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(AIDSmeds.com)—Panacos Pharmaceuticals has issued a press release announcing preliminary results from the first part of a Phase IIb study of its maturation inhibitor bevirimat (PA-457) in patients with HIV resistance to approved medications. While the unpublished data suggest that bevirimat has anti-HIV activity in this patient population, the blood concentrations of bevirimat – along with its effects on viral load – were poorer than anticipated, suggesting that the tablet formulation used in the study did not deliver the drug as expected.
Virus maturation is the process that occurs during the last stages of HIV reproduction, after HIV has been released from the infected cell. It involves the processing of viral proteins and is required for the virus to become infectious. By blocking, or inhibiting, the virus maturation process, new virus cannot go on to infect other cells in the body. Bevirimat, a derivative of a Chinese herb called Syzigium claviflorum, is the first HIV maturation inhibitor to enter phase II clinical trials. Because bevirimat works differently than currently available HIV drugs, it will likely be effective for people who have HIV that is resistant to currently available treatment options.
The objectives of the two-part Phase IIb study currently under way are to examine the efficacy, pharmacokinetics, and safety of bevirimat in HIV-positive people who are no longer responding to their current regimen. The first 14-day part of the study requires patients to take a 400 mg bevirimat tablet (12 patients), or placebo (four patients), in combination with their failing HIV drug regimen. In the second part of the study, patients will be permitted to alter their background regimen, based on the results of drug-resistance testing, while continuing either bevirimat or placebo for an additional ten weeks.
In Phase IIa studies of bevirimat, a 200 mg liquid formulation dose of the drug was found to be active against HIV. A 400 mg tablet version was then developed and was expected to be comparable to the liquid formulation. However, blood samples from those who took bevirimat in the Phase IIb study found that drug levels were about half what was expected and closer to levels that were seen in patients using lower, less effective doses of the liquid formulation of the drug in the earlier Phase IIa study.
Consistent with these lower drug concentrations, the antiviral responses seen in the 400 mg tablet cohort of the Phase IIb study were also lower than expected. At day 15, the mean viral load reduction was 0.36 log in bevirimat-treated patients, compared to a reduction of 0.02 log in placebo-treated patients.
However, a total of three patients on bevirimat had viral load reductions higher than 1 log and continued on to the extended dosing portion of the study, including two who achieved viral loads below 400. One additional patient who had a viral load change of just under 1 log was also permitted to join the second part of the study.
During the initial 15 day dosing period, there were no reports of serious drug-related side effects or withdrawals. These data, Panacos says, continue to confirm the good safety and tolerability profile of bevirimat found in previous studies.
Graham Allaway, Panacos' President and COO said in the press release, "While this first cohort did not produce the bevirimat levels we had hoped for, we were encouraged that some patients exhibited a very good antiviral response. Overall, the data are consistent with the relationship between plasma concentrations and response that we have seen previously, and we believe the results support going to higher doses, potentially with alternative formulations, with the aim of generating greater responses. We are submitting a proposal to the FDA designed to continue bevirimat dose escalation in Phase IIb as soon as possible while we continue to develop an optimized formulation of bevirimat for commercialization."
