Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: A randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial

Hôpital Cochin, Paris, France.
The Lancet Infectious Diseases (Impact Factor: 22.43). 06/2012; 12(9):671-7. DOI: 10.1016/S1473-3099(12)70138-X
Source: PubMed


Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV.
In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 μg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with, number NCT00874770.
48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups.
Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection.
Bristol-Myers Squibb.

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    • "Apart from the mediocre response, the other main disadvantage of interferon is its high cost forming a huge burden on the economy of developing countries, such as Egypt. Novel direct acting antivirals (DAAs) have shown very promising results, but until these results are confirmed and until the substantial cost of these agents is reduced to be feasible for use in developing countries, pegylated interferon will remain the mainstay of treatment for several more years (Pol and others 2012; Lawitz and others 2013a, 2013b). A novel linear 20 kDa pegylated interferon alpha-2a derived from the yeast Hansenula polymorpha (Reiferon Retard , Minapharm Pharmaceuticals, Cairo, Egypt) has been approved for the treatment of HCV in Egypt despite the scarcity of clinical studies supporting its efficacy (Taha and others 2010). "
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    • "Replication complex NS5A inhibitors Daclatasvir (BMS-790052) is a potent and highly selective NS5A replication complex inhibitor with broad genotypic coverage (genotypes 1—5) and a pharmacokinetic profile supportive of QD dosing [Gao et al. 2010]. Daclatasvir is the first NS5A replication complex inhibitor to enter clinical development for the treatment of chronic hepatitis C. Its antiviral efficacy and resistance profile have been reported in phase IIa and IIb studies in combination with PR for 24—48 weeks resulting in around 75% of SVR rate in genotype-1-infected patients (eRVR was 100% in genotype-4-infected patients) [Pol et al. 2012; Hezode et al. 2012b] but poorer results were achieved in experienced patients [Ratziu et al. 2012]. "
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    Preview · Article · Jun 2013 · Therapeutic Advances in Infectious Disease
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    • "HCV NS5A inhibitor daclatasvir (BMS-790052) with potent clinical effects has been found in the HCV replicon system [54]. Daclatasvir is a potent NS5A replication complex inhibitor and increases the antiviral potency of peginterferon and ribavirin [55] (Tables 4). "
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