Compositions and Methods for Treating Hepatitis C Virus
`
`This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional
`
`Application Nos. 61/564,500, filed November 29, 2011, and 61/707,459, filed September
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`5
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`28, 2012, and claims the benefit under 35 U.S.C. § 120 oflntemational Application No.
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`PCT/US2012/055621, filed September 14, 2012, and U.S. Application No. 13/661,509,
`
`filed October 26, 2012, all of which are incorporated by reference in their entireties.
`
`Field of the Invention
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`10
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`Disclosed herein are a composition and unit dosage form for the treatment of
`
`hepatitis C virus (HCV) infection comprising GS-7977 and at least one pharmaceutically
`
`acceptable excipient, as well as methods for making the said composition and unit dosage
`
`form. Also disclosed herein is a method of treating a subject, preferably a human,
`
`infected with hepatitis C virus, said method comprising administering to the subject for a
`
`15
`
`time period an effective amount of GS-7977 and an effective amount of ribavirin. In one
`
`aspect, the method comprises administering to the subject an interferon-free treatment
`
`regimen comprising an effective amount of GS-7977 and an effective amount of ribavirin.
`
`In a particular aspect, the method is sufficient to produce an undetectable amount ofHCV
`
`RNA in the subject for at least 12 weeks after the end of the time period.
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`20
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`Background
`
`Hepatitis C virus ("HCV") infection is a major health problem that leads to
`
`chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial
`
`number of infected individuals, estimated by the World Health Organization to be about
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`25
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`3% of the world's population. (World Health Organization, Hepatitis C (2002).)
`
`According to the U.S. Centers for Disease Control and Prevention, HCV is the most
`
`common blood-borne infection in the United States, with an estimated 3.2 million people
`
`(1.8%) chronically infected in the United States alone. (U.S. Centers for Disease Control
`
`and Prevention, Viral Hepatitis Surveillance - United States, 2010; U.S. Centers for
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`30 Disease Control and Prevention, Morbidity and Mortality Weekly Report 70(17): 537-539
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`(May 6, 2011).) An estimated 150-180 million individuals are chronically infected with
`
`HCV worldwide, with 3 to 4 million people infected each year. (World Health
`
`Organization, Hepatitis C, Fact Sheet No. 164 (July 2012); Ghany et al., Hepatology
`
`(2009) 49(4): 1335-1374.) Once infected, about 20% of people clear the virus, but the
`
`5
`
`rest can harbor HCV for the rest of their lives. Ten to twenty percent of chronically
`
`infected individuals eventually develop liver-destroying cirrhosis or cancer. (Naggie et
`
`al., J. Antimicrob. Chemother. (2010) 65: 2063-2069.) The viral disease is transmitted
`
`parenterally by contaminated blood and blood products, contaminated needles, or
`
`sexually and vertically from infected mothers or carrier mothers to their offspring.
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`10
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`The HCV virion is an enveloped positive-strand RNA virus with a single
`
`oligoribonucleotide genomic sequence of about 9600 bases which encodes a polyprotein
`
`of about 3,010 amino acids. The protein products of the HCV gene consist of the
`
`structural proteins C, El, and E2, and the non-structural proteins NS2, NS3, NS4A and
`
`NS4B, and NS5A and NS5B. The nonstructural ("NS") proteins are believed to provide
`
`15
`
`the catalytic machinery for viral replication. The NS3 protease releases NS5B, the RNA(cid:173)
`
`dependent RNA polymerase, from the polyprotein chain. HCV NS5B polymerase is
`
`required for the synthesis of a double-stranded RNA from a single-stranded viral RNA
`
`that serves as a template in the replication cycle ofHCV. Therefore, NS5B polymerase is
`
`considered to be an essential component in the HCV replication complex. (K. Ishi, et al,
`
`20 Hepatology (1999) 29: 1227-1235; V. Lohmann, et al., Virology (1998) 249: 108-118.)
`
`Inhibition ofHCV NS5B polymerase prevents formation of the double-stranded HCV
`
`RNA and therefore constitutes an attractive approach to the development ofHCV-specific
`
`antiviral therapies.
