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Phase 2 Trial Confirms Baseline Mutation Risk With Maturation Inhibitor
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48th ICAAC
October 25-28, 2008
Washington, DC.
Mark Mascolini
In a placebo-controlled trial bevirimat (PA-457), an HIV-1 maturation inhibitor, lowered viral loads more than 10-fold after 2 weeks of functional monotherapy--as long as bevirimat levels reached 20 mcg/mL and HIV did not harbor mutations that jeopardize response to bevirimat [1]. The findings suggest that bevirimat, if licensed, will be like maraviroc in requiring a pretreatment test to screen out people unlikely to respond to this drug.
This novel antiretroviral prevents maturation of the virus by targeting an HIV-1 Gag cleavage site. Earlier research showed that people without gag gene polymorphisms at positions Q369, V370, or T371 had a better chance of responding to bevirimat [2]. (Polymorphisms are naturally occurring genetic changes not provoked by exposure to an antiretroviral.)
A phase 2 double-blind, placebo-controlled trial originally involved 59 antiretroviral-experienced people, 46 of them adding 250, 300, 350, or 400 mg of bevirimat to a failing regimen for 2 weeks and 13 of them adding placebo. An amended trial plan involving 29 people tested 300 mg of bevirimat liquid against placebo. Two thirds of these 29 people had antiretroviral experience, and half had gag polymorphisms at positions 369, 370, and 371. Everyone had a viral load above 2000 copies when they added bevirimat or placebo.
Among 31 people in the original and amended trial design with a bevirimat trough above 20 mcg/mL and without the risky polymorphisms, viral load fell an average 1.18 log copies/mL during 2 weeks of functional monotherapy, compared with a 0.10 fall in 13 placebo recipients. Response rates were lower in bevirimat-treated people with any of the three polymorphisms. Cohort studies in North America and France indicate that 60% to 68% of HIV-infected people do not have the polymorphisms that blunt response to bevirimat. Jacob Lalezari, who presented the results, noted that other still-unstudied polymorphisms may also affect response to this maturation inhibitor.
Among 75 bevirimat takers evaluated for side effects, 49 (75%) had at least one such problem during the study, compared with 8 of 13 people (61%) randomized to placebo. The most common side effects--diarrhea, nausea, and headache--were as frequent in the placebo group as in the bevirimat group. Five people taking bevirimat (7%) reported abnormal dreams, and 2 people (3%) reported dizziness. No one taking placebo had abnormal dreams or felt dizzy. The only common lab abnormality that affected more people taking bevirimat than placebo was abnormal glucose (13% versus 8%). Total cholesterol and triglycerides rose in 9% to 15% in both study arms. It is difficult to make much of side effect or lab results in such a brief and small study.
A phase 3 trial of bevirimat in antiretroviral-experienced people, now in the planning stage, will test a 100-mg tablet. A pharmacokinetic study found that the 100-mg tablet yields a bevirimat area under the concentration-time curve 68% of that achieved with the oral solution, and a maximum concentration 69% of that attained with the oral formulation [3].
References
1. Lalezari, McCallister S, Gigliotti M, et al. A phase 2 safety and efficacy study of bevirimat in heavily treatment experienced HIV+ patients identifies the target phase 3 study profile. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC. Abstract H-891.
2. Salzwedel K, Reddick M, Matallana C, et al. Role of gag polymorphisms in HIV-1 sensitivity to the maturation inhibitor bevirimat. XVII International HIV Drug Resistance Workshop. June 10-14, 2008. Sitges, Spain. Abstract 8 (http://www.panacos.com/documents/Sitges%20Posters.pdf).
3. Panacos' study 114 supports the company's new tablet formulation of bevirimat (http://www.panacos.com/press_detail.htm?1206537).
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