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BMS-824393 Is a Potent Hepatitis C Virus NS5A Inhibitor With Substantial Antiviral Activity When Given as Monotherapy in Subjects With Chronic G1 HCV Infection
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Reported by Jules Levin
AASLD, The Liver Meeting in Boston, MA, October 29 - November 2, 2010
Nettles RE,1 Wang X,1 Quadri S,1 Wu Y,2 Gao M,3 Belema M,3 Lawitz EJ,4 Goldwater R,5 DeMicco M,6 Marbury T,7 Vutikullird AB,8 Fuentes E,9 Persson A,2 Grasela DM1
1Bristol-Myers Squibb, Research and Development, Hopewell, NJ, United States; 2Bristol-Myers Squibb, Research and Development, Princeton, NJ, United States; 3Bristol-Myers Squibb, Research and Development, Wallingford, CT, United States; 4Alamo Medical Research, San Antonio, TX, United States;
5PAREXEL International, Baltimore, MD, United States; 6Advanced Clinical Research Institute, Anaheim, CA, United States; 7Orlando Clinical Research Center, Orlando, FL, United States; 8West Coast Clinical Trials, Cypress, CA, United States; 9Elite Research Institute, Miami, FL, United States
ABSTRACT
BMS-824393 is a potent NS5A inhibitor with broad genotypic coverage, including
picomolar in vitro potency against genotypes 1a and 1b. In a combined single and multiple ascending-dose study with healthy subjects, BMS-824393 was shown to be well-tolerated and had a pharmacokinetic profile supportive of once-daily dosing.
Methods: The objectives of this open-label, multiple ascending/descending-dose, monotherapy study were to evaluate the antiviral activity, safety, tolerability, and pharmacokinetics of BMS-824393 in treatment-naive subjects with genotype 1 chronic HCV. Men or women, 18 to 60 years of age with HCV RNA ≥105 IU/mL with noncirrhotic compensated liver disease received either 1, 10, 50, or 100 mg of BMS-824393 for 3 days (10 subjects [7 G1a and 3 G1b] per dose group).
Results: Following oral administration, BMS-824393 was readily absorbed with
largely dose-proportional exposures over the studied dose range. BMS-824393
exposures were comparable to those observed in healthy subjects. The mean
terminal half-life of BMS-824393 ranged from 15 to 25 hours. The figure below shows the median decline in HCV RNA up to hour 144 for all doses after BMS-824393 administration at hours 0, 24, and 48.
Median decline in G1a HCV RNA at hour 72 after 3 doses of 1, 10, 50, and 100 mg of BMS-824393 was 2.5 log10, 3.5 log10, 3.9 log10, and 3.5 log10, respectively. Median decline in G1b HCV RNA at hour 72 after 3 doses of 10, 50, and 100 mg of BMS-824393 was 3.9 log10, 3.2 log10, and 3.5 log10, respectively. All BMS-824393 multiple doses were well-tolerated. The only adverse events that occurred in more than 1 subject were headache and backache, both of which occurred in 2 subjects, were mild, and were deemed unrelated to BMS-824393 by the investigator.
Conclusions: BMS-824393 is BMS' second NS5A inhibitor that produces a rapid and robust decline in HCV RNA following multiple doses in patients chronically infected with HCV genotype 1a or 1b. BMS-824393 was well-tolerated following multiple doses of up to 100 mg and has a pharmacokinetic 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 planned to confirm the role of NS5A inhibition in future HCV therapy.
Background & Objectives
NS5A is a multifunctional protein that plays a central role in replication of HCV, treatment of HCV infection making it an attractive target for therapeutic intervention
BMS-824393, a second NS5A inhibitor in development by BMS, is a potent and
highly selective inhibitor of HCV NS5A, with in vitro picomolar potency against
genotypes 1a and 1b
BMS-824393 was well-tolerated in single and multiple doses in healthy subjects
BMS-824393 has demonstrated a pharmacokinetic profile supportive of once-daily dosing
The objectives of the current study were to evaluate the antiviral activity,
pharmacokinetics, safety, and tolerability of BMS- 824393 in subjects
chronically infected with HCV genotype 1
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