Attachment inhibitor may hold promise for future

BMS-488043 demonstrates safety

Bristol-Myers Squibb Co. (BMS) of Princeton, NJ, recently showed through concept data that an attachment inhibitor BMS-488043 can have potent antiviral activity in HIV-1-infected patients.1

"These compounds are part of a class that was developed at Bristol-Myers Squibb," says George Hanna, MD, director of clinical discovery.

When BMS first presented the attachment inhibitor class two years ago, the first compound presented had similar activity to the current product, but it didn’t achieve high enough blood levels, he says.

In a phase II-a study, involving 30 patients of which six received a placebo, there were 12 who received 800 mg twice a day of BMS-488043 and 12 who received 1,800 mg twice a day, Hanna explains.

"What we found was that the maximum drop of the 800 mg was approximately 1 log decline at day eight, and the maximum decline with the 1,800 mg was approximately 1.2 logs decline," he adds. Subjects were given the drug with a high-fat meal because the blood levels of the drug were considerably higher when given with a high-fat meal, Hanna notes.

After patients stopped the medication at day eight, investigators continued to follow their progress for six more days. They observed 27 adverse events of which three were moderate and 24 were mild, he says. "So overall, it was pretty safe and well-tolerated," Hanna says. "There were no serious events and no serious log abnormalities and no discontinuation because of an adverse event."

The most common adverse event was fatigue, and the adverse events did not appear to be dose-related. The subjects’ viral load declines were comparable to viral load declines experienced by patients treated with existing classes of drugs, including protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), Hanna notes.

If the drug continues to do well and eventually makes it to the market, it will be an antiretroviral that could be used by both treatment-naïve patients and antiretroviral-experienced patients who already have developed drug resistance, he explains.

"The greatest need now is for patients who have a virus that has already become resistant to currently available drugs, and so we’re excited about the prospect of having a completely new class to which the virus would not be cross-resistant."

This new class of drugs could be used in various antiretroviral cocktails that include PIs and NRTIs, and there’s the possibility that one day there will be such a thing as an entry inhibitor cocktail, Hanna says. "We’re still studying the whole issue of resistance for this particular drug, and we have noticed that resistance can evolve just as it has evolved with any other antiretroviral medication."

"Because of that we anticipate that this drug will not be used by itself, but as a part of combination therapy," he notes.

Investigators are trying to learn more about the drug response at various drug levels with plans to develop a formulation that would be optimal for patients, Hanna adds.

"We did have some subjects who did not respond as well as others, although the majority of patients had greater than a log decline in viral load," he adds. "So we’re trying to understand what it is that makes these subjects different from others, and when we can understand that, we can optimize the drug and formulation and create a more reliably potent drug."


1. Hanna G, Lalezari J, Hellinger J, et al. Antiviral activity, safety, and tolerability of a novel, oral small-molecule HIV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects. Presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco; February 2004. Abstract 141.