• AI424-007: 48-Week Safety and Efficacy Results from a Phase II Study of a Once-Daily HIV-1 Protease Inhibitor (PI), BMS-232632 (Slide Session 15)
  Authored by K. Squires, J. Gatell, P. Piliero, I. Sanne, R. Wood, and S. M. Schnittman
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There is a continued need to find new and improved drugs to fight HIV. For new protease inhibitors, desirable features include increased convenience, better tolerability, good potency, less effect on lipids and insulin, and ideally, activity against protease resistant virus. Kathleen Squires of USC presented data on a phase II study of the new once-a-day protease inhibitor from Bristol-Myers Squibb that gave some information on how that drug will measure up against these criteria. Although not active against highly protease cross-resistant viruses, the BMS protease retains activity against virus resistant to up to three protease inhibitors.

This study compared three doses of the drug still known by the catchy name of BMS-232632 to nelfinavir in treatment-naive patients. BMS-232 was dosed as 200mg, 400mg, or 500mg once a day, and nelfinavir was dosed at 750mg three times daily. Phase I of the study involved 98 patients who have been followed for 48 weeks. Phase II began after safety review of the Phase I data, and involved 322 patients (about 80/arm). This presentation concentrated on 24-week data for the larger Phase II. After a two-week period of monotherapy, all patients added d4T and ddI.

At 24 weeks, 65-68% of patients on the BMS-232 arms had viral loads less than 400 by intent-to-treat analysis, compared to 63% on the nelfinavir arm. Using the less than 50-copy assay, 30 and 40% of patients were below the limit of detection on the BMS-232 arms' 400mg and 500mg arms, compared to 22% on nelfinavir.

The major side effect of BMS-232 was increased bilirubin, leading to asymptomatic jaundice in some patients. Total cholesterol increased minimally in the BMS-232-treated patients and by 50mg in the nelfinavir-treated patients. Most of the cholesterol increase in the BMS arm was HDL cholesterol, the so-called good cholesterol associated with lower risk of heart disease. Interestingly, the LDL ("bad") cholesterol did not increase on BMS-232, but increased by 30mg on the nelfinavir arm.

Overall, the early indications are that the BMS-232 compound is safe and well tolerated. However, the overall response rates in this small trial are not that impressive. The trial was performed on four continents, and it is not wise to try and make too much from a small trial or to compare one trial with another. Nonetheless, it will be important to see how the efficacy stacks up in the definitive trials with good comparison arms. The lack of effect on cholesterol and the once-a-day dosing could prove to be significant advantages. Another poster at this conference demonstrated that adding ritonavir to BMS-232 greatly increases the trough levels. This may lead to greater efficacy in naive patients and opens the door to trials for protease inhibitor salvage.