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ICAAC 2012: New Long-acting HIV Fusion Inhibitor Albuvirtide Looks Promising in Early Studies

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A new fusion inhibitor that prevents HIV entry into cells showed potent antiviral activity in early clinical studies and has a long half-life suggesting it may be suitable for once-weekly dosing, Chinese researchers reported yesterday at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012) in San Francisco.

Multidrug-resistant HIV remains a concern, especially for highly treatment-experienced people who have used most types of antiretroviral drugs. Fusion inhibitors -- which prevent the HIV envelope from fusing with T-cell membranes to enable cell entry -- may remain active against virus that has developed resistance to commonly used drug classes.

The sole approved fusion inhibitor, enfuvirtide (Fuzeon, formerly known as T-20), must be administered by subcutaneous injection twice-daily, leaving much to be desired in terms of convenience and ease of use.

Albuvirtide (also known as FB006M), a synthetic peptide being developed by Chongqing Frontier Biotechnologies, is chemically related to enfuvirtide, and it also works by binding to the HIV gp41 envelope protein. The new drug binds strongly and forms a conjugate with the human blood protein albumin, however, which enables it to last longer in the body, but also makes it unable to penetrate into the brain or testicles.

In preclinical in vitro and in vivo studies albuvirtide demonstrated potent activity against a broad spectrum of HIV isolates, had a favourable safety profile. Researchers at ICAAC presented results from 2 studies of albuvirtide monotherapy previously untreated people with HIV in Beijing.

The first was a Phase 1 proof-of-concept single dose escalation trial. A total of 55 participants were randomly assigned to receive either single doses of albuvirtide ranging from 20 mg to 640 mg or placebo. The drug was administered by intravenous infusion and patients were hospitalised for observation. All but 1 were treated and analysed, and 2 discontinued treatment prematurely.

About 70% of participants were men and the median age was 38 years. The median HIV viral load was approximately 20,000 copies/mL, the median CD4 T-cell count at study entry was about 400 cells/mm3, and all had at least 250 cells/mm3.

Results

  • Albuvirtide was generally safe and well tolerated at all doses tested.
  • No serious adverse events or injection site reactions were reported.
  • The drug had a good pharmacokinetic profile, with a plasma half-life of 11 days and a linear elimination pattern.
  • Antiviral activity continued for 6 to 10 days after a single dose.

The second study was a Phase 2a open-label trial of single and multiple doses of albuvirtide. The study included 12 treatment-naive participants assigned to receive either 160 mg or 320 mg albuvirtide. They received the drug once-daily for the first 3 days, followed by 2 once-weekly administrations at days 8 and 15.

All participants in this study were gay men. There were some baseline differences between the dose arms. In the 160 mg arm, the average age was 36 years, the median HIV RNA level was about 30,000 copies/mL, and the median CD4 count was 484 cells/mm3. In the 320 mg arm, the average age was 27 years, the median viral load was about 8,000 copies/mL, and the median CD4 count was 406 cells/mm3.

Results

  • Again, albuvirtidewas found to be safe and well-tolerated.
  • There were no serious adverse events, drug-related side effects, or injection site reactions.
  • Participants did not develop detectable antibodies against the drug after multiple injections.
  • In the 160 mg arm viral load declined by 0.68 log10 copies/mL on average and HIV RNA fell to < 0.5 log in 83% of participants.
  • In the 320 mg arm, the mean viral load decrease was 1.05 log copies/mL and 100% reached < 0.5 log.
  • There was a significant dose-response relationship between albuvirtide plasma concentration and viral load suppression.
  • While sustained viral suppression was seen after the first 3 days of dosing, HIV RNA rebounded more rapidly after the once-weekly doses (a possible indicator of drug resistance).

The researchers concluded that albuvirtide produced good viral suppression with a clear relationship between dose and antiviral efficacy, and the 11-day half-life supports once-weekly dosing. Further studies are planned using albuvirtide in combination antiretroviral regimens.

9/11/12

Reference

H Wu, C Yao, RJ Lu, et al. Albuvirtide, the first long-acting HIV fusion inhibitor, suppressed viral replication in HIV-infected adults. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). San Francisco. September 9-12, 2012. Abstract H-554.

Other Source

ICAAC/American Society for Microbiology. First Long-Acting HIV Fusion Inhibitor Albuvirtide Shows Promise in Treating Adults with HIV-1. Press release. September 10, 2012.