Background: BMS-955176 is a 2nd-generation HIV-1 maturation inhibitor (MI). A 1st”‘generation MI (bevirimat) showed clinical efficacy in early-phase studies, but ~50% of subjects had reduced viral susceptibility associated with naturally occurring polymorphisms in Gag. We assessed BMS-955176 antiviral activity, safety, and exposure–response during 10 days of monotherapy in HIV-1, subtype B-infected subjects.
Methods: AI468002 (NCT01803074) is a Phase 2a, randomized, multi-part trial. Forty HIV-1, subtype B-infected subjects with HIV-1 RNA ≥5000 c/mL and CD4+ T-cell counts ≥200 cells/µL were randomized 1:1:1:1 to BMS-955176 dose groups of 5, 10, 20 or 40 mg, then 4:1 to receive an oral suspension of BMS-955176 or placebo once daily (QD) for 10 days. Twenty additional subjects were later randomized to 80 and 120 mg QD dose groups. The primary endpoint was change in HIV-1 RNA from baseline to Day 11; safety and exposure–response were secondary endpoints.
Results: Overall, 60 subjects were randomized to receive either BMS-955176 (n=48) or placebo (n=12). Median change in HIV-1 RNA from baseline to Day 11 ranged from −0.15 to −1.36 log10 c/mL and maximum median change between baseline and Day 24 (study discharge) ranged from −0.50 to −1.70 log10 c/mLacross the BMS-955176 groups. An exposure–response relationship was observed; there was an increase in maximum median response over the range of 5–40 mg QD, which plateaued at ~–1.64 log10 c/mL at doses of 40–120 mg QD. Maximum median declines in HIV-1 RNA were similar for the 40–120 mg QD dose groups regardless of baseline Gag polymorphisms (positions evaluated: V362, Q369, V370, and T371). BMS-955176 was generally well tolerated at all doses. There were no deaths, serious adverse events (SAEs), AEs leading to discontinuation, grade 3–4 related AEs or clinically relevant grade 2–4 laboratory abnormalities.
Conclusions: BMS-955176 achieved maximum median declines of >1 log10 c/mL in HIV-1 RNA at doses of 20–120 mg QD. Response increased with doses up to 40 mg QD, with a plateau of ~–1.64 log10 c/mL observed at 40–120 mg QD. The greatest response achieved was a maximum median change of –1.70 log10 c/mL in the 40 mg group. Unlike 1st-generation MIs, in this proof-of-concept study BMS-955176 showed similar antiviral activity in subjects with wild-type HIV-1 or HIV-1 with Gag polymorphisms. BMS-955176 was generally well tolerated at all doses. Phase 2b studies for BMS-955176 will begin Q2, 2015.