Date: 2015-03-05
Type of information: Presentation of results at a congress
phase: 2a
Announcement: presentation of results at the 2015 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle
Company: BMS (USA - NY)
Product: BMS-955176
Action
mechanism: maturation inhibitor. BMS-955176 is designed to inhibit one of the last steps of the HIV-1 viral lifecycle.
Disease: HIV-1 infection
Therapeutic area: Infectious diseases
Country:
Trial details:
Latest
news: * On February 26, 2015, BMS announced data supporting the clinical development of BMS-955176, an investigational component designed to prevent the maturation of HIV-1. Presented in a late-breaking oral presentation and a poster presentation at the 2015 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, the Phase IIa study findings confirm the antiretroviral activity of BMS-955176 as an HIV-1 maturation inhibitor and support its further clinical development. The Phase IIa, randomized, multi-part trial evaluated BMS-955176 antiviral activity, safety, and exposure-response during 10 days of monotherapy in 40 HIV-1, subtype B-infected patients with HIV-1 RNA ≥5000 c/mL and CD4+ T-cell counts ≥200 cells/µL. Patients were randomized 1:1:1:1 to dose groups of 5, 10, 20 or 40 mg, and then 4:1 to receive an oral suspension of BMS-955176 (n=48) or placebo once daily (n=12) for 10 days. Twenty additional subjects were later randomized to 80 and 120 mg once-daily dose groups. The primary endpoint was change in HIV-1 RNA from baseline to Day 11, and safety and exposure-response were secondary endpoints. Median change in HIV-1 RNA from baseline to Day 11 ranged from −0.15 to −1.36 log10c/mL, and maximum median change between baseline and Day 24 (study discharge) ranged from −0.50 to −1.70 log10 c/mL across the BMS-955176 groups. There was an increase in maximum median response over the range of 5–40 mg, which plateaued at ~–1.64 log10 c/mL at doses of 40–120 mg. Maximum median declines in HIV-1 RNA were similar for the 40–120 mg once-daily dose groups regardless of baseline Gag polymorphisms (positions evaluated: V362, Q369, V370, and T371)
BMS-955176 is designed to inhibit one of the last steps of the HIV-1 viral lifecycle, resulting in the release of immature non-infectious HIV-1 particles to potentially provide a new approach to attacking the virus. In the proof-of-concept study, this next-generation maturation inhibitor drug candidate demonstrated antiviral activity in the presence of baseline HIV mutations not responsive to bevirimat, an earlier maturation inhibitor investigational candidate. BMS-955176 achieved maximum median declines of -1.70 log10 c/mL in HIV-1 RNA at a dose of 40 mg once daily, with a plateau of ~1.64 log10 c/mL observed at 40–120 mg once daily. The study’s primary endpoint of change in HIV-1 RNA from baseline to Day 11 of greater than -1 log10 c/mL in HIV-1 RNA was met.
In this proof-of-concept study, BMS-955176 showed similar maximum median declines in HIV-1 RNA against un-mutated (“wild-type”) HIV-1 or HIV-1 with naturally-occurring mutations (“gag polymorphisms”) at doses of 40, 80, and 120 mg once daily. There were no deaths, serious adverse events, adverse events (AEs) leading to discontinuation, grade 3–4 related AEs or clinically relevant grade 2–4 laboratory abnormalities. With all reported AEs except for G1-2 diarrhea in 4 subjects on BMS-955176, the same or greater percentage of subjects on placebo reported AEs as compared to subjects receiving BMS-955176. Subjects receiving placebo reported headache (42%), abnormal dreams (25%), night sweats (8%), and diarrhea (0%).
