15   AI424-007: 48-Week Safety and Efficacy Results from a Phase II Study of a Once-Daily HIV-1 Protease Inhibitor (PI), BMS-232632.

K. Squires*¹, J. Gatell², P. Piliero³, I. Sanne⁴, R. Wood⁵, and S. M. Schnittman⁶.
¹Univ. of Alabama at Birmingham;²Hosp. Clin. y Provincial, Barcelona, Spain;³Albany Med. Coll., NY;⁴WHC Infectious Diseases Clin. Trials Unit, Johannesburg, South Africa;⁵Diana, Princess of Wales HIV Res. Fndn., Capetown, South Africa; and⁶Bristol-Myers Squibb, Wallingford, CT.

Background:BMS-232632 (BMS) is a PI with potent activity in vitro (EC₅₀2-5 nM), a favorable resistance profile, and a PK profile that supports once-daily dosing.

Methods:This phase II, 2-staged randomized study compares the safety and antiretroviral activity of 3 dose levels of BMS with nelfinavir (NFV) 750 mg tid both as monotherapy (2 wk) and in combination with didanosine (ddI) and stavudine (d4T) in antiretroviral-naive subjects with greater than or equal to 2000 copies/mL HIV RNA. Interim analyses at 24 and 48 wk were planned.

Results:Ninety-two subjects were treated (98 randomized) in stage I (med f/u 32 wk), and 166 were treated (265 randomized) in stage II (med f/u 16 wk). Baseline RNAs were 4.80 and 4.65 log₁₀copies/mL in the 2 stages, respectively. Significant proportions of subjects achieved <400 and <50 copies/mL HIV RNA in all treatment groups at 12 (stage II) and 24 wk (stage I). For example, with BMS 400 mg once daily at 12 wk in stage II (n=265), 70% of subjects achieved <400 copies/mL and 31% achieved <50 copies/mL HIV RNA. BMS has been well tolerated both alone and in combination. Common adverse events in stage II were diarrhea (17% BMS, 51% NFV), infection and nausea (13% BMS, 7% NFV). Asymptomatic unconjugated hyperbilirubinemia not associated with hepatic transaminitis, the most common lab abnormality seen with BMS (71%), was dose dependent and predominantly grade 1-2. Increases in CD4⁺cell count were seen in all treatment groups. To date, no significant elevations in cholesterol, LDL-cholesterol, or triglycerides were observed in the BMS arm, in contrast to the NFV arm, which demonstrated prompt, sustained rises of 20-50 mg/dL. Results of stage I, 48 wk efficacy and safety including lipid measurements will be presented.

Conclusions:These results support the safety and tolerability and antiretroviral efficacy of BMS as a once-daily PI in a combination regimen compared with a reference regimen.