THERAPEUTIC CLAIM Treatment of hepatitis C 

CHEMICAL NAMES 

1. Carbamic acid, N,N'-[[1,1'-biphenyl]-4,4'-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-

 pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]bis-, C,C'-dimethyl ester 

2. dimethyl N,N'-(biphenyl-4,4'-diylbis{1H-imidazole-5,2-diyl-[(2S)-pyrrolidine-2,1-

 diyl][(1S)-1-(1-methylethyl)-2-oxoethane-2,1-diyl]})dicarbamate 

MOLECULAR FORMULA C40H50N8O6

MOLECULAR WEIGHT 738.9 

SPONSOR Bristol-Myers Squibb 

CODE DESIGNATION BMS-790052 

CAS REGISTRY NUMBER 1009119-64-5

THERAPEUTIC CLAIM Treatment of hepatitis C 

CHEMICAL NAMES 

1. Carbamic acid, N,N'-[[1,1'-biphenyl]-4,4'-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-

 pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]bis-, C,C'-dimethyl ester, 

 hydrochloride (1:2) 

2. dimethyl N,N'-(biphenyl-4,4'-diylbis{1H-imidazole-5,2-diyl-[(2S)-pyrrolidine-2,1-

 diyl][(1S)-1-(1-methylethyl)-2-oxoethane-2,1-diyl]})dicarbamate dihydrochloride 

MOLECULAR FORMULA C40H50N8O6 . 2 HCl 

MOLECULAR WEIGHT 811.8 

SPONSOR Bristol-Myers Squibb 

CODE DESIGNATION BMS-790052-05 

CAS REGISTRY NUMBER 1009119-65-6 

Hepatitis C virus (HCV) is a major global health problem, with an estimated 150-200 million people infected worldwide, including at least 5 million in Europe (Pawlotsky, Trends Microbiol, 2004, 12: 96-102). According to the World Health Organization, 3 to 4 million new infections occur each year. The infection is often asymptomatic; however, the majority of HCV-infected individuals develop chronic infection (Hoof agle, Hepatology, 2002, 36: S21-S29; Lauer et al, N. Engl. J. Med., 2001, 345: 41-52; Seeff, Semin. Gastrointest., 1995, 6: 20-27). Chronic infection frequently results in serious liver disease, including fibrosis and steatosis (Chisari, Nature, 2005, 435: 930-932). About 20% of patients with chronic HCV infection develop liver cirrhosis, which progresses to hepatocellular carcinoma in 5% of the cases (Hoofnagle, Hepatology, 2002, 36: S21-S29; Blonski et al, Clin. Liver Dis., 2008, 12: 661-674; Jacobson et al, Clin. Gastroenterol. Hepatol, 2010, 8: 924-933; Castello et al., Clin. Immunol, 2010, 134: 237-250; McGivern et al., Oncogene, 2011, 30: 1969-1983).

Chronic HCV infection is the leading indication for liver transplantations (Seeff et al., Hepatology, 2002, 36: 1-2). Unfortunately, liver transplantation is not a cure for hepatitis C; viral recurrence being an invariable problem and the leading cause of graft loss (Brown, Nature, 2005, 436: 973-978; Watt et al, Am. J. Transplant, 2009, 9: 1707-1713). No vaccine protecting against HCV is yet available. Current therapies include administration of ribavirin and/or interferon-alpha (IFN-Cc), two non-specific anti-viral agents. Using a combination treatment of pegylated IFN-CC and ribavirin, persistent clearance is achieved in about 50% of patients with genotype 1 chronic hepatitis C. However, a large number of patients have contraindications to one of the components of the combination; cannot tolerate the treatment; do not respond to interferon therapy at all; or experience a relapse when administration is stopped. In addition to limited efficacy and substantial side effects such as neutropenia, haemo lytic anemia and severe depression, current antiviral therapies are also characterized by high cost. To improve efficacy of standard of care (SOC), a large number of direct acting antivirals (DAAs) targeting viral polyprotein processing and replication have been developed (Hofmann et al, Nat. Rev; Gastroenterol. Hepatol., 2011, 8: 257-264). These include small molecule compounds targeting HCV nonstructural proteins including the HCV protease, polymerase and NS5A protein. Although a marked improvement of antiviral response was observed when protease inhibitors were combined with SOC (Hofmann et al, Nat. Rev; Gastroenterol. Hepatol, 2011, 8: 257-264; Bacon et al, New Engl. J. Med., 2011, 364: 1207-1217; McHutchison et al, New Engl. J. Med., 2010, 362: 1292-1303; Poordad et al, New Engl. J. Med., 201 1, 364: 1195-1206; Hezode et al, New Engl. J. Med., 2009, 360: 1839-1850; Kwo et al, Lancet, 2010, 376: 705-716), toxicity of the individual compounds and rapid development of viral resistance in a substantial fraction of patients remain major challenges (Pawlotsky, Hepatology, 2011, 53: 1742-1751; Pereira et al, Nat. Rev. Gastroenterol. Hepatol., 2009, 6: 403-411; Sarrazin et al, Gastroenterol., 2010, 138: 447-462). New therapeutic approaches against HCV are therefore still needed. HCV entry into target cells is a promising target for antiviral preventive and therapeutic strategies since it is essential for initiation, spread, and maintenance of infection (Timpe et al, Gut, 2008, 57: 1728-1737; Zeisel et al, Hepatology, 2008, 48: 299-307). Indeed, HCV initiates infection by attaching to molecules or receptors on the surface of hepatocytes. Current evidence suggests that HCV entry is a multistep process involving several host factors including heparan sulfate (Barth et al, J. Biol. Chem., 2003, 278: 41003-41012), the tetraspanin CD81 (Pileri et al, Science, 1998, 282: 938-941), the scavenger receptor class B type I (SR-BI) (Zeisel et al, Hepatology, 2007, 46: 1722-1731; Bartosch et al, J. Exp. Med., 2003, 197: 633-642; Grove et al, J. Virol, 2007, 81 : 3162-3169; Kapadia et al, J. Virol, 2007, 81 : 374- 383; Scarselli et al, EMBO J., 2002, 21 : 5017-5025), Occludin (Ploss et al, Nature, 2009, 457: 882-886) and Claudin-1 (CLDN1), an integral membrane protein and a component of tight-junction strands (Evans et al, Nature, 2007, 446: 801-805). Furthermore, Niemann-Pick CI -like cholesterol absorption receptor has been identified as a new hepatitis C virus entry factor (Sainz et al, Nature Medicine, 2012, 18: 281-285).

