HIV attachment inhibitor BMS-663068 matches atazanavir in phase 2b study

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.

Glossary

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

treatment-experienced

A person who has previously taken treatment for a condition. Treatment-experienced people may have taken several different regimens before and may have a strain of HIV that is resistant to multiple drug classes.

phase II

The second stage in the clinical evaluation of a new drug or intervention, in which preliminary data on effectiveness and additional information about safety is collected among a few hundred people with the disease or condition.

treatment failure

Inability of a medical therapy to achieve the desired results. 

opportunistic infection (OI)

An infection that occurs more frequently or is more severe in people with weakened immune systems, such as people with low CD4 counts, than in people with healthy immune systems. Opportunistic infections common in people with advanced HIV disease include Pneumocystis jiroveci pneumonia; Kaposi sarcoma; cryptosporidiosis; histoplasmosis; other parasitic, viral, and fungal infections; and some types of cancer. 

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.

Sub-group analysis

In a poster presented at IDWeek 2015, Judith Feinberg of the University of Cincinnati and colleagues reported findings from a post-hoc sub-group analysis of virological and immunological response through week 48 according to sex, age (above or below 40 years), race/ethnicity (white, black or other), baseline viral load (above or below 100,000 copies/ml) and baseline CD4 T-cell count (above or below 200 cells/mm3).

At 48 weeks, viral suppression rates were statistically similar regardless of sex, age, race/ethnicity, baseline viral load or CD4 count in the combined BMS-663068 dose groups and the atazanavir/ritonavir group:

  • Men: 81% vs 96%
  • Women: 85% vs 78%
  • Age <40: 85% vs 86%
  • Age >40: 81% vs 90%
  • White: 82% vs 83%
  • Black: 86% vs 90%
  • Other race/ethnicity: 81% vs 92%
  • Low baseline viral load: 88% vs 96%
  • High baseline viral load: 76% vs 71%
  • Lower baseline CD4 count: 86% vs 96%
  • Higher baseline CD4 count: 78% vs 79%.

Average CD4 cell gains were similar with BMS-663068 and boosted atazanavir regardless of sex, age, race/ethnicity or baseline CD4 count. However, in both treatment groups, people who started with high viral loads saw larger CD4 cell increases.

“At week 48, virologic responses were generally similar across the BMS-663068 and atazanavir/ritonavir arms in treatment-experienced subjects, regardless of gender, race, age, baseline viral load, or baseline CD4+ T-cell count,” the researchers concluded.

Based on results from the phase 2b study, a phase 3 trial of BMS-663068 (NCT02362503) is now underway. This study is recruiting treatment-experienced people who are currently on a failing regimen and have drug resistance to or are unable to take at least three classes of antiretrovirals. Those with at least one other fully active drug will be randomised to receive 600mg twice-daily BMS-663068 or placebo with an optimised background regimen, while those with no fully active antiretrovirals will be enrolled in a non-randomised cohort.

References

Feinberg J et al. HIV-1 attachment inhibitor prodrug BMS-663068 in antiretroviral-experienced subjects: week 48 subgroup analysis. IDWeek 2015, abstract 1075, 2015.

Abstract on IDWeek 2015 website: https://idsa.confex.com/idsa/2015/webprogram/Paper51890.html

Lalezari J et al. Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial. Lancet HIV 2(10):e427-437, 2015.