Randomized Placebo-Controlled Study of the Safety, Tolerability, Antiviral Activity, and Pharmacokinetics of 10-Day Monotherapy With BMS-986001, a Novel HIV NRTI, in Treatment-Experienced HIV-1–Infected Subjects

Abstract

To investigate the safety, tolerability, pharmacokinetics, and antiviral activity of BMS-986001 (a nucleoside reverse transcriptase inhibitor) in treatment-experienced, HIV-1-infected subjects not exposed to antiretroviral treatment in the previous 3 months. Thirty-two HIV-1-infected subjects were randomized (3:1) to receive BMS-986001 or placebo once daily for 10 days in this double-blind, placebo-controlled, dose-escalating monotherapy phase IIa study. There were 4 treatment groups (100, 200, 300, and 600 mg, all once daily) of 8 subjects each (BMS-986001, n = 6/placebo n = 2). BMS-986001 was generally well tolerated, with no discontinuations due to adverse events and no deaths occurring. Adverse events were experienced by 22 of 24 BMS-986001-treated subjects and did not seem to be dose related. The majority were mild and considered unrelated or unlikely to be related to the study drug. The pharmacokinetics of BMS-986001 were dose proportional. Median decrease in plasma HIV-1 RNA from baseline to day 11 was 0.97, 1.15, 1.28, and 1.15 log10 copies/mL for BMS-986001 at 100, 200, 300, and 600 mg, respectively. Plasma area under the curve correlated with the antiviral activity of BMS-986001, indicating that area under the curves produced by 100-600 mg doses were on the upper end of the exposure-response curve. One subject with a single thymidine analog mutation at baseline responded well to BMS-986001. Administration of BMS-986001 for 10 days resulted in substantial decreases in plasma HIV-1 RNA levels for all dose groups and was generally well tolerated. These data support continued clinical development of BMS-986001 at a dose of 100 mg, once daily or greater. EUDRACT Number 2008-004810-29.