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IDWeek 2015: 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 IDWeek 2015 this week in San Diego, showed that response rates were similar regardless of demographics or 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 blockthe 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 beneficial for people with HIV who are highly treatment-experienced and have extensively resistant virus.

BMS-663068 -- the first drug in its class -- 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 (Selzentry), BMS-663068 binds to the virus not the cell itself, and it is active against HIV that uses either CCR5 or CXCR4 co-receptors.

Study AI438011 (NCT01384734) looked at the safety, efficacy, and dose-response characteristics of BMS-663068 in previously treated people with HIV. Trial participants were randomized to receive either BMS-663068 or ritonavir-boosted atazanavir (Reyataz) as part of a combination regimen.

Jay Lalezari from 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). 48-week results were presented at this year's CROI.

The study enrolled 254 participants at 53 hospitals and outpatient clinics in 10 countries in North and South America, Europe, 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 failed first- or second-line ART and about half had at least 1 major mutation conferring resistance to at least 1 widely used antiretroviral drug class; however, they were required to still be sensitive to BMS-626529 and other drugs used in the study according to resistance tests.

Participants were randomly allocated to 5 treatment arms receiving BMS-663068 at doses of 400 mg or 800 mg twice-daily, 600 mg or 1200 mg once-daily, or 300/100 mg atazanavir/ritonavir. Everyone also took 400 mg raltegravir (Isentress) and 300 mg tenofovir disoproxil fumarate (Viread). Participants receiving BMS-663068 had a higher daily pill burden, which could have an effect on adherence.

Results

• 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:

o   BMS-663068 400 mg twice-daily: 80% at 24 weeks, 82% at 48 weeks;

o   BMS-663068 800 mg twice-daily: 69% and 61%, respectively;

o   BMS-663068 600 mg once-daily: 76% and 69%, respectively;

o   BMS-663068 1200 mg once-daily: 72% and 68%, respectively;

o   Atazanavir/ritonavir: 75% and 71%, respectively.

• Mean CD4 cell gains at 48 were also similar across treatment arms.
• BMS-663068 was generally safe and well-tolerated at all doses tested.
• At 24 weeks 7% of patients in all BMS-663068 groups combined experienced serious adverse events, compared with 10% in the boosted atazanavir group.
• 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 adverse events leading to treatment discontinuation were considered related to BMS-663068.
• No notable trends in laboratory abnormalities were seen in the BMS-663068 groups, 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.

In a poster presented at IDWeek, Judith Feinberg from the University of Cincinnati and colleagues reported findings from a post hoc subgroup 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).

• 48-week viral suppression rates were statistically similar regardless of sex, age, race/ethnicity, baseline viral load, or CD4 count:

o   Men: 81% in combined BMS-663068 groups vs 96% on atazanavir/ritonavir;

o   Women: 85% vs 78%, respectively;

o   Age <40: 85% vs 86%, respectively;

o   Age >40: 81% vs 90%, respectively;

o   White: 82% vs 83%;

o   Black: 86% vs 90%;

o   Other race/ethnicity: 81% vs 92%;

o   Low baseline viral load: 88% vs 96%;

o   High baseline viral load: 76% vs 71%;

o   Baseline CD4 count >200 cells/mm³: 86% vs 96%;

o   Baseline CD4 count <200 cells/mm³: 78% vs 79%.

• Mean CD4 cell gains were similar with BMS-663068 and boosted atazanavir regardless of sex, age, race/ethnicity, or baseline CD4 count, but in both arms people starting with high viral loads saw larger 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) opened earlier this year. This study is recruiting treatment-experienced people who are currently on a failing regimen and are resistant to or unable to take at least 3 classes of antiretrovirals. Those who still have at least 1 fully active drug will be randomized to receive 600 mg twice-daily BMS-663068 or placebo with an optimized background regimen, while those with no fully active antiretrovirals will be enrolled in a non-randomized cohort.

10/11/15

References

J Feinberg, J Lalezari, M Martins, et al (AI438011 study team). HIV-1 Attachment Inhibitor ProdrugBMS-663068 in Antiretroviral-Experienced Subjects: Week 48 Subgroup Analysis. IDWeek 2015. San Diego, October 7-11, 2015. Abstract 1075.

JP Lalezari, GH Latiff, C Brinson, et al (AI438011 Study Team). 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. October 2015.