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(12) Patent Application Publication (10) Pub. No.: US 2015/0150897 A1 Denning Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0150897 A1 Denning Et Al US 2015O150897A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0150897 A1 Denning et al. (43) Pub. Date: Jun. 4, 2015 (54) METHODS OF TREATING HEPATITIS C (52) U.S. Cl. VIRUS INFECTION IN SUBJECTS WITH CPC ......... A61K3I/7072 (2013.01); A61 K3I/7056 CRRHOSIS (2013.01); A61 K3I/4184 (2013.01); A61 K 31/4188 (2013.01) (71) Applicant: Gilead Pharmasset LLC, Foster City, CA (US) (57) ABSTRACT (72) Inventors: Jill M. Denning, Raleigh, NC (US); John G. McHutchison, Woodside, CA (US); G. Mani Subramanian, Los Altos MethodsOCS ofOT treatinga 19811S hepatitis C V1S 1C1Ofect 1 a SU1Cbject H11 s CA (US); William T Sym onds with cirrhosis comprising administering to the Subject an III. San Francisco, CA (US) 9 effective amount of Compound 1. 21) Appl. No.: 14/557,156 ( ) pp O 9 (Compound 1) (22) Filed: Dec. 1, 2014 O Related U.S. Application Data NH (60) Provisional application No. 61/910,631, filed on Dec. O s 2, 2013. O Y- O SN1 NO Publication Classification O e-na O s (51) Int. Cl. Hof 2. A 6LX3L/7072 (2006.01) A6 IK3I/484 (2006.01) A6 IK3I/488 (2006.01) A6 IK3I/7056 (2006.01) US 2015/O150897 A1 Jun. 4, 2015 METHODS OF TREATING HEPATITIS C HCV RNA levels below about 25 IU/mL in subject with VIRUS INFECTION IN SUBJECTS WITH cirrhosis comprising administering to the Subject an effective CRRHOSIS amount of Compound 1. Also disclosed are methods of main taining HCV RNA levels below about 25 IU/mL in subject CROSS REFERENCE TO RELATED with cirrhosis comprising administering to the Subject an APPLICATIONS effective amount of Compound 1. Such achieving or main taining HCV RNA levels below about 25 IU/mL in subject 0001. This application claims the benefits of U.S. Provi with cirrhosis may beat or for a time period after the duration sional Application No. 61/910,631, filed on Dec. 2, 2013, the of administration of Compound. This time period may be entire disclosure of which is incorporated herein by reference. from about 1 week to about 48 weeks. Also disclosed are FIELD methods of treating hepatitis C virus infection, methods of achieving HCV RNA levels below about 25 IU/mL, and 0002 This application relates to methods of preventing, methods of maintaining HCV RNA levels below about 25 treating or reducing the risk of hepatitis C virus infection in a IU/mL in Subject with cirrhosis comprising administering to subject with cirrhosis. the subjecta 5'-mono-, di- or triphosphate metabolite of Com pound 1. In various methods, Compound 1 may be concomi BACKGROUND tantly administered with at least one additional anti-HCV 0003. An estimated 170-180 million people are chroni agent. In some of these methods, this additional anti-HCV cally infected with hepatitis C virus (HCV) worldwide agent can be an NS5A inhibitor, such as Compound A or (Ghany et al., “Diagnosis, Management, and Treatment of Compound B. In some methods the additional anti-HCV Hepatitis C: An Update.” Hepatology (2009) 49(4): 1335-74). agent is ribavirin. In the United States (US), an estimated 3 million people have chronic HCV infection (Dienstag et al., “American Gastro DETAILED DESCRIPTION enterological Association Technical Review on the Manage ment of Hepatitis C. Gastroenterology (2006) 130(1):231 0007. The abbreviation ALT refers to alanine ami 64). Chronic HCV infection can cause chronic liver disease, notransferase. Increased serum ALT levels can accompany cirrhosis, liver failure, hepatocellular carcinoma (HCC) and hepatocellular injury or necrosis of striated muscle. In addi death. The complications of chronic HCV account for the tion, release of ALT from the cytosol may occur secondary to most common indication for liver transplantation in the US. cellular necrosis or as a result of cellular injury with mem 0004. The progression to cirrhosis is often clinically brane damage. An increased serum ALT level is one indica silent, and some patients are not known to have HCV until tion of hepatic damage. they present with the complications of end-stage liver disease 0008. The abbreviation “AST’ refers to aspartate ami or HCC. Cirrhosis is currently classified as compensated or notransferase, an enzyme normally found in the blood in low decompensated based on clinical outcomes. Features of dec levels. Increased serum AST may result from disease or dam ompensated cirrhosis include the development of ascites, age to an organ, including the liver. An increased serum AST Variceal hemorrhage, hepatic encephalopathy, or liver insuf level is one indication of hepatic damage. ficiency (jaundice) (Garcia-Tsao, et al., Hepatology (2010) 0009. The term “body mass index” (BMI) refers to the 51(4): 1445-49). In the US, deaths