BMS-488043 is an experimental anti-HIV drug under development by Bristol-Myers Squibb. It is sometimes called simply 043.

BMS-488043 belongs to a new class of entry or fusion inhibitors which aims to prevent the gp120 molecule of HIV attaching to the CD4 receptor. By blocking gp120, BMS-488043 may be able to prevent CD4 T-cells from becoming infected with HIV.

As an entry inhibitor which targets the interaction between virus and the primary CD4 receptor, 043 is effective against viruses that utilise either the CCR5 or CXCR4 co-receptors. See Preventing viral attachment or fusion in Anti-HIV therapy: Ways of attacking HIV for further discussion of entry inhibitors and how they work.

Current research

Preliminary studies of BMS-488043 have been conducted in HIV-positive and HIV-negative people.

A 14-day dosing study involving in healthy volunteers showed that levels five to ten times above the minimum target concentration were achieved when BMS-488043 was given at doses of 1200 and 1800mg twice daily with a high-fat meal (Hanna 2004a).

In study AI430-003, 30 HIV-positive individuals were randomised to receive BMS-488043 (800 or 1800mg twice daily) or placebo for eight days. The peak reduction in viral load was observed at day 9, averaging 1.23 log₁₀ in the 1800mg group and 1.01 log₁₀ in the 800mg group, although viral load rebounded slowly in the majority of patients. The average CD4 cell count increase was 106 cells/mm³ in the those taking BMS-488043 and 6 cells/mm³ in those taking placebo. Adverse events and laboratory abnormalities were mild, and BMS will now move forward with refining the dose in a larger phase I / II study (Hanna 2004b).

Resistance

Test tube research has provided some preliminary information about the likely resistance profile of BMS-488043. BMS-488043 resistance mutations mainly occur within the envelope protein gp120. They include V68A, M426L, M434I, S440R, and M475I. Mutations M426L or M475I, which are near to the CD4 receptor contact points, confer the highest levels of resistance. Another contact site mutation, W427V, stops the CD4 receptor from binding to gp120 but also eliminates the binding of the drug to gp120.

Mutation S375W, deep within the binding cavity, diminishes binding to BMS-488043. This demonstrates that the drug binds to gp120 at a specific region that overlaps with the CD4-gp120 binding site (Lin 2004).

References

Hanna G et al. Safety, tolerability, and pharmacokinetics of a novel, small-molecule HIV-1 attachment inhibitor, BMS-488043, after single and multiple oral doses in healthy subjects. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 535, 2004a.

Hanna G et al. Antiviral activity, safety and tolerability of a novel oral small molecule HIV-1 attachment inhibitor BMS-488043 in HIV-1 infected subjects. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 141, 2004b.

Lin PF et al. Characterization of a small molecule HIV-1 attachment inhibitor BMS-488043: virology, resistance and mechanism of action. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 534, 2004.