion. If an active compound is substantially water-soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

[0069] In some embodiments, the compositions can be formulated in a unit dosage form, each dosage containing from about 25 mg to about 600 mg of each of the active ingredients. For compositions containing faldaprevir, TD-6450, and/or ribavirin, a unit dosage may contain, for example, from about 60 mg to about 180 mg of faldaprevir; about 60 mg to about 240 mg of TD-6450; and/or from about 500 mg to about 600 mg of ribavirin. For compositions containing faldaprevir, TD-6450, and lomibuvir, a unit dosage may contain, for example, from about 60 mg to about 180 mg of faldaprevir; about 60 mg to about 240 mg of TD-6450; and from about 100 mg to about 400 mg of lomibuvir. For compositions containing faldaprevir, TD-6450, and merimepodib, a unit dosage may contain, for example, from about 60 mg to about 180 mg of faldaprevir; about 60 mg to about 240 mg of TD-6450; and/or from about 25 mg to about 100 mg of merimepodib.

[0070] In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) from about 60 mg to about 240 mg of faldaprevir and from about 30 mg to about 240 mg of TD-6450. In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) from about 60 mg to about 120 mg of faldaprevir and from about 60 mg to about 120 mg of TD -6450. In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) about 120 mg of faldaprevir and from about 60 mg to about 120 mg of TD-6450. In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) about 60 mg of faldaprevir and from about 60 mg to about 120 mg of TD-6450. In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) about 120 mg of faldaprevir and about 60 mg of TD-6450. In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) about 120 mg of faldaprevir and about 120 mg of TD-6450. In some aspects of any of these embodiments, each of the active agents is administered to the subject in a separate dosage form (e.g., any of the dosage forms described herein), either simultaneously or consecutively.

[0071] In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) from about 60 mg to about 240 mg of faldaprevir; from about 30 mg to about 240 mg of TD-6450; and from about 1000 mg (e.g., when subject weighs less than about 75 kg) to about 1200 mg (e.g., when subject weighs more than 75 kg) of ribavirin. In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) from about 60 mg to about 120 mg of faldaprevir; from about 60 mg to about 120 mg of TD-6450; and from about 1000 mg (e.g., when subject weighs less than about 75 kg) to about 1200 mg (e.g., when subject weighs more than 75 kg) of ribavirin. In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) about 120 mg of faldaprevir; from about 60 mg to about 120 mg of TD-6450; and from about 1000 mg (e.g., when subject weighs less than about 75 kg) to about 1200 mg (e.g., when subject weighs more than 75 kg) of ribavirin. In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) about 60 mg of faldaprevir; from about 60 mg to about 120 mg of TD-6450; and from about 1000 mg (e.g., when subject weighs less than about 75 kg) to about 1200 mg (e.g., when subject weighs more than 75 kg) of ribavirin. In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) about 120 mg of faldaprevir; about 60 mg of TD- 6450; and from about 1000 mg (e.g., when subject weighs less than about 75 kg) to about 1200 mg (e.g., when subject weighs more than 75 kg) of ribavirin. In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) about 120 mg of faldaprevir; about 60 mg of TD-6450; and about 1000 mg of ribavirin (e.g., when subject weighs less than about 75 kg). In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) about 120 mg of faldaprevir; about 60 mg of TD-6450; and about 1200 mg of ribavirin (e.g., when subject weighs more than 75 kg). In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) about 120 mg of faldaprevir; about 120 mg of TD- 6450; and from about 1000 mg (e.g., when subject weighs less than about 75 kg) to about 1200 mg (e.g., when subject weighs more than 75 kg) of ribavirin. In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) about 120 mg of faldaprevir; about 120 mg of TD-6450; and about 1000 mg of ribavirin (e.g., when subject weighs less than about 75 kg). In some embodiments, the combination therapy of the present invention comprises administering to the subject (e.g., in need of treatment) about 120 mg of faldaprevir; about 120 mg of TD-6450; and about 1200 mg of ribavirin (e.g., when subject weighs more than 75 kg). In some aspects of any of these embodiments, each of the active agents is administered to the subject in a separate dosage form (e.g., any of the dosage forms described herein), either simultaneously or consecutively. In some aspects of any of these embodiments, faldaprevir and TD-6450 are each administered to the subject once daily and ribavirin is administered to the subject twice daily (e.g., in equal amounts of 500 mg or 600 mg depending on the weight of the subject as described herein).

