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New gp41 Fusion Inhibitor Has Long Half-Life, Anti-HIV Activity in HIV+ Naïve
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52nd ICAAC, September 9-12, 2012, San Francisco
Mark Mascolini
Albuvirtide, a maleimide-modified peptide derived from the HIV-1 gp41 sequence, had a plasma half-life of 11 days in antiretroviral-naive adults treated intravenously [1]. In a multiple-dose study of naive adults, monotherapy with the novel agent suppressed viral loads by an average 0.68 to 1.05 log10 copies/mL, depending on the dose used.
Like enfuvirtide, this investigational fusion inhibitor targets gp41--but by a different mechanism of action. Previous research showed that albuvirtide is active against HIV-1 variants resistant to enfuvirtide and that it has activity against HIV-1 subtypes A, B, and C and recombinants found in China [2]. Research to date indicates that albuvirtide does not penetrate the brain or testicles.
Chinese investigators reported results of two trials involving antiretroviral-naive adults in Beijing with a viral load of 5000 copies or higher and a CD4 count of 250 or higher. In the first trial participants received a single dose of albuvirtide (from 20 to 640 mg) or placebo. Fifty-four participants were treated and analyzed; 2 discontinued therapy during the study. The group included 39 men and 15 women with a median age of 37.5, a median viral load of 20,000 copies, and a median CD4 count of 389.5.
In the second monotherapy trial participants received multiple doses of 160 or 320 mg on days 1, 2, and 3. Then the dosing switched to once weekly and doses were administered on days 8 and 15. All study participants were gay men. Median ages were 35.5 in the 160-mg group and 26.5 in the 320-mg group. Median pretreatment viral load and CD4 count were 4.45 log10 copies/mL and 484 CD4s in the 160-mg group and 3.9 log and 406.5 CD4s in the 320-mg group. Weight averaged 65 kg in both studies, lower than weights in many Western HIV populations. All participants in both groups received albuvirtide by intravenous infusion.
In the single-dose study, albuvirtide's plasma half-life averaged 11 days. Participants tolerated albuvirtide well: there were no injection-site reactions and no serious adverse events. Elimination kinetics were linear. Albuvirtide monotherapy suppressed plasma viremia for 6 to 10 days.
In the multiple-dose study, there were no serious adverse events and no drug-related adverse events of any kind. There were no injection site reactions through the 5 doses. No anti-albuvirtide antibodies could be detected in plasma for up to 42 days.
Average maximum drop in viral load was 0.68 log10 copies/mL with the 160-mg dose (range (0.22 to 1.04 log) and 1.05 log10 copies/mL with the 320-mg dose (range 0.69 to 1.67 log). Proportions of people with at least a 0.5-log reduction in viral load were 83% in the 160-mg group and 100% in the 320-mg group. Throughout the studies, albuvirtide dose correlated with viral load decline (r = 0.681, P < 0.01). However, in the multiple-dose study viral load rebounded after day 15, the day on which the last dose was given. The researchers are analyzing samples to see if emergence of resistant virus explains this finding.
Albuvirtide is being developed by Chongqing Frontier Biotechnologies (http://frontierbiotech.com/english/).
References
1. Wu H, Yao C, Lu RJ. Albuvirtide, the first long-acting HIV fusion inhibitor, suppressed viral replication in HIV-infected adults. 52nd Interscience Conference on Antimicrobials and Chemotherapy (ICAAC). September 9-12, 2012. San Francisco. Abstract H-554.
2. Chong H, Yao X, Zhang C, et al. Biophysical property and broad anti-HIV activity of albuvirtide, a 3-maleimimidopropionic acid-modified peptide fusion inhibitor. PLoS One. 2012;7(3):e32599. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0032599.
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