`
`A number of potential molecular targets for drug development of direct acting
`
`25
`
`antivirals as anti-HCV therapeutics have now been identified including, but not limited
`
`to, the NS2-NS3 autoprotease, the N3 protease, the N3 helicase, and the NS5B
`
`polymerase. The RNA-dependent RNA polymerase is essential for replication of the
`
`single-stranded, positive sense, RNA genome, and this enzyme has elicited significant
`
`interest among medicinal chemists. Another auxiliary protein ofHCV is referred to as
`
`30 NS5A. The NS5A nonstructural protein is a phosphoprotein, with no apparent enzymatic
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`activity; however it acts as a multifunctional regulator of cellular pathways, including
`
`host cell growth, immunity and innate immunity, and virus replication. (Appel et al., J.
`
`Virol. (2005) 79: 3187-3194; Evans et al., Proc. Natl. Acad. Sci. USA (2004) 101: 13038-
`
`13043; Gale et al., Nature (2005) 436: 939-945; Gale et al., Virology (1997) 230: 217-
`
`5
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`227; Ghosh et al., J. Gen. Virol. (1999) 80(Pt 5): 1179-1183; Neddermann et al., J. Virol.
`
`(1999) 73: 9984-9991; Polyak et al., Hepatology (1999) 29: 1262-1271; Shimakami et al.,
`
`J. Virol. (2004) 78: 2738-2748; Shirota et al., J. Biol. Chem. (2002) 277: 11149-11155;
`
`and Tan et al., Proc. Natl. Acad. Sci. U.S. A. (1999) 96: 5533-5538.) NS5A is associated
`
`with host cell membranes through its N-terminal amphipathic helix, where it is a part of
`
`10
`
`the replication complex. (Elazar et al., J. Virol. (2004) 78: 11393-11400 and Penin et al.,
`
`J. Biol. Chem. (2004) 279: 40835-40843.) Recent studies suggest that NS5A is organized
`
`into three domains: the first 213 amino acids in the N-terminal domain constitutes
`
`domain I and contains a zinc binding motif suggesting that the protein is a zinc
`
`metalloprotein and domains II and III are in the C-terminal region of the protein.
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`15
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`(Tellinghuisen et al., J. Biol. Chem. (2004) 279: 48576-48587 and Tellinghuisen et al.,
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`Nature (2005) 435: 374-379.) NS5A exists in two phosphorylated forms: a basal form of
`
`56 kD and a hyperphosphorylated form of 58 kD. The protein is phosphorylated at
`
`specific sites, primarily on serine residue within domains II and III, by host cell kinases.
`
`(Ide et al., Gene (1997) 201: 151-158; Kaneko et al., Biochem. Biophys. Res. Commun.
`
`20
`
`(1994) 205: 320-326; Katze et al., Virology (2000) 278: 501-513; Reed et al., J. Biol.
`
`Chem. (1999) 274: 28011-28018; Reed et al., J. Virol. (1997) 71: 7187-7197; and Tanji
`
`et al., J. Virol. (1995) 69: 3980-3986.)
`
`The initially-approved standard of care ("SOC") for the treatment of chronic HCV
`
`infection is a combination therapy with pegylated interferon alfa-2a or pegylated
`
`25
`
`interferon alfa-2b ( collectively "peginterferon" or "PEG") used alone or in combination
`
`with ribavirin ("RBV"). The primary goal of treatment for chronic hepatitis C is a
`
`sustained virologic response ("SVR"), which refers to an undetectable level of serum
`
`HCV RNA maintained for a period of time post-treatment. Host factors including age,
`
`body weight, race, and advanced fibrosis influence the outcome of treatment (Dienstag
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`30
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`and McHutchison Gastroenterology (2006)130: 231-264 and Missiha et al.,
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`Gastroenterology (2008) 134: 1699-1714), but are poor predictors of response. In
`
`contrast, viral factors like the genotype and the on-treatment pattern of viral response can
`
`be used to determine the likelihood of treatment success and guide treatment duration
`
`individually, and they have proven to be very useful in clinical practice. (Ge et al., Nature
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`5
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`(2009) 461: 399-401.)
