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A Randomized, Double-Blind, Multiple-Dose Study of the Pan-Genotypic NS5A Inhibitor Samatasvir in Patients Infected with Hepatitis C Virus Genotype 1, 2, 3 Or 4

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A Randomized, Double-Blind, Multiple-Dose Study of the Pan-Genotypic NS5A Inhibitor Samatasvir in Patients Infected with Hepatitis C Virus Genotype 1, 2, 3 Or 4 Accepted Manuscript A randomized, double-blind, multiple-dose study of the pan-genotypic NS5A inhibitor samatasvir in patients infected with hepatitis C virus genotype 1, 2, 3 or 4 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 PII: S0168-8278(14)00014-2 DOI: http://dx.doi.org/10.1016/j.jhep.2014.01.003 Reference: JHEPAT 4997 To appear in: Journal of Hepatology Received Date: 8 October 2013 Revised Date: 29 December 2013 Accepted Date: 6 January 2014 Please cite this article as: Vince, B., Hill, J.M., Lawitz, E.J., O’Riordan, W., Webster, L.R., Gruener, D.M., Mofsen, R.S., Murillo, A., Donovan, E., Chen, J., McCarville, J.F., Sullivan-Bólyai, J.Z., Mayers, D., Zhou, X-J., A randomized, double-blind, multiple-dose study of the pan-genotypic NS5A inhibitor samatasvir in patients infected with hepatitis C virus genotype 1, 2, 3 or 4, Journal of Hepatology (2014), doi: http://dx.doi.org/10.1016/j.jhep. 2014.01.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 1 A randomized, double-blind, multiple-dose study of the pan-genotypic NS5A 2 inhibitor samatasvir in patients infected with hepatitis C virus genotype 1, 2, 3 or 4 3 Bradley Vince1, John M. Hill2, Eric J. Lawitz3, William O’Riordan4, Lynn R. Webster5, 4 Daniel M. Gruener6, Ricky S. Mofsen7, Abel Murillo8, Eileen Donovan9, Jie Chen9, 5 Joseph F. McCarville9, John Z. Sullivan-Bólyai9, Douglas Mayers9, Xiao-Jian Zhou9 6 1Vince and Associates Clinical Research, Overland Park, KS; 2Avail Clinical Research, 7 DeLand, FL; 3Alamo Medical Research, San Antonio, TX; 4eStudySite, San Diego, CA; 8 5CRI Lifetree Clinical Research, Salt Lake City, UT; 6CRI Worldwide, Philadelphia, PA; 9 7St. Louis Clinical Trials, St. Louis, MO; 8AMPM Research Clinic, Miami, FL; 9Idenix 10 Pharmaceuticals, Inc., Cambridge, MA 11 Contact information: Xiao-Jian Zhou, Idenix Pharmaceuticals Inc., 320 Bent street, 4th 12 floor, Cambridge MA, USA 02141-2025. Tel. +1 617 995 9805; Fax: +1 617 995 9817; 13 E-mail address: [email protected] 14 Keywords: Samatasvir; NS5A inhibitor; hepatitis C virus; pan-genotypic anti-HCV 15 activity 16 Electronic word count: 6007 17 Number of figures and tables: 4 Figures; 4 Tables 18 Trial registration number: ClinicalTrials.gov Identifier: NCT01508156 2 19 Abbreviations: HCV, hepatitis C virus; NS5A, nonstructural protein 5A; DAA, direct- 20 acting antiviral agent; EC50, 50% effective concentration; CYP, cytochrome P450; HBV, 21 hepatitis B virus; HIV, human immunodeficiency virus; QD, once daily; BID, twice daily; 22 AE, adverse event; BMI, body mass index; HCC, hepatocellular carcinoma; ECG, 23 electrocardiogram; SAE, serious adverse event; PK, pharmacokinetic(s); AM, morning; 24 PM, evening; Cmax, maximum concentration; Tmax, time to Cmax; Cτ, predose trough 25 concentration; AUC, area under curve; t1/2, half-life; EC90, 90% effective concentration 26 Conflict of interest: 27 B.V., J.M.H., E.J.L., W.O’R., L.R.W., D.M.G., R.S, A.M. were clinical investigators 28 contracted by Idenix Pharmaceuticals, Inc to conduct the reported study. E.D., J.C., 29 J.F.M., J.Z.S.B, D.M., X.J.Z. are employees of Idenix Pharmaceuticals, Inc. 30 Financial support: This study was sponsored by Idenix Pharmaceuticals, Inc., 31 Cambridge, MA, USA. 32 3 33 Abstract 34 Background & Aims: Samatasvir is a pan-genotypic inhibitor of the hepatitis C (HCV) 35 nonstructural protein 5A (NS5A). This study evaluated the antiviral activity, 36 pharmacokinetics and safety of samatasvir monotherapy in treatment-naïve subjects 37 infected with HCV genotype 1-4. 38 Methods: Thirty-four genotype 1 and thirty genotype 2, 3 or 4 subjects were randomized 39 to receive for 3 days placebo or samatasvir 25-100 mg per day. Plasma samples for HCV 40 RNA, pharmacokinetics and sequencing were collected up to day 10. 41 Results: Samatasvir achieved potent antiviral activity across genotypes: mean maximum 42 reductions from baseline were 3.2-3.6 (genotype 1a), 3.0-4.3 (genotype 1b), 3.2-3.4 43 (genotype 3) and 3.6-3.9 (genotype 4) log10/mL respectively; no viral rebound was 44 observed during the 3-day treatment period. For genotype 2 HCV, samatasvir was active 45 in subjects with NS5A L31 polymorphism at baseline (individual range 2.5-4.1 log10/mL), 46 but showed minimal activity in those with baseline M31 polymorphism. Samatasvir 47 exhibited a long plasma half-life of approximately 20 hours which supports once daily 48 dosing. Samatasvir was well tolerated in all subjects with no safety-related 49 discontinuations or serious adverse events. The most common adverse events included 50 constipation, nausea and headache and occurred at similar frequency in active and 51 placebo subjects. All events were mild or moderate in intensity. There were no patterns 52 or dose dependence of adverse events, vital signs, laboratory parameters or 53 electrocardiograms. 