New NRTI BMS-986001 Potently Suppresses HIV in Early Monotherapy Study

BMS-986001, a novel thymidine nucleoside reverse transcriptase inhibitor (NRTI) being developed by Bristol-Myers Squibb, demonstrated good antiviral activity and appeared safe and well-tolerated in a 10-day monotherapy study, researchers reported in the July 1, 2013, Journal of Acquired Immune Deficiency Syndromes.

Antiretroviral therapy (ART) has improved dramatically since the advent of effective combination treatment, but there is still a need for new drugs for individuals who have developed drug resistance, cannot tolerate, or do not respond well to existing options. Thymidine nucleoside analogs have potent activity against HIV, but the 2 available drugs in this class -- zidovudine (AZT; Retrovir) and stavudine (d4T; Zerit) -- are associated with numerous side effects.

Laurent Cotte from INSERM in Lyon and colleagues conducted a Phase 2a clinical trial to evaluated the safety, tolerability, antiviral activity, and pharmacokinetics of BMS-986001 in previously treated HIV patients.

The analysis included 32 adults with HIV who were treatment-experienced but had not used antiretroviral drugs during the preceding 3 months. Most (about 80%) were men and the median age was approximately 45 years. They had previous taken a median of 4 antiretrovirals, reaching a maximum of 12. They had viral loads of at least 5000 copies/mL and stable CD4 T-cell counts of >250 cells/mm³ at baseline. People with impaired liver or kidney function or hepatitis B or C coinfection were excluded.

Participants were randomly assigned (3:1) to receive BMS-986001 monotherapy at doses of 100, 200, 300, or 600 mg once-daily, or else placebo, for 10 days.

Results

• Median decreases in plasma viral load from baseline to day 11 were -0.97, -1.15, -1.28, and -1.15 log copies/mL, respectively, in the 100, 200, 300, and 600 mg BMS-986001 dose groups, compared with -0.11 in the placebo group.
• 3 people showed decreased response to BMS-986001 on day 11, but none of them had NRTI-associated resistance mutations detected.
• 1 individual with a single pre-existing thymidine analog mutation at baseline responded well to BMS-986001.
• CD4 cell counts rose overall, but gains varied across arms with no clear pattern.
• BMS-986001 pharmacokinetics were dose-proportional.
• BMS-986001 plasma area under the curve, or total drug exposure, correlated with antiviral activity.
• BMS-986001 was generally safe and well-tolerated, with no early discontinuations due to adverse events.
• Most participants (84%) reported some treatment-emergent adverse events, including fatigue, headache, and gastrointestinal symptoms.
• Adverse events were mostly mild, did not appear to be dose-related, and were considered unlikely to be related to the study drug.

"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," the study authors concluded. "These data support continued clinical development of BMS-986001 at a dose of 100 mg, once-daily or greater."

A Phase 2b trial of BMS-986001 at doses of 100, 200, and 400 mg, as part of triple therapy with lamivudine (Epivir) and efavirenz (Sustiva) for treatment-naive patients, is currently underway but is no longer recruiting participants.

6/19/13

Reference

L Cotte, P Dellamonica, F Raffi, et al. 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. Journal of Acquired Immune Deficiency Syndromes 63(3):346-354. July 1, 2013.