Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1

Abstract

The antiviral activity, resistance profile, pharmacokinetics (PK), safety, and tolerability of BMS‐790052, a nonstructural protein 5A (NS5A) replication complex inhibitor, were evaluated in a double‐blind, placebo‐controlled, sequential panel, multiple ascending dose study. Thirty patients with chronic hepatitis C virus (HCV) genotype 1 infection were randomized to receive a 14‐day course of BMS‐790052 (1, 10, 30, 60, or 100 mg once daily or 30 mg twice daily) or placebo in a ratio of 4:1. The mean maximum decline from baseline in HCV RNA ranged from 2.8 to 4.1 log10 IU/mL; the placebo group showed no evidence of antiviral activity. Most patients experienced viral rebound on or before day 7 of treatment with BMS‐790052 monotherapy; viral rebound was associated with viral variants that had been previously implicated in resistance development in the in vitro replicon system. The PK profile was supportive of once‐daily dosing with median peak plasma concentrations at 1‐2 hours postdose and mean terminal half‐life of 12‐15 hours. Steady state was achieved following 3‐4 days of daily dosing. BMS‐790052 was well tolerated in all dose groups, with adverse events occurring with a similar frequency in BMS‐790052‐ and placebo‐treated groups. There were no clinically relevant changes in vital signs, laboratory, or electrocardiogram parameters. Conclusion: BMS‐7590052 is the first NS5A replication complex inhibitor with multiple dose proof‐of‐concept in clinic. At doses of 1‐100 mg daily, BMS‐790052 was well tolerated, had a PK profile supportive of once‐daily dosing, and produced a rapid and substantial decrease in HCV‐RNA levels in patients chronically infected with HCV genotype 1. (HEPATOLOGY 2011

Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS-790052 in Humans: In Vitro and In Vivo Correlations

“…5 In this study, the variant with Q30R-H58D substitutions displayed the highest level of resistance (>400,000-fold) ( Table 2). Though Q30R is a common genotype 1a BMS-790052-resistant mutation, 5,6 the H58D substitution was not detected in the European HCV database. However, H58D was also identified in patient Q who, like patient S, was a member of the 100-mg cohort.…”

“…Five patients in each panel were randomized to receive a 14-day course of orally administered BMS-790052 or placebo in a ratio of 4:1; thus, a total of 24 patients received BMS-790052. 6 The study was approved by the institutional review boards in all study centers and conducted in accord with good clinical practice and the ethical principles that have their origin in the Declaration of Helsinki. 6 Informed written consent was obtained from all patients.…”

“…6 Informed written consent was obtained from all patients. HCV RNA levels were determined using the Roche Cobas TaqMan HCV Test, v2.0 (lower limit of quantification, 25 IU/mL; lower limit of detection, 10 IU/mL; Roche, Pleasanton, CA) at baseline and days 1 (2,4,6,8,12,16, and 20 hours post-first dose), 2,3,4,5,7,9,11,14,15,16,17,21, and 28. Viral breakthrough was defined as an HCV RNA increase by at least 0.5 log 10 after HCV RNA nadir while receiving BMS-790052.…”

“…The complete study design and resistance analysis methodology have been described elsewhere. 5,6 (days 1 [4,8, and 12 hours post-first dose], 2, 4, 7, and 14) for all patients receiving BMS-790052 when HCV RNA levels were >1,000 IU/mL and, in some instances, when HCV RNA levels were <1,000 IU/ mL. Variants identified within the N-terminal region of NS5A by population sequencing are shown in Tables 1 and 2.…”

“…In contrast, viral breakthrough was observed less often in patients infected with HCV genotype 1b, and, in several patients, HCV RNA dropped below the level of quantitation (<25 IU/mL). 6 The primary aims of the genotypic and phenotypic analysis of specimens from the MAD study were to (1) determine whether clinically relevant resistant variants identified during 14 days of monotherapy with BMS-790052 would correlate with resistance selected in vitro; (2) assess the prevalence of variants at baseline and the emergence of resistance at different times during dosing; and (3) examine the resistance profile and replicative ability (i.e., fitness) of variants. This article describes the viral variants identified by population sequencing and the phenotypic analysis of these variants using transient replicon replication assays.…”