January 16, 2014

Journal of Hepatology

Article in Press

Bradley Vince,John M. Hill,Eric J. Lawitz,William O’Riordan,Lynn R. Webster,Daniel M. Gruener,Ricky S. Mofsen,Abel Murillo,Eileen Donovan, Jie Chen,Joseph F. McCarville,John Z. Sullivan-Bólyai,Douglas Mayers,Xiao-Jian Zhou

Received 8 October 2013; received in revised form 29 December 2013; accepted 6 January 2014. published online 15 January 2014.

Abstract

Background & Aims

Samatasvir is a pan-genotypic inhibitor of the hepatitis C (HCV) nonstructural protein 5A (NS5A). This study evaluated the antiviral activity, pharmacokinetics and safety of samatasvir monotherapy in treatment-naïve subjects infected with HCV genotype 1-4.

Methods

Thirty-four genotype 1 and thirty genotype 2, 3 or 4 subjects were randomized to receive for 3 days placebo or samatasvir 25-100 mg per day. Plasma samples for HCV RNA, pharmacokinetics and sequencing were collected up to day 10.

Results

Samatasvir achieved potent antiviral activity across genotypes: mean maximum reductions from baseline were 3.2-3.6 (genotype 1a), 3.0-4.3 (genotype 1b), 3.2-3.4 (genotype 3) and 3.6-3.9 (genotype 4) log10/mL respectively; no viral rebound was observed during the 3-day treatment period. For genotype 2 HCV, samatasvir was active in subjects with NS5A L31 polymorphism at baseline (individual range 2.5-4.1 log10/mL), but showed minimal activity in those with baseline M31 polymorphism. Samatasvir exhibited a long plasma half-life of approximately 20 hours which supports once daily dosing. Samatasvir was well tolerated in all subjects with no safety-related discontinuations or serious adverse events. The most common adverse events included constipation, nausea and headache and occurred at similar frequency in active and placebo subjects. All events were mild or moderate in intensity. There were no patterns or dose dependence of adverse events, vital signs, laboratory parameters or electrocardiograms.

Conclusions

Samatasvir 25-100 mg monotherapy for 3 days was well tolerated and induced a rapid and profound reduction in plasma HCV RNA in subjects infected with HCV genotype 1-4. Samatasvir is being evaluated in combination with other direct-acting antiviral agents in subjects with HCV infection.

Abbreviations: HCV, hepatitis C virus, NS5A, nonstructural protein 5A, DAA, direct-acting antiviral agent, EC50, 50% effective concentration, CYP, cytochrome P450, HBV, hepatitis B virus, HIV, human immunodeficiency virus, QD, once daily, BID, twice daily, AE,adverse event, BMI, body mass index, HCC, hepatocellular carcinoma, ECG, electrocardiogram, SAE, serious adverse event, PK,pharmacokinetic(s), AM, morning, PM, evening, Cmax, maximum concentration, Tmax, time to Cmax, Cτ, predose trough concentration, AUC,area under curve, t1/2, half-life, EC90, 90% effective concentration

Keywords: Samatasvir, NS5A inhibitor, Hepatitis C virus, Pan-genotypic anti-HCV activity, IDX719, NS5A, Chronic hepatitis C, Pan-genotypic antiviral activity, Direct-acting antiviral agents, Pharmacokinetics

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