Featured news from NHIVNA

HIV-related news from NAM

HIV attachment inhibitor BMS-663068 matches atazanavir in phase 2b study
Liz Highleyman, 2015-10-14 08:20:00

Bristol-Myers Squibb’s HIV attachment inhibitor BMS-663068 (fostemsavir), which prevents the virus from binding to T-cells, demonstrated good antiviral activity and was well-tolerated at 24 weeks, according to study results published recently in Lancet HIV. Findings from a subgroup analysis at 48 weeks, presented at the IDWeek 2015 conference in San Diego, showed that response rates were similar regardless of demographic characteristics, baseline viral load or CD4 cell count.

Combination antiretroviral therapy (ART) consists of drugs that target different steps of the HIV lifecycle. None of the currently approved drugs block the first step, initial attachment of the virus to a host cell; fusion inhibitors like enfuvirtide (Fuzeon) affect a slightly later step. Drugs that work in novel ways are particularly important for people with HIV who have taken lots of different treatments already (highly treatment-experienced people) and who have extensively drug-resistant virus.

BMS-663068 is a pro-drug or precursor of BMS-626529, which binds directly to the gp120 protein that makes up part of the ‘spikes’ on HIV’s outer surface, thereby preventing viral attachment to CD4 T-cells. Unlike maraviroc (Celsentri), BMS-663068 binds to the virus itself, not to the cells, and it is active against HIV that uses either CCR5 or CXCR4 co-receptors.

Study AI438011 looked at the safety, efficacy and dose-response characteristics of BMS-663068 in previously treated people with HIV. Trial participants were randomised to receive either BMS-663068 or ritonavir-boosted atazanavir (Reyataz) as part of a combination regimen.

Jay Lalezari of Quest Clinical Research in San Francisco and colleagues published 24-week primary results from this ongoing trial in the October issue of Lancet HIV. These results were previously presented in part at the 2014 Conference on Retroviruses and Opportunistic Infections (CROI). The 48-week results were presented in part at this year’s CROI.

The study enrolled 254 participants at 53 hospitals and outpatient clinics in ten countries in Europe, North and South America, and Africa between July 2011 and July 2012. A majority (60%) were men, 38% were white, 30% were black and the median age was 39 years.

Overall, participants had relatively advanced disease, with a mean CD4 count of 230 cells/mm3, nearly 40% having less than 200 cells/mm3 and just over 40% having high baseline viral load. Many had experienced treatment failure on first- or second-line ART and about half had at least one major mutation conferring resistance to at least one widely used antiretroviral drug class; however, to participate they were required to still have virus that was sensitive to BMS-626529 and other drugs used in the study.

Participants were randomly allocated to five treatment arms receiving BMS-663068 at doses of 400 or 800mg twice daily, 600 or 1200mg once daily, or 300/100mg atazanavir/ritonavir. Everyone also took 400mg raltegravir (Isentress) and 300mg tenofovir disoproxil fumarate (Viread). Of note, participants receiving BMS-663068 had a higher daily pill burden, which could have an effect on adherence.

Virological response rates, or the proportion of participants with viral load <50 copies/ml, were statistically similar across study arms in the 24-week primary analysis and at 48 weeks:

  • BMS-663068 400mg twice-daily: 80% at 24 weeks and 82% at 48 weeks
  • BMS-663068 800mg twice-daily: 69% and 61%, respectively
  • BMS-663068 600mg once-daily: 76% and 69%, respectively
  • BMS-663068 1200mg once-daily: 72% and 68%, respectively
  • Atazanavir/ritonavir: 75% and 71%, respectively.

Mean CD4 cell gains at 48 weeks were also similar across treatment arms.

BMS-663068 was generally safe and well-tolerated at all doses tested. At 24 weeks, 7% of participants in all BMS-663068 groups combined experienced serious adverse events, compared with 10% in the boosted atazanavir group. Just 2% of BMS-663068 recipients and 4% of boosted atazanavir recipients discontinued treatment early due to adverse events. None of the serious adverse events or events leading to treatment discontinuation were considered related to BMS-663068. No notable trends in laboratory abnormalities were seen in the BMS-663068 group, while boosted atazanavir was more likely to cause elevated bilirubin.

“In a comparison with ritonavir-boosted atazanavir, efficacy and safety of BMS-663068 up to the week 24 analysis support continued development of BMS-663068, which is being assessed in a phase 3 trial in heavily treatment-experienced individuals,” the Lancet HIV study authors concluded.