The HIV maturation inhibitor bevirimat was well tolerated in a 32-person study presented this week at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco. While antiviral activity was not particularly impressive overall, a genotypic test can predict which patients are likely to respond well.
Maturation inhibitors work at a late stage of the HIV lifecycle, interfering with final assembly and "budding" of new virus particles. The most advanced candidate in this class, bevirimat dimeglumine, has had a far-from-smooth path through the development pipeline.
The drug, originally called PA-457, was discovered by Panacos Pharmaceuticals. While it demonstrated promising antiviral activity in early studies, a tablet formulation had poor bioavailability, leading to lower than expected blood concentrations.
Bevirimat demonstrated more favourable results in Study 203, a Phase II trial presented at last year's ICAAC, after researchers improved the formulation and determined that genotypic testing can predict likely responders. Myriad Pharmaceuticals acquired all rights to the drug in January 2009, giving it the new designation MPC-4326.
At this year's meeting, Mark Bloch and colleagues presented findings from Study 204, an open-label Phase II trial. Most of the 32 participants were starting antiretroviral therapy for the first time, but the cohort also included some treatment-experienced patients who were resistant to one or more approved drugs and had been on stable therapy for at least eight weeks (except for a washout period of at least three days before starting bevirimat).
All participants were men, 97% were white, and the average age was 40 years. At the time of enrolment, the mean CD4 count was about 400 cells/mm3 and the mean viral load was about 63,000 copies/ml. Due to safety concerns identified in animal studies using much higher doses, people with a history of seizures or strokes were excluded.
Participants received bevirimat monotherapy at doses of either 200 mg or 300 mg, using 50 mg tablets, taken with food for 14 days.
By the end of the dosing period, overall viral load decreased by an average of 0.54 log10 copies/ml in the 200 mg arm and 0.70 log10 copies/ml in the 300 mg arm. But responses were highly variable across individual patients.
Using data from 100 participants in two prior Phase II trials, researchers developed a predictive algorithm based on five key polymorphisms, or specific variations, in the HIV gag gene. This algorithm identified responders with 80% accuracy and non-responders with 89% accuracy.
When participants were classified according to the algorithm, predicted responders experienced an average viral load decrease of 1.15 log10 copies/ml, compared with just 0.17 log10 copies/ml for predicted non-responders.
Overall viral load decreases did not differ significantly between the 200 mg and 300 mg arms. However, among participants predicted to be good responders on the basis of genotypic testing, viral load decline was greater in the 300 mg arm.
Bevirimat was generally well tolerated. While most participants reported at least one adverse event, these were usually mild or moderate. The most common side-effects were headache and gastrointestinal symptoms (including one grade 3 case of constipation). There were no severe laboratory abnormalities or clinical events.
The researchers concluded that the 50 mg tablet formulation of bevirimat was "safe and well tolerated," and trough (lowest-ever) concentrations remained above the target level using both the 200 mg and 300 mg twice-daily doses.
Researchers have also developed a 100 mg tablet formulation of bevirimat. As reported in a poster at the conference, the new tablet had a favourable pharmacokinetic and safety profile over 15 days of dosing. Again, the most common adverse events were gastrointestinal side-effects and headache.
Myriad plans to begin a Phase IIb study of bevirimat in the near future using the 100 mg tablet.
Bloch M et al. Efficacy, safety and pharmacokinetics of MPC-4326 (bevirimat dimeglumine) 200mg BID and 300mg BID monotherapy administered for 14 days in subjects with HIV-1 infection. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract H-1230, 2009.
Lalezari J et al. Pharmacokinetics and safety of a novel 100 mg tablet formulation of MPC-4326 in subjects with HIV-1 infection. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract A1-1309, 2009.