54 Conclusions: Samatasvir 25-100 mg monotherapy for 3 days was well tolerated and 55 induced a rapid and profound reduction in plasma HCV RNA in subjects infected with 4 56 HCV genotype 1-4. Samatasvir is being evaluated in combination with other direct-acting 57 antiviral agents in subjects with HCV infection. (265 words) 58 Keywords: Samatasvir, IDX719, NS5A, chronic hepatitis C, pan-genotypic antiviral 59 activity, direct-acting antiviral agents, pharmacokinetics 60 Introduction 61 Direct-acting antiviral agents (DAAs) have radically reshaped the treatment paradigm of 62 chronic hepatitis C virus (HCV) infection. While pegylated interferon still remains as an 63 essential component of the current optimal treatment regimens containing either 64 telaprevir or boceprevir, major efforts are being devoted towards the development of 65 interferon-free all oral regimens by combining multi-class DAAs with or without 66 ribavirin. A number of newer DAAs with improved safety profile and antiviral activity 67 are expected to soon receive regulatory approval, bringing better treatment options to 68 HCV-infected patients [1]. 69 Amongst various classes of DAAs, nonstructural protein 5A (NS5A) replication 70 complex inhibitors have thus far been the most potent in suppressing viral replication 71 [2,3]. These compounds have been shown to induce multi-log reductions in plasma HCV 72 RNA within hours of a single low dose [4,5]. While NS5A inhibitors are most active 73 against HCV genotype 1b, many showed much less replicon activity against other 74 genotypes, particularly genotype 2 and genotype 3 [2,3]. Considering the high 75 prevalence of multiple HCV genotypes across many geographic regions, it’s highly 76 desirable for a DAA to possess pan-genotypic antiviral activity [6]. In that context, 5 77 several newer NS5A inhibitors with in vitro pan-genotypic antiviral activity are being 78 developed (samatasvir, ACH-3102, GS5816, PPI668) [2,3]. To our knowledge, among 79 these candidates, samatasvir, as a single agent, was the first to demonstrate pan-genotypic 80 activity in HCV-infected patients [5]. 81 Samatasvir (IDX719), a novel NS5A inhibitor of HCV replication, exhibits potent 82 and pan-genotypic anti-HCV activity with in vitro 50% effective concentration (EC 50) 83 values ranging from 2 to 24 pM against HCV of genotypes 1a, 1b, 2a, 3a, 4a and 5a. 84 There is only a 12-fold shift in EC50 values from the most sensitive genotype 4a to the 85 least sensitive genotype 2a. With a 50% cytotoxicity concentration >50 µM, samatasvir 86 has a high selectivity index of at least 2,000,000 [7,8]. Fig. 1 illustrates the chemical 87 structure of samatasvir. 88 Samatasvir showed limited or no inhibition of human CYP enzymes or human 89 transporters, and underwent very limited metabolism in vitro. In replicon studies, 90 samatasvir demonstrated additive antiviral activity with other HCV therapeutic agents 91 and no negative pharmacodynamic interaction with commonly used antiviral agents 92 against hepatitis B (HBV) and human immunodeficiency virus (HIV). Together, these 93 favorable characteristics make samatasvir an ideal component of all-oral DAA regimens 94 [8]. 95 Samatasvir was evaluated in a two-part clinical study. Part one included single- 96 dose escalation and repeat dose administration in healthy subjects and an exploratory 97 single-dose administration in subjects infected with HCV genotype 1, 2 or 3. Results 98 from part one, reported elsewhere, showed that single and repeat doses of samatasvir up 6 99 to 100 mg in healthy volunteers and single doses up to 100 mg in HCV-infected subjects 100 were well-tolerated and achieved pharmacologically relevant drug exposure. Samatasvir 101 exhibited dose-proportional plasma exposure and long plasma half-life, supporting once 102 daily (QD) dosing [5]. Single doses of samatasvir demonstrated substantial pan-genotypic 103 antiviral activity of up to 3.7 log10 IU/mL in patients with genotype 1, 2 or 3 HCV [5]. 104 Part two of the study, reported here, evaluated the safety, pharmacokinetics (PK) 105 and antiviral activity of samatasvir as a single agent following multiple doses up to 100 106 mg daily for 3 days in subjects infected with HCV genotype 1, 2, 3 or 4. 107 Materials and methods 108 Study Design 109 This was a multicenter, randomized, double-blind, placebo-controlled, parallel-panel, 110 multiple-dose study of samatasvir as a single agent dosed for 3 days in treatment-naïve 111 patients with chronic HCV genotype 1, 2, 3 or 4.
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