`
`In spite of an encouraging response in some patients to SOC treatment, the overall
`
`response to peginterferon/ribavirin combination therapy among patients infected with
`
`Hepatitis C virus is only about 50%. SVR rates are <50% for patients infected with
`
`genotype 1 HCV treated with a prolonged duration (48-72 weeks) of
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`10
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`peginterferon/ribavirin therapy. (Naggie et al., J. Antimicrob. Chemother. (2010) 65:
`
`2063-2069.) Accordingly, there is a need to provide a therapy resulting in improved SVR
`
`compared to the outcome of treatment with peginterferon alone or in combination with
`
`ribavirin. There is also a need to provide a therapy that reduces the time in which patients
`
`show evidence of complete viral suppression (negative HCV status) following the
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`15
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`initiation of treatment.
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`Peginterferon alfa-2a ("PEG-IFN-a-2a" or "peginterferon a-2a"), marketed under
`
`the trademark PEGASYS®, is an antiviral administered by subcutaneous injection
`
`indicated for, among other things, treatment of chronic hepatitis C ("CHC") when
`
`administered alone or in combination with ribavirin. PEGASYS® is indicated for the
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`20
`
`treatment of CHC in patients with compensated liver disease not previously treated with
`
`interferon alpha, in patients with histological evidence of cirrhosis and compensated liver
`
`disease, and in adults with CHC/HIV co-infection. Combination therapy using PEG-IFN(cid:173)
`
`a-2a and ribavirin is recommended unless the patient has contraindication to or
`
`significant intolerance to ribavirin.
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`25
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`Peginterferon alfa-2b ("PEG-IFN-a-2b" or "peginterferon a-2b"), marketed under
`
`the trademark PEGINTRON®, is also administered by subcutaneous injection and is
`
`indicated for use alone or in combination with ribavirin to treat CHC in patients with
`
`compensated liver disease. Like PEG-IFN-a-2a, PEG-IFN-a-2b has undesirable side
`
`effects.
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`Ribavirin ("RBV"), marketed under the trademark COPEGUS®, is a nucleoside
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`analogue indicated for the treatment of CHC virus infection in combination with
`
`peginterferon in patients 5 years of age and older with compensated liver disease not
`
`previously treated with peginterferon, and in adult CHC patients co-infected with HIV.
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`5
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`Ribavirin alone is not approved for the treatment of CHC. (COPEGUS® FDA-approved
`
`label, revised 08/2011.) Clinical trials have shown that ribavirin alone can normalize
`
`alanine aminotransferase ("ALT") levels transiently during the course of treatment in
`
`some patients with CHC infections. However, these studies have reported that ribavirin
`
`alone did not reduce HCV RNA levels during or after therapy and did not produce any
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`10
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`sustained virologic response. (Di Bisceglie et al., Ann. Intern. Med. (1995) 123(12): 897-
`
`903; Dusheiko et al., J. Hepatology (1996) 25: 591-598; Bodenheimer, Jr., et al.,
`
`Hepatology (1997) 26(2): 473-477.) One clinical study reported observing a decrease in
`
`HCV RNA from treatment with ribavirin monotherapy (1.0 to 1.2 g daily for 24 weeks);
`
`however, the observed HCV RNA decrease was transient and no patient receiving
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`15
`
`ribavirin monotherapy cleared HCV RNA. (Pawlotsky et al., Gastroenterology (2004)
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`126: 703-714.)
`
`Treatment of CHC using peginterferon alone or in combination with ribavirin has
`
`several disadvantages. First and foremost, this therapy is not effective for many patients.
`
`For instance, certain Phase 3 clinical trials using the combination of peginterferon and
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`20
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`ribavirin reported SVR rates of 54 to 63%, but additional studies show that the SVR rates
`
`may be much lower in certain populations. (Feurstadt et al., Hepatology (2010) 51(4):
`
`1137-1143.) Second, use of peginterferon and ribavirin is associated with certain adverse
`
`events. For instance, the boxed warning on the PEGASYS® label states that use of
`
`peginterferon may cause or aggravate fatal or life-threatening neuropsychiatric,
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`25
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`autoimmune, ischemic, and infectious disorders. (PEGASYS® (peginterferon alfa-2a)
`
`FDA-approved label, revised 09/2011.) Additionally, the boxed warning on the
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`COPEGUS® label states that ribavirin adverse effects may include hemolytic anemia and
`
`that significant "teratogenic and embryocidal effects have been demonstrated in all animal
`
`species exposed to ribavirin." (COPEGUS® (ribavirin) FDA-approved label, revised
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`30
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`08/2011.) Finally, the peginterferon/ribavirin treatment protocol is quite expensive.