associated with chronic ratio of a subjects weight to the subjects height. BMI is HCV are more likely to be caused from decompensated cir expressed in units of kg/m2 and is calculated as follows: rhosis rather than HCC. Studies have estimated the 3-, 5-, and 10-year survival rates of compensated cirrohisis to be 96%, 91% and 79%, respectively (Chenet al., “The Natural History weightpounds) x 703 weight in kilograms of Hepatitis C Virus (HCV) Infection.” Int. J. Med. Sci. BMI (height in inches)? O (height- in meters)? (2006)3(2):47-52). The cumulative probability of an episode of clinical decompensation is 5% at 1 year and increases to 30% at 10 years from the diagnosis of cirrhosis (Id.). Once (0010. The Child-Pugh (CPT) score, which may also be decompensated cirrhosis occurs, the 5-year Survival rate falls referred to as the Child-Pugh Turcotte score, is measured on to 50% (Id.). a scale of 5-15 and is used to assess the prognosis of chronic 0005 While interferon-based therapy may be initiated at a liver disease in subjects with cirrhosis. low doses in Subjects with decompensated cirrhosis, many (0011 “Cirrhosis” refers a CPT score of greater than 5 and Subjects who become decompensated have already tried and includes both compensated cirrhosis and decompensated cir failed such therapy and/or cannot tolerate the side effects rhosis. A CPT score of 5-6 generally correlates with compen from a course of interferon therapy. Thus, new treatment sated cirrhosis, and a CPT score of 7-15 generally correlates options for patients with cirrhosis of varying stages are to decompensated cirrhosis. greatly needed. 0012 “Effective amount” refers to an amount of a com pound which, when administered to a subject in need thereof, SUMMARY is sufficient to effect treatment for diseases, conditions, or 0006 Disclosed herein are methods of treating hepatitis C disorders for which the compound has utility. The effective virus infection in a subject with cirrhosis comprising admin amount will vary depending on the compound, the disease istering to the Subject an effective amount of Compound 1. In and its severity, and the age, weight, and other conditions of Some methods, the Subject also has portal hypertension. In the subject being or to be treated. various methods, Compound 1 may be administered for a 0013 The terms “infected with. HCV,” “HCV infection duration, wherein the duration ranges from about 1 week to and similar terms refer to a documented HCV infection, about 48 weeks. Also disclosed are methods of achieving including acute and chronic infection. HCV infection can be US 2015/O150897 A1 Jun. 4, 2015 shown, for instance, by a positive anti-HCV antibody test, HCV RNA, or HCV genotyping test. 0014 HCV Viral Load (HCV RNA test, Quantitative) refers to the detection and measurement of the number of viral RNA particles in blood. s 00.15 Viral genotyping is used to determine the kind, or 1s. genotype, of the HCV virus present. There are at least 6 major Y- HNIII P-O O N types of HCV (GT 1-6); the most common in the United States is genotype 1. The abbreviation “GT refers to geno > O O -ne type. 0016. The abbreviation “IL28B' refers to interleukin 28B, which is one isoform of the interleukin-28 (IL28) cytokine. A single nucleotide polymorphism (SNP) in the IL28B pro moter region is identified and is used to predict response to (See U.S. Pat. Nos. 7,964,580, 8,642,756, and 8,618,076). interferon treatment in subjects with HCV. 0029 Compound 1 is a nucleotide analog prodrug, the 0017. The abbreviation “IU' refers to international unit, 5'-triphosphate metabolite of which is a potent and selective which is a measure of the amount of a Substance based on its inhibitor of HCV replication mediated by the HCV NS5B biological activity or effect. RNA dependent RNA polymerase (Sofia et al., J.Med. Chem. 0018. The abbreviation “LLOQ' refers to the lower limit (2010) 53(19):7202-7218). of quantification. As used herein in reference to HCV RNA 0030 Compound 1 is converted in vivo to its 5'-mono-, di measurements, the LLOQ is about 25 IU/mL (as measured by and triphosphate metabolites (Id.), represented by the follow a Roche Cobas(R Taqman R. Version V2.0 Assay for HCV). ing chemical structures: 0019. The Milan criteria are applied as a basis for selecting subjects with cirrhosis and hepatocellular carcinoma for liver transplantation. The Milan criteria are defined as follows: (1) a single lesion with a maximum size of 5 cm or (2) up to 3 lesions with the largest not exceeding 3 cm; and (3) no evi dence of vascular invasion or extrahepatic manifestations of the cancer as evidenced by imaging (MaZZaferro et al., “Liver Transplantation for the Treatment of Small Hepatocellular Carcinomas in Patients with Cirrhosis.” N. Engl. J. Med. (1996) 334:693-700).
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