Daclatasvir (USAN^[1]) (formerly BMS-790052) is an experimental drug candidate for the treatment of hepatitis C. It is being developed by Bristol-Myers Squibb.

Daclatasvir's mechanism of action involves inhibition of the HCV nonstructural protein NS5A.^[2][3] Recent research suggests that it targets two steps of the viral replication process, enabling rapid decline of HCV RNA.^[4]

Daclatasvir has been tested in combination regimens with pegylated interferon and ribavirin,^[5] as well as with other direct-acting antiviral agents including asunaprevir^[6][7][8][9] and sofosbuvir.^[10]

It may be many years before the symptoms of hepatitis C infection appear. However, once they do, the consequences are significant: patients may have developed fibrosis, cirrhosis or even liver cancer, with the end result being liver failure. Even if diagnosed early, there’s no guarantee of a cure. Only around half of patients respond to the standard therapy of an interferon plus the antiviral drug ribavirin, and while two add-on antiviral therapies were approved in 2011, the treatment period is long with no guarantee of a cure, and for non-responders treatment options remain limited.

A new drug with a different mechanism is being developed by Bristol-Myers Squibb, in conjunction with Pharmasset. Daclatasvir targets non-structural protein 5A, which is an important component of the viral replication process, although its precise role in this remains unclear. The drug is active in single oral doses, and may have potential as part of a treatment regimen that avoids the use of interferon, and in patients who do not respond to standard therapy.

In an open label Phase IIa study, 10 patients with chronic hepatitis C genotype 1b infection who did not respond to standard therapy were given daclatasvir in once daily 60mg doses, plus another experimental drug, BMS-790052, which is an NSP 3 protease inhibitor, in initial twice-daily 600mg doses, later reduced to 200mg twice a day.2 Nine patients completed 24 weeks of treatment, with the 10th discontinuing after 10 weeks. In those who completed the course, HCV RNA was undetectable at week 8, and remained so until the end of the trial, with all achieving a sustained virologic response. It was also undetectable post-treatment in the patient who discontinued.

Daclatasvir has also been investigated as monotherapy in a double blind, placebo-controlled, sequential panel, multiple ascending dose study.3 Thirty patients with chronic geno-type 1 hepatitis C infection were randomised to receive a 14 day course of the drug, in once daily doses of 1, 10, 30, 60 or 100mg, 30mg twice a day, or placebo. There was no evidence of antiviral activity in the placebo group, but the mean maximum decline of 2.8 to 4.1 log IU/ml. Most experienced viral rebound on or before day 7 of treatment, which was associated with viral variants that had previously been implicated in resistance development. It was well tolerated in all dose groups.

 M. Gao et al. Nature 2010, 465, 96

The European Medicines Agency’s Committee for Medicinal Products for Human Use(CHMP) has given an opinion on the use of daclatasvir in combination with sofosbuvir in the treatment of chronic (long-term) hepatitis C virus (HCV) infection, in a compassionate-use programme.

Compassionate-use programmes are set up at the level of individual Member States. They are intended to give patients with a life-threatening, long-lasting or seriously disabling disease with no available treatment options access to treatments that are still under development and that have not yet received amarketing authorisation. In this specific case, Sweden has requested an opinion from the CHMP on the conditions under which early access through compassionate use could be given to daclatasvir, for the use in combination with sofosbuvir, with or without ribavirin, for a specific patient population.

The recommended compassionate use is intended for adult patients at a high risk of their liver being no longer able to function normally (decompensation) or death within 12 months if left untreated, and who have a genotype 1 infection. Further, it is recognised that the potential benefit of such combination therapy may extend to patients infected with other HCV genotypes.

Daclatasvir and sofosbuvir are both first-in-class anti-viral medicines against HCV. These medicines have been studied in combination, with or without ribavirin, in aclinical trial which included treatment-naive (previously untreated) HCV genotype-1, -2 and -3 infected patients, as well as patients with genotype 1 infection who have previously failed telaprevir or boceprevir treatment. Results from the trial indicate high efficacy, also in those who have failed treatment with these protease inhibitors. Many such patients have very advanced liver disease and are in urgent need of effective therapy in order to cease the progression of liver injury.

This is the second opinion provided by the CHMP on compassionate use of medicines in development for the treatment of hepatitis C. Overall, it isthe fourth time compassionate use has been assessed by the CHMP.

The aim of the CHMP assessment and opinion on a compassionate-use programme for new medicinal products is to ensure a common approach, whenever possible, regarding the criteria and conditions of use under Member States' legislation. The opinion provides recommendations to the EU Member States that are considering setting up such a programme, and its implementation is not mandatory. In addition to describing which patients may benefit from the medicine, it explains how to use it and gives information on safety.

The assessment report and conditions of use of daclatasvir in combination with sofosbuvir with or without ribavirin in this setting will be published shortly on the Agency's website.