Study May Point Way Forward for Bevirimat
October 26, 2008
A study presented at the joint 2008 ICAAC/IDSA in Washington, DC may help point the way forward for development of Panacos' experimental maturation inhibitor, bevirimat. The study, presented by Dr. Jay Lalazari, found that genetic variations in HIV might be a good predictor of success using bevirimat.
Bevirimat is the first maturation inhibitor to be developed. It works near the same site as protease inhibitors, but rather than blocking the protease enzyme it attaches to its protein target or substrate, specifically a site called Capsid-SpI.
Development of bevirimat has been hampered by two issues. The first was formulation problems. The first formulation used in studies was a liquid, which worked well but was thought to be undesirable for commercial development. The first tablet formulation failed to provide adequate drug levels, forcing Panacos to revert to the liquid formulation for the phase 2 studies. Panacos reports having successfully developed a new tablet formulation that it will use for further development.
The other challenge for bevirimat has been a high degree of patient-to-patient variability in responses. Some people experienced very good reductions in HIV levels, while others had very little. These differences were not explained by drug levels or typical drug resistance -- leaving the future of the drug in doubt.
This study sought to explain this variability by looking at small changes in an HIV protein called Gag. It specifically looked at whether changes in any of three positions -- 369, 370 and 371 -- might reduce bevirimat's activity.
While there was an average drop in HIV levels of around 1 log, the reductions were much lower for people whose HIV had any of those three changes -- called polymorphisms. The company looked at the Los Alamos HIV database and found that over 60% of people with HIV were free of such polymorphisms. The 369 polymorphism seems to cause the most profound reduction in bevirimat's activity, followed by 370 and 371.
When people with those polymorphisms were removed from the analysis, bevirimat seemed to result in an average reduction in viral load of around 1.18l logs. This is a fairly good result, but not spectacular.
The future of bevirimat is clouded by uncertainty around Panacos' ability to raise enough money to conduct larger trials. To show the value of this drug, Panacos will need to do such trials. Perhaps this study will point the way forward, focusing future study on people who are free of these three polymorphisms. It remains to be seen whether this will be enough to rescue this somewhat troubled drug.
It should be pointed out that while questions remain about bevirimat's potency, it seems well tolerated, with no clear signal of any safety concerns.
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