[0072] The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active materials calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The compositions according to the invention can be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the composition actually administered and the therapeutic regimen of administration will usually be determined by a physician according to relevant circumstances.

[0073] For preparing solid compositions such as tablets, the principal active ingredients may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compounds in the composition. When referring to these preformulation compositions as homogeneous, the active ingredients are typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 25 to about 600 mg of the active ingredients of the composition.

[0074] The tablets or pills containing a composition of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0075] The liquid forms in which the compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0076] The amount of the composition that is administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of

administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a HCV infection in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. In prophylactic applications, compositions can be administered to a patient who has been exposed or potentially exposed to HCV, wherein HCV infection is likely to occur absent effective intervention. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.

[0077] The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the composition preparations typically will be between 3 and 11, or from 5 to 9, or from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

Kits

[0078] The present invention also includes pharmaceutical kits (also referred to as packages) useful, for example, in the treatment or prevention of HCV infection, which include one or more containers containing the pharmaceutical agents of the compositions of the invention, either together or separate and optionally in combination with at least one pharmaceutically acceptable carrier, and together comprising a therapeutically effective amount of a composition of the invention. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.

[0079] The target patient population for the following examples is treatment- naive noncirrhotic subjects infected with HCV genotype 4. EXAMPLES

Example 1. Treatment of a patient with a faldaprevir/TD-6450 combination

[0080] After a patient is determined to be infected with HCV genotype 4, where HCV RNA was measured to be greater than or equal to 10,000 IU/mL, the patient is orally administered 120 mg of faldaprevir once per day (QD) and orally administered 60 or 120 mg of TD-6450 QD. The once per day administrations are continued for a period of 12 weeks. HCV RNA is measured during the treatment and for up to 12 weeks after the end of treatment to determine viral load. In addition, viral sequencing samples are obtained to monitor for viral resistance mutations.

Example 2. Treatment of a patient with a faldaprevir/TD-6450/ribavirin

combination

[0081] After a patient weighing less than 75 kg is determined to be infected with HCV genotype 4, where HCV RNA was measured to be greater than or equal to 10,000 IU/mL, the patient is orally administered 120 mg of faldaprevir QD, orally administered 60 or 120 mg of TD-6450 QD and orally administered ribavirin 500 mg BID. The combination therapy is continued for a period of 12 weeks. HCV RNA is measured during the treatment and for up to 12 weeks after the end of treatment to determine viral load. In addition, viral sequencing samples are obtained to monitor for viral resistance mutations.

[0082] For example, 16 treatment-naive patients who were chronically infected with genotype 4 hepatitis C virus were administered 120 mg of faldaprevir QD, either 60 mg or 120 mg of TD-6450 QD, and 500 mg ribavirin (<75 kg patient) or 600 mg of ribavirin (>75 kg patient) BID for 12 weeks. After 3 weeks of treatment, one hundred percent (16/16) of patients had HCV RNA below the lower limit of quantitation (<LL0Q, 15 IU/mL), with all 16 patients achieving sustained virological response after four weeks (SVR4). Further, the 11 patients who were followed for 12 weeks post-treatment all achieved a sustained viral response (SVR12). No patient experienced a virologic breakthrough or relapse. Adverse events of diarrhea and vomiting were mild and infrequent, occurring in 1 and 2 patients, respectively. [0083] While the invention has been described in detail and with reference to specific examples thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

[0084] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0085] All references cited herein are incorporated herein by reference in their entireties.

Claims

WHAT IS CLAIMED IS:

1. A method for the treatment of hepatitis C virus (HCV) in a subject infected with HCV comprising administering to said subject an effective amount of Compound 1 (faldaprevir) having the structure:

(Compound 1),

or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 2 (TD-6450) having the structure:

(Compound 2), or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein said effective amount of Compound 1 is 120 mg/day.

