By Liz Highleyman

Maturation inhibitors interfere with the final stage of HIV replication, when viral proteins are assembled, packaged, and "bud" out through the host cell membrane to form new virus particles. Bevirimat targets HIV Gag proteins that make up the capsid, or inner "capsule" that contains the viral genetic material.

Bevirimat is the most advanced maturation inhibitor candidate in development. Originally known by the Panacos Pharmaceuticals designation PA-457, the drug demonstrated promising activity in early studies, but a tablet formulation had poor bioavailability and produced a lower-than-expected response.

Researchers then conducted further studies using a more bioavailable liquid formulation, with improved outcomes, as reported at ICAAC 2008. Post-hoc analyses showed that patients whose HIV carried specific polymorphisms (variations at a single site on the genome) were more likely to respond to bevirimat. Myriad Pharmaceuticals acquired the drug in January 2009 and renamed it MPC-4326.

This year, researchers presented findings from a Phase 2 trial known as Study 204. This trial included 32 participants, most of whom were starting antiretroviral therapy (ART) for the first time. However, 6 were treatment-experienced patients with resistance to approved drugs; these individuals underwent a "washout" period of at least 3 days before starting bevirimat.

All participants were men, the average age was 40 years, most (97%) were white (the study was conducted in Australia), the mean CD4 count was about 400 cells/mm3, and the mean viral load was about 63,000 copies/mL.

In this open-label study, patients received bevirimat monotherapy at doses of 200 mg or 300 mg twice-daily (BID) with food for 14 days, using a 50 mg tablet shown to be better absorbed than the original tablet formulation.

Investigators looked at response rates stratified by predicted response, using a predictive algorithm based on 5 polymorphisms in the HIV Gag gene that was developed using data from 100 participants in previous trials. The algorithm identified responders with 80% accuracy and non-responders with 89% accuracy.

Results

	Patients achieved trough (lowest between doses) drug levels exceeding the 90% effective concentration (EC90) using both the 200 mg and 300 mg dosages.
	After 14 days, viral load decreased by an average of 0.54 log10 copies/mL in the 200 mg arm and by 0.70 log10 copies/mL in the 300 mg arm.
	Participants classified as likely responders according to the algorithm had an average viral load decrease of 1.15 log10 copies/mL, compared with 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.
	Among predicted responders, however, mean HIV RNA decline was significantly greater in the 300 mg compared with the 200 mg arm (1.38 vs 0.89 log10 copies/mL, respectively).
	The drug was generally well-tolerated, with most adverse events being mild to moderate.
	The most common adverse events were headache (22%) and gastrointestinal symptoms including nausea (16%), diarrhea (16%), and constipation (13%).
	There were no serious clinical adverse events or laboratory abnormalities.