Background:  BMS-488043 is a novel, oral small-molecule attachment inhibitor of HIV-1 that blocks viral entry by preventing the binding of the viral envelope protein gp120 to cellular CD4 receptors. Potent and selective inhibition is observed in vitro against macrophage-, T-, and dual-tropic HIV-1. Phase I studies in healthy subjects have demonstrated promising oral bioavailability and a good safety profile.

Methods:  The antiviral activity, safety, and tolerability of BMS-488043 were evaluated in a placebo-controlled ascending multiple-dose study in HIV-1-infected adults. Inclusion criteria included being antiretroviral naive or off any antiretrovirals for >16 weeks, CD4⁺ cell count >250 cells/mL, and plasma viral load  5000-500,000 copies/mL. Two groups of 15 subjects (12 active/3 placebo per group) received 800- or 1800-mg doses of BMS-488043 or placebo every 12 hours for 8 days with a high fat meal. Viral load was assessed daily.

Results:  Preliminary data are available for the 800-mg group (12 receiving BMS-488043 and 3 placebo). Subjects had baseline mean viral load of 4.66 log₁₀ copies/mL (4.71 for BMS-488043 and 4.44 for placebo) and 403 CD4⁺ cells/mL (413 for BMS-488043 and 367 for placebo). On day 8, mean viral load changes were -0.73 log₁₀ copies/mL (range, +0.34 to -1.43) for BMS-488043 and -0.02 (range, +0.45 to -0.26) for placebo. The mean maximal viral load declines from baseline during the 2-week period after starting the study drug were -1.00 log₁₀ copies/mL (range -0.24 to -1.76) for BMS-488043 and -0.30 (range, -0.22 to -0.38) for placebo. None of placebo-treated subjects had a maximal viral load decline >0.5 log₁₀ copies/mL, whereas 8/12 (67%) BMS-488043-treated subjects had a viral load decline >0.5 log₁₀, 7/12 (58%) had a viral load decline >1.0 log₁₀, and 3/12 (25%) had a viral load decline >1.5 log₁₀. Mean change from baseline in CD4⁺ cell counts was +106 cells/mL (range, -214 to +272) for BMS-488043 and +6 (range, -35 to +47) for placebo. There were no serious adverse events and no discontinuations from the study. Mono-therapy with 8 days of BMS-488043 was generally safe and well-tolerated.

Conclusions:  Orally bioavailable small-molecule inhibitors of HIV-1 attachment to CD4 can have potent antiviral activity in HIV-1-infected subjects, providing a proof-of-concept for this new class of antiretrovirals. Further development of BMS-488043 and this class of compounds is warranted.

Keywords: New agents; Entry inhibitors; Attachment inhibitors