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`Given these disadvantages, there has been a recognized need to develop new anti-HCV
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`drug substances and treatment regimens.
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`The FDA recently approved two additional drug products for the treatment of
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`genotype 1 CHC, boceprevir and telaprevir, both of which are HCV NS3/4 protease
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`5
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`inhibitors. Boceprevir, marketed under the trademark VICTRELIS®, is indicated for the
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`treatment of genotype 1 CHC infection, in combination with interferon and ribavirin, in
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`adult patients (2: 18 years of age) with compensated liver disease, including cirrhosis, who
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`are previously untreated or who have failed previous interferon and ribavirin therapy.
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`Telaprevir, marketed under the trademark INCIVEK®, is indicated, in combination with
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`10
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`interferon and ribavirin, for the treatment of genotype 1 CHC in adult patients with
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`compensated liver disease, including cirrhosis, who are treatment-na"ive or who have been
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`previously treated with interferon-based treatment, including prior null responders, partial
`
`responders, and relapsers. Both boceprevir and telaprevir are approved for administration
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`in combination with peginterferon and ribavirin only; neither is approved for
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`15 monotherapy or for administration with ribavirin alone. (INCIVEK® (telaprevir) FDA(cid:173)
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`approved label, revised 06/2012; VICTRELIS® (boceprevir) FDA-approved label,
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`revised 07/2012.)
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`The introduction of both boceprevir and telaprevir has increased the therapeutic
`
`options available to BCV-infected patients; however, both treatment regimens have
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`20
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`certain disadvantages. A principle disadvantage is that the boceprevir and telaprevir
`
`regimens still require the use of peginterferon. Additional disadvantages are summarized
`
`below.
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`Boceprevir (used in combination with peginterferon a-2a and ribavirin) has a
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`complicated dosing regimen, e.g., 800 mg ( 4 x 200 mg) three times daily ( every 7 to 9
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`25
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`hours) with food. Moreover, late-stage clinical studies show that boceprevir used in
`
`combination with peginterferon and ribavirin results in a 66% SVR rate. (Manns et al.,
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`Liver Int'l (2012) 27-31.) Additionally, the boceprevir regimen must be administered for
`
`48 weeks, which means that the treatment costs are quite expensive. Finally, use of
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`boceprevir in combination with peginterferon and ribavirin is presently limited to those
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`30
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`subjects infected with HCV genotype 1.
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`The telaprevir regimen (used in combination with peginterferon and ribavirin)
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`requires a dosing regimen of 750 mg (2 x 375 mg) three times daily (7-9 hours apart) with
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`food. An SVR rate of 79% was reported for patients receiving telaprevir in combination
`
`with peginterferon and ribavirin for 12 weeks. (Jacobson et al., New Engl. J. Med.
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`5
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`(2011) 364: 2405-2416.) However, reports reveal that about half of the treated patients
`
`developed a skin rash or itching, and a small number of patients developed the severe
`
`Stevens-Johnson Syndrome, a life-threatening skin condition, in which case the regimen
`
`must be terminated. Finally, use of telaprevir in combination with peginterferon and
`
`ribavirin is presently limited to those subjects infected with HCV genotype 1. Although
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`10
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`the treatment period is reduced for telaprevir as compared to that for boceprevir, the
`
`treatment costs for the two regimens are about the same.
`
`Despite the additional options offered by the boceprevir and telaprevir regimens,
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`these alternative treatments still have disadvantages. Further, genotype 1 patients who
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`fail therapy with boceprevir and/or telaprevir in combination with peginterferon and
`
`15
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`ribavirin may develop undesirable NS3 protease inhibitor resistance. (E.g., Pawlotsky,
`
`Hepatology (2011) 53(5): 1742-1751.) There is a need for improved treatment regimens
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`that are more effective, safe, tolerable, shorter in duration, and which are associated with
`
`reduced rates of viral breakthrough and/or viral resistance. In particular, there is a need
`
`for interferon-free treatment regimens that are effective for treating CHC but result in
`
`20
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`reduced side-effects compared to treatment regimens involving interferon or
`
`peginterferon. There is also a need for interferon-free treatment regimens for patients
`
`suffering from CHC infection who are interferon-ineligible or interferon-intolerant.
