Published in the Bulletin of Experimental Treatments for AIDS Summer 1999 issue, by the San Francisco AIDS Foundation.

Summer 1999 Table of Contents

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BMS-232632: A Once Daily Protease Inhibitor in Development

By Nicholas Cheonis

Among anti-HIV drugs currently in the pipeline, BMS-232632, an HIV-1 protease inhibitor (PI) being developed by Bristol-Myers Squibb, displays significant promise. Based on early evidence showing it to be a powerful new agent against HIV replication, BMS-232632 has been slated for fast-track development. Preliminary studies indicate that it also could become the first PI ever to be approved for once-a-day dosing.

BMS-232632 is active against a wide range of HIV-1 strains in vitro. Like all PIs, BMS-232632 works by preventing the HIV protease enzyme from functioning normally-that is, breaking apart long strands of viral protein into separate proteins (i.e., viral core and enzymes), a step that is necessary for the virus to continue replicating. This new PI appears to be highly effective against viral reproduction: comparative test-tube studies have shown that BMS-232632 is more potent-up to 19-fold-than any of the other currently approved HIV-1 PIs. In laboratory tests, BMS-232632 is able to reduce HIV viral yield by 50% at concentrations (2-5 nM [nanomolar]) well below those of the currently licensed drugs in its class. If this new PI remains as potent in vivo as it is in the test tube, it may be prescribed in low doses, which could result in fewer of the side effects that are often associated with PIs, such as body fat abnormalities and sharp increases in blood lipid levels. Until more clinical data are collected, however, such projections are speculative.

Resistance Profile

One of the most attractive features of this new PI is its resistance profile, which appears to be quite different from those of the existing PIs. A cross-resistance study involving five other PIs indicates that BMS-232632 has activity against HIV that is resistant to nelfinavir (Viracept), saquinavir (Fortovase), and amprenavir (Agenerase); virus resistant to indinavir (Crixivan) and ritonavir (Norvir) displayed partial cross-resistance to the new PI. In reciprocal experiments, results showed that BMS-232632-resistant virus remains sensitive to saquinavir while showing some resistance to the other PIs. BMS-232632 therefore could become a viable treatment option for many people who have already developed resistance to the presently available protease-inhibiting drugs.

Genotypic and phenotypic analyses have indicated that the most significant mutation for BMS-232632 resistance occurs at codon 88, which is different from the other five PIs. Researchers also have found that BMS-232632 works synergistically (with enhanced effects) when combined with other PIs and with most of the nucleoside analogs, which may lead to more potent drug therapy combinations down the line.

Clinical Trial Data

At the 6th Conference on Retroviruses and Opportunistic Infections (CROI) this past February, a research team from Bristol-Myers Squibb reported on a randomized, double-blind, placebo-controlled phase I study of BMS-232632 in volunteers who were not infected with HIV. Single oral doses of 100, 300, 600, 900, and 1,200 mg were given to five groups of eight subjects. In each dose group six subjects were given drug and two were given placebo.

Data from this initial clinical trial of BMS-232632 showed that the drug was well tolerated. Bioavailability of a capsule formulation was approximately 60% relative to that of an oral solution. Treatment-related adverse events were generally mild and reversible; a few cases of diarrhea and gastrointestinal discomfort were reported. Among those subjects taking the two highest doses, 3/16 (18.7%) experienced asymptomatic, reversible elevations of unconjugated bilirubin. High bilirubin levels indicate a disturbance in bile pigment metabolism in the liver.

Much of the interest in BMS-232632 stems from its potential dosing schedule. The group of test subjects taking doses above 300 mg daily demonstrated serum concentrations of drug that were high (above the IC50 for HIV) for more than a 24-hour period. Pharmacokinetic data also show that the drug has a long intracellular half-life (the time required for half of the original dose to be eliminated). These results suggest that once daily dosing of BMS-232632, which is not possible with the currently available PIs, may be feasible. It also serves as good news for those concerned about adhering to anti-HIV drug regimens with complicated dosing schedules; many people on treatment have found it nearly impossible to follow regimens requiring multiple doses of drugs taken several times a day.

A 48-week, multinational phase II trial is currently enrolling to study the activity of three dose levels of BMS-232632 in treatment-naive HIV positive persons. Participants will be randomized to take both ddI (Videx) and d4T (Zerit) with either BMS-232632 or nelfinavir. For more information, call 203-677-6746.

Once Daily Antiretrovirals

If BMS-232632 is approved, it could be combined in future with the nucleoside analog drugs ddI and d4T. New York-based Bristol-Myers Squibb recently filed for U.S. marketing approval of their once daily form of ddI, which already is available in Europe. They also are working to develop a once-a-day formulation of d4T. With a drug "cocktail" of once daily forms of ddI, d4T, and BMS-232632, people may be able to take only three anti-HIV pills a day versus eight or more tablets a day on some current regimens.

Nicholas Cheonis is Editorial Assistant of BETA.

Gong, Y. and others. Resistance profile and drug combination studies of an HIV-1 protease inhibitor BMS-232632. 6th Conference on Retroviruses and Opportunistic Infections. Chicago. January 31-February 4, 1999. Abstract P603.

Hammer, Scott M. New developments in antiretroviral therapy. The PRN Notebook, Online Edition (www.prn.org). June 1999.

Levin, Jules. ICAAC highlights, day 3-Saturday-clinical studies. Natap (www.natap.org) coverage of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 98). San Diego. September 24-27, 1998.

O'Mara, E.M. and others. BMS-232632: single and multiple oral dose safety and pharmacokinetic study in healthy volunteers. 6th CROI. Abstract 604.

Schnittman, Steve. Bristol-Myers Squibb. Personal communication. June 3, 1999.

Thommes, Jim. I-79: anti-viral activity and resistance profile of an HIV-1 protease inhibitor BMS-232632. The Body (www.thebody.com) coverage of ICAAC 98.

Page last updated 5 October 1999