Mechanism of Action|Clinical Trials|Publications

Overview

The Company's lead compound, bevirimat (PA-457), is the first in the new class of HIV drugs called Maturation Inhibitors that specifically block a late step in processing of the HIV Gag protein. Following bevirimat treatment, virus particles released from HIV-infected cells are non-infectious and virus replication is terminated. This antiviral target is unique to Panacos and the Company is building a strong intellectual property position around its ground-breaking discovery.

Studies have shown that bevirimat is a potent inhibitor of HIV isolates that are resistant to currently approved drugs. Furthermore, bevirimat exhibits potent antiviral activity in an animal model of HIV infection, the SCID mouse model. Following oral administration of bevirimat to HIV-infected SCID mice, the level of HIV replication was reduced by more than 90%.  Bevirimat also potently inhibited replication of an HIV strain resistant to the approved drug AZT in this animal model.

Bevirimat has several other positive characteristics supporting its further development. These include data from several studies demonstrating that the compound should not be subject to metabolic interactions with currently approved HIV drugs, reducing the chance of drug-drug interactions when used in combination therapy. Indeed, bevirimat is synergistic in antiviral activity when tested in mixtures with approved drugs.

In addition to its utility as a new therapy for patients failing current treatments due to drug resistance, Panacos believes bevirimat may also be suitable for first-line therapy of HIV infection.

Mechanism of Action

Bevirimat is the first in a new class of HIV drugs called Maturation Inhibitors. Bevirimat blocks HIV maturation by inhibiting the final step in the processing of the HIV Gag protein.   The resulting virus particles are structurally defective and are incapable of spreading infection around the body. The mechanism of action of bevirimat is described in a November 2003 publication in the journal Proceedings of the National Academy of Sciences of the USA (Li et al., Proc. Natl. Acad. Sci. USA, 100, 13555-13560 (2003)).

An animation showing bevirimat's mechanism of action can be found here.

Clinical Trials

Phase 1a Clinical Trial

The safety and pharmacokinetics of this compound were examined in uninfected, healthy male volunteers following a single oral dose of 25 to 250 mg. bevirimat was well tolerated and exhibited good oral bioavailability and favorable pharmacokinetics. All doses produced mean circulating plasma levels which exceeded the target therapeutic concentration. At doses of 50 mg or above, bevirimat levels continued to exceed the target concentration even at 24 hours after administration. These results suggest that bevirimat will be suitable for once daily oral dosing, the gold standard for HIV drugs. This study was the subject of a presentation at the XV International AIDS Conference in Bangkok, Thailand (July 2004).

Phase 1b Clinical trial

Based on the promising results of the first clinical study, bevirimat was advanced into a multiple dose Phase 1 trial to examine the safety and pharmacokinetics of the compound in uninfected, healthy volunteers. In this study, bevirimat was administered once daily for 10 days. Plasma concentrations at all dose levels were well above the level predicted to provide therapeutic benefit in HIV-infected patients.  The drug was well tolerated.  The results of this study were presented at the Twelfth Annual Conference on Retroviruses and Opportunistic Infections in Boston in February 2005.

Phase 1/2 Trial

Based on the Phase 1 results, a Phase 1/2 study was carried out in HIV-infected patients to analyze pharmacokinetics and to determine the antiviral effect of a single oral dose of bevirimat in patients not on other therapy.  Positive preliminary results were announced in November 2004 from this proof-of-concept study.  A significant reduction in the level of virus in the plasma, known as viral load, of up to approximately 0.7 log10 was seen in patients receiving the highest dose levels, including patients with HIV strains resistant to existing classes of anitiretroviral drugs. Mean viral load decreased in the two highest dose groups and was significantly different from placebo at multiple time points following dosing. These findings are similar to results obtained in single dose clinical trials of other potent HIV drugs including the approved drug tenofovir* provide proof of concept for the antiviral activity of bevirimat.

*(Barditch-Crovo, P., et al.  (2001). Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults.  Antimicrob. Agents. Chemother., 45, 2733-2739.)

Phase 2a Trial

A multi-dose Phase 2a study was performed in HIV-infected patients at several sites in the U.S. and was designed to demonstrate the antiviral potency of bevirimat following its once-daily oral dosing for 10 days in HIV-infected patients who were not on other antiretroviral therapy.   The results of this study were reported on August 22, 2005.

Phase 2b Trial

Panacos announced the commencement of a multicenter Phase 2b trial (Study 203) studying the effects of combination therapy in HIV-infected patients on June 12, 2006.  Details regarding the trial's commencement can be found here.  First cohort results can be found here.  Subsequent to the first cohort results, the trial was redesigned and continued using a liquid formulation of the drug while work is ongoing to develop potentially commercializable liquid and solid dosage forms.   Information about the trial redesign can be found here.

• Press release on the second (250 mg liquid dose) cohort
• Press release on the third (300 mg liquid dose) cohort
• Press release on the fourth (350 mg liquid dose) cohort
• Press release on the topline results for Study 203 as well as the discovery of predictors to response for bevirimat

Publications

Listed below are scientific publications and presentations at scientific meetings.