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`GS-7977 ( also called sofosbuvir and formerly called PSI-7977) is a nucleotide
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`analog prodrug currently in Phase 2/Phase 3 trials for treatment of chronic HCV infection.
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`25
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`Several Phase 2 clinical trials have been conducted to evaluate the efficacy, safety
`
`and tolerability of GS-7977 400 mg administered for 8 or 12 weeks with or without
`
`ribavirin and optionallypeginterferon in subjects with GTl, GT2 or GT3 HCV. The
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`results of these trials, along with the results if in vitro studies, revealed several potential
`
`and hereto unknown advantages ofHCV treatment regimens utilizing GS-7977 in
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`combination with ribavirin. These results provide a basis for the disclosed and claimed
`
`method and composition for treating HCV infection.
`
`Summary
`
`5
`
`Disclosed herein are a composition and unit dosage form for the treatment of
`
`hepatitis C virus (HCV) infection comprising GS-7977 and at least one pharmaceutically
`
`acceptable excipient, as well as methods for making said composition and unit dosage
`
`form.
`
`Also disclosed herein is a method of treating a subject, preferably a human,
`
`10
`
`infected with hepatitis C virus, said method comprising administering to the subject for a
`
`time period an effective amount of GS-7977 and an effective amount of ribavirin. In one
`
`aspect, the method comprises administering to the subject an interferon-free treatment
`
`regimen comprising an effective amount of GS-7977 and an effective amount of ribavirin.
`
`In a particular aspect, the method is sufficient to produce an undetectable amount ofHCV
`
`15
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`RNA in the subject for at least 12 weeks after the end of the time period.
`
`Brief Description of the Drawings
`
`Figure 1.
`
`Plot of Mean HCV RNA (log 10 IU/mL) versus time during treatment and
`
`20
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`for up to 12 weeks after the end of treatment ("EQT") for HCV GT2/GT3
`
`treatment-na"ive patients receiving a combination of GS-7977 ( 400 mg
`
`QD) and RBV (1000/1200 mg BID based on weight) for 12 weeks
`
`(ELECTRON Group 1 ).
`
`25
`
`Figure 2.
`
`Fold-change in EC 50 for HCV replicons containing 1 b, la, 2a, 2b, 3a, 4a,
`
`and 5a NS5B harboring the S282T mutation ( compared to the
`
`corresponding wild-type) treated with GS-7977 or ribavirin.
`
`Figure 3.
`
`Percentage of wild-type at S282 position in HCV replicons before and
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`30
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`after treatment with GS-7977, ribavirin, and a combination of GS-7977
`
`and ribavirin in long-term passaging study (15-30 days).
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`Detailed Description
`
`Definitions
`
`The phrase "a" or "an" entity as used herein refers to one or more of that entity; for
`
`5
`
`example, a compound refers to one or more compounds or at least one compound. As
`
`such the terms "a" (or "an") "one or more" and "at least one" can be used
`'
`'
`'
`interchangeably herein.
`
`The term "about" ( also represented by "~") has its plain and ordinary meaning of
`
`"approximately" except as related to an amount of GS-7977, an amount of ribavirin, or an
`
`10
`
`amount ofHCV RNA. As related to an amount of GS-7977, an amount ofribavirin, or
`
`an amount ofHCV RNA, the qualifier "about" reflects the standard experimental error.
`
`The terms "optional" or "optionally" as used herein means that a subsequently
`
`described event or circumstance may but need not occur, and that the description includes
`
`instances where the event or circumstance occurs and instances in which it does not.
`
`15
`
`The term "subject" as used herein means a mammal. Preferably the subject is a
`
`human.
`
`The term "effective amount" as used herein means an amount sufficient to reduce
`
`symptoms of the HCV infection in a subject.
`
`The term "undetectable amount" refers to an amount ofHCV RNA, as determined
`
`20
`
`by the assay methodology described herein, that is less than the limit of detection
`
`("LOD") of about 15 IU/mL.
`
`A sustained virologic response (SVR) for a patient treated according to one of the
`
`treatment regimens described herein is defined as a patient who completes the HCV
`
`treatment regimen and who has an undetectable amount ofHCV RNA (i.e.,< about 15
`
`25
`
`IU/mL) for a period of time post-treatment as measured in accordance with the assay
`
`methodology described herein. SVR-N is the abbreviation for sustained virologic
`
`response N weeks after completion of one of the HCV treatment regimens disclosed
`
`herein. For example, SVR-4 is the abbreviation for sustained virologic response 4 weeks
`
`after completion of one of the HCV treatment regimens disclosed herein.
