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-1Infected Subjects

Cotte, Laurent MD*; Dellamonica, Pierre MD; Raffi, Francois MD, PhD; Yazdanpanah, Yazdan MD, PhD§; Molina, Jean-Michel MD; Boué, François MD; Urata, Yasuo MSc#; Chan, H. Phyllis PhD**; Zhu, Li PhD**; Chang, Ih PhD**; Bertz, Richard PhD**; Hanna, George J. MD**; Grasela, Dennis M. PharmD, PhD**; Hwang, Carey MD, PhD**

JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e3182965d12
Clinical Science
Abstract

Objective: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Trial registration: EUDRACT Number 2008-004810-29.

Author Information

*Service d'hépatologie et de sida, Hôtel-Dieu, Hospices Civils de Lyon and INSERM U1052, Lyon, France;

Service d'infectiologie, Université de Nice Sophia Antipolis and CHU, Nice, France;

University of Nantes, Nantes, France;

§Service Universitaire des Maladies Infectieuses et du Voyageur, Centre Hospitalier de Tourcoing, Tourcoing, France;

Department of Infectious Diseases, Hópital Saint-Louis, AP-HP and INSERM U941, University of Paris Sorbonne Cité, Paris, France;

Hôpital Antoine Beclère, Paris, France;

#Oncolys BioPharma, Tokyo, Japan; and

**Bristol-Myers Squibb, Research and Development, Princeton, NJ.

Correspondence to: Carey Hwang, MD, PhD, Bristol-Myers Squibb, Research and Development, PO Box 5400, Princeton, NJ 08543-5400 (e-mail: carey.hwang@bms.com).

Supported by Oncolys Pharma and Bristol-Myers Squibb. The authors had full access to all the data and take full responsibility for the accuracy of the data analysis. The authors received no financial support or compensation for this publication.

Presented in part at the 50th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, MA, September 12–15, 2010 (Abstract H-933) and at the 13th International Workshop on Clinical Pharmacology of HIV Therapy, Barcelona, Spain, April 16–18, 2012 (poster O_06).

F.R. has received research funding or honoraria from, or consulted for, Abbott, Avexa, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Merck & Co., Pfizer, Roche, and ViiV Healthcare; Y.Y. has received travel grants, honoraria for presentations at workshops, and consultancy honoraria from Abbott, Bristol-Myers Squibb, Boehringer-Ingelheim, Gilead, Merck, Roche, Tibotec, and ViiV Healthcare. H.P.C., L.Z., I.C., R.B., G.J.H., D.M.G., and C.H. are employees of Bristol-Myers Squibb.

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Received December 07, 2012

Accepted April 09, 2013

© 2013 Lippincott Williams & Wilkins, Inc.