AEGiS-11CROI: Antiviral Activity, Safety, and Tolerability of a Novel, Oral Small-molecule HIV-1 Attachment Inhibitor, BMS-488043, in HIV-1-infected Subjects a Novel, Oral Small-Molecule HIV-1 Attachment Inhibitor, BMS-488043, in HIV-1-Infected Subjects

11th Conference on Retroviruses and Opportunistic Infections

San Francisco, California - February 8 - 11, 2004

Antiviral Activity, Safety, and Tolerability of a Novel, Oral Small-molecule HIV-1 Attachment Inhibitor, BMS-488043, in HIV-1-infected Subjects a Novel, Oral Small-Molecule HIV-1 Attachment Inhibitor, BMS-488043, in HIV-1-Infected Subjects

Conf Retroviruses Opportunistic Infect. 2004 Feb 8-11;11th:Abstract No. 141

G Hanna¹, J Lalezari², J Hellinger³, D Wohl⁴, T Masterson¹, W Fiske¹, J Kadow¹, P Lin¹, M Giordano¹, R Colonno¹, and D Grasela¹
¹Bristol-Myers Squibb Co., Princeton, NJ, USA; ²Quest Clin. Res., San Francisco, CA, USA; ³Community Res. Initiative of New England, Boston, MA, USA; and ⁴Univ. of North Carolina at Chapel Hill, USA

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 naïve 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.

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Copyright © 2004 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.