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`30
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`The term "preparation" or "dosage form" is intended to include both solid and
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`liquid formulations of the active compound and one skilled in the art will appreciate that
`
`an active ingredient can exist in different preparations depending on the desired dose and
`
`pharmacokinetic parameters.
`
`The term "unit dosage form" refers to a physically discrete unit containing a
`
`5
`
`predetermined quantity of the active compound. Preferred unit dosage forms are those
`
`containing a daily dose or unit daily sub-dose, or an appropriate fraction thereof, of GS-
`
`7977.
`
`The terms "pharmaceutically acceptable excipient" and "pharmaceutical
`
`excipient" as used herein refer to a compound that is used to prepare a pharmaceutical
`
`10
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`composition, and is generally safe, non-toxic and neither biologically nor otherwise
`
`undesirable, and includes excipients that are acceptable for veterinary use as well as
`
`human pharmaceutical use.
`
`RVR is the abbreviation for rapid virologic response and refers to an undetectable
`
`level ofHCV RNA in the blood at week 4 of treatment. The occurrence ofRVR has been
`
`15
`
`reported to be predictive of ultimate SVR for a full treatment course of 48 weeks with
`
`peginterferon/ribavirin combination treatment in HCV GT-I patients. (Poordad et al.,
`
`Clin. Infect. Dis. (2008) 46: 78-84.)
`
`QD means that the dose is administered once a day.
`
`BID means that the dose is administered twice a day.
`
`20
`
`TID means that the dose is administered three times a day.
`
`QID means that the dose is administered four times a day.
`
`The highest activities of alanine aminotransferase (ALT) are found in hepatocytes
`
`and striated (skeletal and cardiac) muscle cells. Increased serum ALT activity can
`
`accompany hepatocellular injury or necrosis of striated muscle. With cell injury or death,
`
`25 ALT escapes from the cytosol. In addition, release of ALT from the cytosol can occur
`
`secondary to cellular necrosis or as a result of cellular injury with membrane damage.
`
`Determination of ALT activity is a relatively sensitive indicator of hepatic damage.
`
`Mechanisms of increased activity of ALT in serum include enzyme release from damaged
`
`cells or induction of enzyme activity, such as increased enzyme synthesis from drug
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`administration. (Zeuzem, et al., Aliment Pharmacol Ther. 2006 Oct 15; 24(8) 1133-
`
`1149).
`
`The interleukin 28B (IL28B) gene encodes a cytokine distantly related to type I
`
`interferons and the IL-IO family. The IL28B gene, interleukin 28A (IL28A), and
`
`5
`
`interleukin 29 (IL29) are three closely related cytokine genes that form a cytokine gene
`
`cluster on a chromosomal region mapped to 19q 13. Expression of the cytokines encoded
`
`by the three genes can be induced by viral infection. All three cytokines have been shown
`
`to interact with a heterodimeric class II cytokine receptor that consists of interleukin 10
`
`receptor, beta (ILlORB), and interleukin 28 receptor, alpha (IL28RA). (National Center
`
`10
`
`for Biotechnology Information, Entrez Gene Entry for IL28B, Gene ID: 282617, updated
`
`on 23-Oct-2010.)
`
`Body mass index ("BMI") is a measurement based on a person's weight and
`
`height and is used to estimate a healthy body weight based on a person's height, assuming
`an average body composition. The units of BMI are kg/m2
`
`.
`
`15
`
`LOD is the abbreviation for limit of detection. As used herein with regard to
`
`HCV RNA measurements, in one aspect LOD is from about 1 IU/mL to about 60 IU/mL,
`
`more preferably from about 5 IU/mL to about 30 IU/mL, and even more preferably from
`
`about 10 IU/mL to about 20 IU/mL. In a particularly preferred embodiment, the LOD is
`
`about 15 IU/mL.
`
`20
`
`GT is the abbreviation for genotype.
`
`IU is the abbreviation for international unit, which is a measure of the amount of a
`
`substance based on biological activity or effect.
