Early results from a Phase IIB study into a maturation inhibitor have yielded disappointing results. Panacos Pharmaceuticals has announced that although bevirimat (PA-457) demonstrated activity against HIV, plasma concentrations of the drug were lower than had been anticipated. Investigators believe that this is because the tablet formulation used in the study did not deliver the expected levels of the drug. But the company behind the drug, Panacos Pharmaceuticals, is pressing ahead with its development and plans to address the issues with formulation.
The Phase IIB study was designed to establish the anti-HIV efficacy and safety of bevirimat. It included a total of 16 patients, all of whom were extensively pre-treated and failing their current antiretroviral regimens due to resistance. Patients were randomised on a three-to-one basis to receive bevirimat or a placebo on top of their failing therapy for 14 days. At the end of this period of functional monotherapy, resistance tests were used to determine the optimal antiretroviral therapy for patients, and they then continued to take bevirimat or the placebo as determined by randomisation. By day 15 of randomisation, patients assigned to the bevirimat arm were required to have a 1 log10 or greater reduction in viral load.
Results released after the 14-day functional monotherapy stage of the study showed that two patients taking bevirimat had achieved a viral load below 400 copies/ml and another patient had experienced a fall in his viral load of 1 log10. However, overall, the antiviral activity of bevirimat was lower than anticipated due to lower than expected plasma levels of the drug, the mean reduction in viral load being 0.36 log10 copies/ml.
An earlier bioavailability study had lead the investigators to select a 400mg tablet dose of bevirimat. This study has suggested that such a dose would achieve concentrations comparable to the 200mg oral solution. However, the anti-HIV activity and plasma concentrations seen with the 400mg tablet were comparable to the 100mg oral solution. The investigators are attributing this to problems with the formulation of the tablet specially designed for the Phase IIB study.
The mean viral load reduction seen during functional monotherapy with the 400mg tablet was comparable to the day eleven reduction seen in individuals taking the 100mg oral solution in the earlier dose-ranging study.
Although the results are disappointing, they are sufficiently promising for the drug company behind the research to press on with further development plans.
“While this first cohort study did not produce the bevirimat levels hoped for, we are encouraged that some patients exhibited a very good antiviral response”, said Graham Allaway, Chairman of Panacos Pharmaceuticals which is developing the drug. He added, “Overall, the data are consistent with the relationship between plasma concentrations and response that we have seen previously, and we believe that the results support going to higher doses, potentially with alternative formulations, with the aim of generating greater responses.”
Panacos will be submitting a proposal to the US Food and Drug Administration to continue the Phase IIB study. The company has pledged to “continue to develop an optimized formulation of bevirimat for commercialization.”