3. The method according to claim 2, wherein Compound 1 is administered once per day.

4. The method according to claim 1, wherein said effective amount of Compound 2 is from 60 mg/day to 240 mg/day.

5. The method according to claim 4, wherein said effective amount of Compound 2 is 120 mg/day.

6. The method according to claim 4, wherein said effective amount of Compound 2 is 60 mg/day

7. The method according to any one of claims 4 to 6, wherein Compound 2 is administered once per day.

8. The method according to any one of claims 1 to 6, wherein said method further comprises administering an effective amount of ribavirin to said subject.

9. The method according to claim 8, wherein said effective amount of ribavirin is from 1000 mg/day to 1200 mg/day.

10. The method according to claim 9, wherein ribavirin is administered twice daily in equal amounts.

11. The method according to any one of claims 1 to 6, wherein said method further comprises administering an effective amount of an NS5B polymerase inhibitor to said subject.

12. The method according to claim 11, wherein said NS5B polymerase inhibitor is VX-222.

13. The method according to claim 12, wherein said effective amount of VX-222 is 800 mg/day.

14. The method according to claim 13, wherein VX-222 is administered twice daily in equal amounts.

15. The method according to any one of claims 1 to 6, wherein said method further comprises administering an effective amount of an IMPDH inhibitor to said subject.

16. The method according to claim 15, wherein said IMPDH inhibitor is VX-497.

17. The method according to claim 16, wherein said effective amount of VX-497 is 100 mg/day.

18. The method according to claim 17, wherein VX-497 is administered twice daily in equal amounts.

19. The method according to claim 1, wherein multiple doses of Compound 1 and multiple doses of Compound 2 are administered to said subject over a combination treatment period of 12 weeks.

20. The method according to claim 1, wherein said hepatitis C virus is genotype 4.

21. The method according to claim 1, wherein said hepatitis C virus is genotype lb.

22. The method according to claim 1, wherein said subject is a non-responder, a partial responder, a relapse responder, or a null responder to a direct acting agent against HCV, such as an inhibitor of HCV NS3/4A protease or an inhibitor of HCV NS5B polymerase.

23. The method according to claim 1, wherein said treatment does not comprise interferon or pegylated interferon.

24. A pharmaceutical composition comprising Compound 1 (faldaprevir) having the structure:

(Compound 1),

or a pharmaceutically acceptable salt thereof, and Compound 2 having the structure:

(Compound 2), or a pharmaceutically acceptable salt thereof.

25. The pharmaceutical composition according to claim 24, comprising Compound 1 in the amount of 120 mg and Compound 2 in the amount of 120 mg.

26. The pharmaceutical composition according to claim 25, comprising Compound 1 in the amount of 120 mg and Compound 2 in the amount of 60 mg.

27. The pharmaceutical composition according to any one of claims 24 to 26, wherein said pharmaceutical composition further comprises ribavirin.

28. The pharmaceutical composition according to claim 27, comprising ribavirin in the amount of 1000 mg to 1200 mg.

29. A package comprising one or more pharmaceutically acceptable dosage forms containing Compound 1, or a pharmaceutically acceptable salt thereof, and one or more dosage forms of Compound 2, or a pharmaceutically acceptable salt thereof, and instructions directing the administration of said dosage forms for the treatment of HCV infection in a patient.

30. The package according to claim 29, further comprising ribavirin, or a pharmaceutically acceptable salt thereof.

31. The package according to any one of claims 29 or 30, wherein said dosage form of Compound 1 is 120 mg.

32. The package according to any one of claims 29 or 30, wherein said dosage form of Compound 2 is 120 mg.

33. The package according to any one of claims 29 or 30, wherein said dosage form of Compound 2 is 60 mg.

34. The package according to any one of claims 29 or 30, further comprising VX-222, or a pharmaceutically acceptable salt thereof.

35. The package according to claim 34, wherein said dosage form of VX-222 is 800 mg divided into two separate and equal dosages.

36. The package according to any one of claims 29 or 30, further comprising VX-497, or a pharmaceutically acceptable salt thereof.

37. The package according to claim 36, wherein said dosage form of VX-497 is 100 mg, divided into two separate and equal dosages.