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BMS-790052, a First-in-Class Potent Hepatitis C Virus NS5A Inhibitor, Demonstrates Multiple-Dose Proof-of-Concept in Subjects With Chronic GT1 HCV Infection (potent, mean maximal 5.7 log reduction)
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Reported by Jules Levin
AASLD Nov 2 2010 Boston
Nettles RE,1 Sevinksy H,1 Chung E,1 Burt D,2 Xiao H,1 Marbury T,3 Goldwater R,4 DeMicco M,5 Rodriguez-Torres M,6 Fuentes E,7 Vutikullird A,8 Lawitz E,9 Persson A,2 Bifano M,1 and Grasela DM1
1Bristol-Myers Squibb, Research and Development, Hopewell, NJ; 2Bristol-Myers Squibb, Research and Development, Princeton, NJ; 3Orlando Clinical Research Center, Orlando, FL; 4PAREXEL International, Baltimore, MD; 5Advanced Clinical Research Institute, Anaheim, CA; 6Fundacion de Investigacion de Diego, Santurce, Puerto Rico;
7Elite Research Institute, Miami, FL; 8West Coast Clinical Trials, Cypress, CA; 9Alamo Medical Research, San Antonio, TX.
ABSTRACT
Background: NS5A plays a central role in hepatitis C virus (HCV) replication. BMS-790052 is a first-in-class and potent NS5A inhibitor with broad genotypic coverage. In a multiple ascending-dose (MAD) study with healthy subjects, BMS-790052 was shown to be well-tolerated and had a pharmacokinetic (PK) profile supportive of once-daily dosing.
Methods: The objectives of this randomized, double-blind, placebo-controlled, MAD monotherapy study were to evaluate the antiviral activity, safety, tolerability, and PK of BMS-790052 in treatmen-tnaive subjects infected with genotype 1 HCV. Men and women, 18 to 60 years of age with HCV RNA ≥105 IU/mL with noncirrhotic compensated liver disease, were eligible to participate in the study. Patients were randomized to receive 14 days of 1, 10, 30, 60, or 100 mg once-daily (QD) or 30 mg twice-daily (BID) of BMS-790052 or placebo (5 patients per dose; active:placebo = 4:1).
Results: Following oral administration, BMS-790052 was readily absorbed with largely dose-proportional exposures over the studied dose range. The mean terminal half-life of BMS-790052 was approximately 13 to 15 hours. Mean maximum declines in HCV RNA in genotype 1a- and 1binfected subjects after multiple doses of 1, 10, 30, 60, and 100 mg QD and 30 mg BID BMS-790052 were as follows:
The antiviral effect was not sustained for the entire 14 days of dosing and some subjects experienced viral rebound on or before day 7 of dosing. All BMS-790052 multiple doses were welltolerated and had a safety profile similar to that of placebo. There were no serious adverse events or discontinuations due to adverse events. The only adverse event that occurred in >10% of subjects
was headache, reported in 5 (20.8%) subjects receiving BMS-790052 and 2 (33.3%) placebo recipients.
Conclusions: BMS-790052 is a potent NS5A inhibitor that produces a robust decline in HCV RNA following multiple doses in subjects chronically infected with either HCV genotype 1a or genotype 1b. A subsequent clinical study of BMS-790052 in treatment-naive genotype 1 HCV subjects demonstrated potent early antiviral activity against both genotypes 1a and 1b when combined with
pegylated interferon/ribavirin. BMS-790052 was well-tolerated in multiple doses of up to 100 mg and has a PK profile that supports once-daily dosing. These results support the importance of inhibiting NS5A-mediated HCV replication in the treatment of HCV. Further studies are under way to confirm the role of NS5A inhibition in HCV therapy.
BACKGROUND & OBJECTIVES
NS5A is a multifunctional protein required for in vivo and in vitro hepatitis C virus (HCV) replication; it has no known human homologues, making it an attractive target for therapeutic intervention1
BMS-790052 is a first-in-class, potent, and highly selective inhibitor of HCV NS5A, with in vitro picomolar potency
BMS-790052 was generally well-tolerated in single doses of up to 100 mg in patients with chronic HCV genotype 1
A multiple ascending-dose (MAD) study of BMS-790052 in healthy subjects demonstrated a pharmacokinetic (PK) profile that supports once-daily dosing
BMS-790052 produced a robust decline in HCV RNA following a single dose in subjects chronically infected with HCV genotype 1
The objectives of the current MAD study were to evaluate the antiviral activity, PK, safety, and tolerability of BMS-790052 in subjects chronically infected with HCV genotype 1
1. Gao M, et al. Nature. 2010;465:96-100.
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