`
`There are several recognized HCV Genotypes (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11),
`
`which can be further categorized by different sub-types: 1 (1 a, 1 b, and 1 c ), 2 (2a, 2b, 2c ),
`
`25
`
`3 (3a and 3b), 4 (4a, 4b, 4c, 4d, and 4e), 5 (5a), 6 (6a), 7 (7a and 7b), 8 (8a and 8b), 9
`
`(9a), 10 (10a), and 11 (I la). Genotype 1 is the predominant form found in North and
`
`South America, Europe, Asia, Australia, and New Zealand. Genotypes 2 and 3 are also
`
`widely distributed throughout North America, Europe, Australia, East Asia and some
`
`portions of Africa. In some portions of Africa, Genotype 4 predominates, while in others
`
`30
`
`(such as South Africa) genotype 5 predominates. The method disclosed herein is
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`contemplated to be independently effective for the treatment of each of the HCV
`
`genotypes, and in particular each genotype-sub-type.
`
`The term "interferon-free" as used herein refers to a treatment regimen that does
`
`not involve the administration of interferon or pegylated interferon to the subject.
`
`5
`
`GS-7977, (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-
`
`dihydropyrimidin-1 (2H)-yl )-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-
`
`yl)methoxy )(phenoxy )phosphoryl )amino )propanoate, available from Gilead Sciences,
`
`Inc., is described and claimed in U.S. Patent No. 7,964,580. (See also US 2010/0016251,
`
`US 2010/0298257, US 2011/0251152 and US 2012/0107278.) GS-7977 has the
`
`10
`
`structure:
`
`0
`
`0
`
`;PrO
`
`NH
`
`(
`,,' 0 H
`II
`O N~O
`'
`HN 111"P -O~
`~
`OPh HO
`.. F
`,
`
`GS-7977 can be crystalline or amorphous. Examples of preparing crystalline and
`
`amorphous forms of GS-7977 are disclosed in US 2010/0298257 (US 12/783,680) and
`
`15 US 2011/0251152 (US 13/076,552), both of which are incorporated by reference.
`
`Polymorphic Forms 1-6 of GS-7977 disclosed in US 2010/0298257 and/or US
`
`2011/0251152 have the following characteristic X-ray powder diffraction (XRPD) pattern
`
`28-values measured according to the XRPD methods disclosed therein:
`
`(1) 28-reflections (0
`
`) at about: 5.2, 7.5, 9.6, 16.7, 18.3, and 22.2 (Form 1);
`
`20
`
`(2) 28-reflections (0
`
`) at about: 5.0, 7.3, 9.4, and 18.1 (Form 1);
`
`(3) 28-reflections (0
`
`) at about: 4.9, 6.9, 9.8, 19.8, 20.6, 24.7, and 26.1 (Form 2);
`
`(4) 28-reflections (0
`
`) at about: 6.9, 9.8, 19.7, 20.6, and 24.6 (Form 3);
`
`(5) 28-reflections (0
`
`) at about: 5.0, 6.8, 19.9, 20.6, 20.9, and 24.9 (Form 4);
`
`(6) 28-reflections (0
`
`) at about: 5.2, 6.6, 7.1, 15.7, 19.1, and 25.0 (Form 5); and
`
`25
`
`(7) 28-reflections (0
`
`) at about: 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0, 18.8, 19.4,
`
`19.8, 20.1, 20.8, 21.8, and 23.3 (Form 6).
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`Polymorphic Forms 1 and 6 are alternatively characterized by the following
`
`characteristic XRPD pattern 28-values measured according to the methods disclosed in
`
`US 2010/0298257 (US 12/783,680) and US 2011/0251152 (US 13/076,552):
`
`(1) 28-reflections ( 0
`
`) at about: 5.0 and 7.3 (Form 1); and
`
`5
`
`(2) 28-reflections ( 0
`
`) at about: 6.1 and 12.7 (Form 6).
`
`In one aspect, the disclosed composition comprises polymorphic Form 6 of GS-
`
`7977. It has been found that Form 6 has a melt onset of approximately 121 °Candis not
`
`hygroscopic, with less than 0.2% moisture sorption at room temperature and 90% RH.
`
`Form 6 is chemically stable when stored under opened conditions at 40°C/75% RH for 30
`
`10
`
`days.
