On December 19, Panacos Pharmaceuticals announces the first results from a Phase IIb study of its investigational HIV maturation inhibitor, bevirimat (PA-457). While bevirimat demonstrated anti-HIV activity, plasma concentrations obtained with the tested tablet formulation were lower than anticipated, suggesting that the formulation used in this study did not deliver the drug as expected.

Two days later, the company announced that it had filed an Investigational New Drug Application with the U.S. Food and Drug Administration (FDA) for a second-generation HIV maturation inhibitor, PA-1050040. Following FDA review, the company plans to begin Phase I clinical trials in the first quarter of 2007.

Following are edited excerpts from 2 press releases from Panacos announcing the recent developments:

First Cohort Results of Phase 2b Study

WATERTOWN, Mass.--(BUSINESS WIRE)--Dec. 19, 2006--Panacos Pharmaceuticals, Inc. (Nasdaq:PANC), a biotechnology company dedicated to developing the next generation of antiviral therapeutic products, today announced preliminary results from the first cohort of a Phase IIb study of bevirimat (PA-457) in patients failing HIV therapy due to drug resistance. The data confirm the clinical antiviral activity of bevirimat shown in previous studies; however, the bevirimat plasma concentrations were lower than anticipated, suggesting that the tablet formulation used for this study did not deliver the drug as expected.

After 14 days of dosing with 400 mg of bevirimat tablets administered on top of patients' failing background regimens, an antiviral effect was seen in the bevirimat treatment group. Two out of twelve patients with multiple-drug-resistant HIV who received bevirimat achieved an undetectable level of virus. These two patients and one other individual had a viral load reduction of greater than 1 log₁₀. However, the overall antiviral response in this first cohort was less than expected, in line with the patients' lower than anticipated bevirimat plasma concentrations.

A previous bioavailability study had predicted that the plasma concentrations, and therefore the antiviral response, of the 400 mg tablet dose would be comparable to the highest (200 mg) dose of the oral solution used in the Phase IIa study. Instead, both the plasma concentrations and the antiviral response observed in the 400 mg tablet cohort were similar to the 100 mg Phase IIa oral solution dose.

The data suggest that the lower plasma concentrations of drug resulted from the properties of the 50 mg tablet, a prototype designed specifically for use in the Phase IIb trial. Panacos has been working for some time on new tablet formulations for late-stage development and commercialization. Preliminary analysis of the safety profile of bevirimat in the first cohort indicated that bevirimat was generally safe and well tolerated.

Graham Allaway, PhD, Panacos' President and Chief Operating Officer, said, "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."

First Cohort Results

The initial Phase IIb bevirimat tablet dose of 400 mg was chosen based on an earlier clinical bioavailability study indicating that the tablet had approximately 60% of the oral bioavailability of an oral solution formulation. As a result, this 400 mg tablet dose was expected to be comparable to a 200 mg oral solution dose, which in a 10 day bevirimat Phase 2a monotherapy study had generated a median 1 log₁₀ viral load reduction. However, analysis of bevirimat plasma levels in this Phase IIb study found that these levels were about half what was expected and closer to levels that were seen in patients using 100 mg of oral solution in the earlier Phase IIa study.

Consistent with these lower drug plasma 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 log₁₀ in bevirimat-treated patients compared to 0.02 log₁₀ reduction in placebo-treated patients. A total of three patients on bevirimat had greater than 1 log₁₀ reduction in viral load and continued on to the extended dosing portion of the study, including two who achieved an undetectable level of virus (less than 400 viral copies/ml). One additional patient who had a viral load change of just under 1 log₁₀ on day 15 was continued on therapy by special investigator request.

During the initial 15-day dosing period, there were no reports of drug-related serious adverse events or withdrawals due to adverse events. One patient on bevirimat withdrew after 12 days for reasons not related to the drug. A Day 15 viral load sample was obtained from that patient and the patient was not replaced. These data continue to confirm the good safety and tolerability profile of bevirimat found in previous studies.

Given the similar bevirimat plasma concentrations seen in the Phase IIb 400 mg tablet cohort and the 100 mg oral solution cohort in the Phase IIa study, the viral load changes in the two studies were compared. The mean viral load changes on day 11, the appropriate comparator time point, were -0.39 log₁₀ and -0.37 log₁₀ in the current study and the Phase IIa 100 mg cohort respectively. In the current study, four of the twelve patients (33%) had a greater than 0.5 log₁₀ reduction in viral load on day 11, and three of these had a greater than a 1 log₁₀ reduction. In the 100 mg liquid dose cohort of the prior Phase IIa study, three of six (50%) had greater than a 0.5 log₁₀ viral load reduction, and no patients had greater than a 1 log₁₀ reduction.

Panaco Files IND for Second-Generation Maturation Inhibitor

WATERTOWN, Mass.--(BUSINESS WIRE)--Dec. 21, 2006--Panacos Pharmaceuticals, Inc. (Nasdaq: PANC), a biotechnology company dedicated to developing the next generation of antiviral therapeutic products, today announced that it has filed an Investigational New Drug (IND) Application with the U.S. Food and Drug Administration (FDA) for the company's second-generation HIV maturation inhibitor, PA-1050040. Following review by the FDA, the company intends to begin Phase I clinical trials of this new agent in the first quarter of 2007.

Maturation inhibition is a new target discovered by Panacos scientists and their academic collaborators. The first-in-class HIV maturation inhibitor, bevirimat (PA-457), has shown significant anti-HIV activity in HIV patients and is in Phase IIb clinical testing. The company's second-generation maturation inhibitor program is designed to identify analogs of bevirimat with different pharmacological properties. Specific goals are to develop second-generation compounds that retain activity against HIV strains resistant to bevirimat, should these resistant strains appear in the clinic in the future.

In vitro studies with PA-1050040 have shown that the compound has a lower level of binding to human serum proteins than bevirimat, which may result in greater levels of free drug in patients dosed with the compound and thus the potential ability to inhibit HIV strains that exhibit partial bevirimat resistance. Furthermore, PA-1050040 retains wild-type activity against one of two bevirimat-resistant HIV isolates that represent the most-frequently mutated amino acids found by in vitro resistance-selection experiments performed to date. These amino acids flank the HIV-1 capsid-SP1 cleavage site and the results suggest PA-1050040 may bind differently than bevirimat to this region of the viral Gag protein, which is the target for maturation inhibitor activity.

Graham Allaway, PhD, President and Chief Operating Officer of Panacos, commented, "Bevirimat, our first-generation maturation inhibitor, has shown the potential clinical value of maturation inhibitors. As the discoverers of this new HIV drug target, we intend to build a franchise in maturation inhibition. PA-1050040 represents one of a large number of second-generation maturation inhibitors currently in pre-clinical testing. We believe that maturation inhibitors have the potential to be important agents in the fight against HIV, and are pleased to be able to announce this step forward."

The current IND will allow Panacos to examine the pharmacokinetics of PA-1050040 following single doses in humans. The Company intends to file additional INDs for other second-generation maturation inhibitors during 2007 and then select a candidate based partly on human pharmacokinetics to take into multiple dosing human clinical studies.

1/12/07

Sources

Panacos Pharmaceuticals. First Cohort Results of Phase 2b Study. Press release. December 19, 2006.

Panacos Pharmaceuticals. Panacos Files IND for Second-Generation Maturation Inhibitor. Press release. December 21, 2006.