`
`In one aspect, GS-7977 is substantially free from its corresponding phosphorous(cid:173)
`
`based diastereomer (S)-isopropyl 2-(((R)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-
`
`dihydropyrimidin-1 (2H)-yl )-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-
`
`yl)methoxy )(phenoxy )phosphoryl )amino )propanoate. In one embodiment, GS-7977 is at
`
`15
`
`least 95% free from its corresponding phosphorous-based diastereomer. In another
`
`embodiment, GS-7977 is at least 97% free from its corresponding phosphorous-based
`
`diastereomer. In another embodiment, GS-7977 is at least 99% free from its
`
`corresponding phosphorous-based diastereomer. In a further embodiment, GS-7977 is at
`
`least 99.9% free from its corresponding phosphorous-based diastereomer.
`
`20
`
`Ribavirin, 1-~-D-ribofuranosyl-IH-1,2,4-triazole-3-carboxamide, is described in
`
`the Merck Index (12th Edition), monograph no. 8365. (See also U.S. Patent No.
`
`4,530,901.)
`
`As used herein, "treatment" or "treating" is an approach for obtaining beneficial or
`
`desired clinical results. Beneficial or desired clinical results include, but are not limited
`
`25
`
`to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not
`
`worsening) state of disease, delay or slowing of disease progression, amelioration or
`
`palliation of the disease state, and remission (whether partial or total), whether detectable
`
`or undetectable. "Treatment" can also mean prolonging survival as compared to expected
`
`survival if not receiving treatment. "Treatment" is an intervention performed with the
`
`30
`
`intention of preventing the development or altering the pathology of a disorder. The term
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`"treatment" of an HCV infection, as used herein, also includes treatment or prophylaxis of
`
`a disease or a condition associated with or mediated by HCV infection, or the clinical
`
`symptoms thereof.
`
`5
`
`Compositions and Unit Dosage Forms
`
`A first embodiment is directed to a composition for the treatment of hepatitis C
`
`virus (HCV) comprising a) GS-7977, and b) a pharmaceutically acceptable excipient.
`
`In a first aspect of the first embodiment, the composition for the treatment of
`
`HCV comprises from about 25% to about 35% w/w of GS-7977. In another aspect, the
`
`10
`
`composition comprises from about 30% to about 35% w/w of GS-7977. In another
`
`aspect, the composition comprises from about 25%, about 26%, about 27%, about 28%,
`
`about 29%, about 30%, about 31 %, about 32%, about 33%, about 34%, or about 35%
`
`w/w of GS-7977. In one subembodiment, the composition comprises about 30% w/w of
`
`GS-7977. In another subembodiment, the composition comprises about 33% w/w of GS-
`
`15
`
`7977. In another subembodiment, the composition comprises about 33.33% w/w of GS-
`
`7977.
`
`In a second aspect of the first embodiment, the composition comprises crystalline
`
`GS-7977. In one subembodiment, the composition comprises crystalline GS-7977 having
`
`XRPD 28-reflections (0
`
`) at about: (1) 5.2, 7.5, 9.6, 16.7, 18.3, and 22.2; (2) 5.0, 7.3, 9.4,
`
`20
`
`and 18.1; (3) 4.9, 6.9, 9.8, 19.8, 20.6, 24.7, and 26.1; (4) 6.9, 9.8, 19.7, 20.6, and 24.6; (5)
`
`5.0, 6.8, 19.9, 20.6, 20.9, and 24.9; (6) 5.2, 6.6, 7.1, 15.7, 19.1, and 25.0; or (7) 6.1, 8.2,
`
`10.4, 12.7, 17.2, 17.7, 18.0, 18.8, 19.4, 19.8, 20.1, 20.8, 21.8, and 23.3. In another
`
`subembodiment, the composition comprises crystalline GS-7977 having XRPD 28-
`
`reflections (0
`
`) at about: (1) 5.0 and 7.3; or (2) 6.1 and 12.7. In one preferred
`
`25
`
`subembodiment, the composition comprises crystalline GS-7977 having XRPD 28-
`
`reflections (0
`
`) at about: (1) 5.2, 7.5, 9.6, 16.7, 18.3, and 22.2; or (2) XRPD 28-reflections
`
`0
`
`) at about: 5.0, 7.3, 9.4, and 18.1. In another pr