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IDWeek 2014: HIV Attachment Inhibitor BMS-663068 Works Well Across Patient Subgroups

An experimental attachment inhibitor that binds to the surface of the HIV envelope and prevents it from attaching to and entering CD4 T-cells demonstrated good virological response rates and tolerability regardless of age, sex, or race/ethnicity, according to research presented at IDWeek 2014, now underway in Philadelphia.

Antiretroviral therapy (ART) combines drugs from different classes that interfere with various steps of the HIV lifecycle. But no existing drugs target the very first step, initial attachment of the virus to a vulnerable host cell; CCR5 blockers like maraviroc (Selzentry) and fusion inhibitors like enfuvirtide (Fuzeon) work at slightly later steps. A new class of drugs with a unique resistance profile would be especially beneficial to people with extensive treatment experience and drug resistance.

Cynthia Brinson from Central Texas Clinical Research and colleagues conducted a Phase 2b trial (AI438011) of the safety, efficacy, and dose-response relationship of BMS-663068 or fostemsavir, a pro-drug of BMS-626529.

The study included 251 treatment-experienced participants. The median age was 39 years and the patient population was diverse, with 40% women and nearly 60% non-white participants (about half of these being black and the rest "other" or multiracial). The median baseline viral load was approximately 4.8 log copies/mL, with about 40% having >100,000 copies/mL. The media CD4 count was quite low at approximately 230 cells/mm³, with nearly 40% having below 200 cells/mm³.

Participants were randomly allocated to receive 1 of 4 doses of BMS-663068 (400 or 800 mg twice-daily or 600 or 1200 mg once-daily) or else once-daily ritonavir-boosted atazanavir (Reyataz), all in combination with tenofovir (Viread) and raltegravir (Isentress). They were determined to be susceptible (not resistant) to all study drugs.

Results

• Primary 24-week results were previously reported at this year's Retrovirus Conference, showing response rates (HIV RNA <50 copies/mL) of 80%, 69%, 77%, and 72%, respectively, for the 4 BMS-663068 dose arms and 75% in the atazanavir arm.
• Week 24 response rates were comparable across all BMS-663068 dose arms and the atazanavir arm regardless of sex, age, or race/ethnicity.
• Response rates for people with baseline viral load <100,000 copies/mL were higher than those for people with lower levels, both for BMS-663068 and for atazanavir.
• Likewise, response rates for people with baseline CD4 counts >200 cells/mm³ were higher than those for people with lower levels, both for BMS-663068 and for atazanavir.
• Again, however, there were no major differences in response rates across demographic groups in either the high or low viral load or CD4 cell strata.
• Mean CD4 cell gains were also similar across all arms regardless of sex, age, or baseline CD4 count -- though the increase appeared to be a bit lower for black participants receiving BMS-663068 compared to those taking atazanavir.

"Virologic response rates were comparable across BMS-663068 and atazanavir/ritonavir arms through Week 24 regardless of gender, age, and race, baseline viral load, or baseline CD4+ T-cell count," the researchers concluded.

Although sample sizes were small, they saw a "suggestion of a trend" for larger CD4 cell gain across all arms for people with baseline HIV RNA >100,00 copies/mL versus <100,000 copies/mL.

These results, they added, "support continued development of BMS-663068."

In a related poster (to be presented on October 11), investigators looked at the safety profile of BMS-663068 in the same study. According to the published study abstract, the most common adverse event reported by BMS-663068 recipients was headache (14%), which was not dose-related. There were no BMS-663068-related adverse events leading to treatment discontinuation. About 7% of people taking BMS-663068 and 10% taking atazanavir experienced serious adverse events, but none were deemed related to the study drugs.

About 9% of participants across the BMS-633068 arms experienced grade 2-4 (moderate to severe) drug-related adverse events, but these were mostly single instances and again no dose relationship was seen. There was "no noticeable trend" for grade 3-4 laboratory abnormalities, and severe hematological (blood cell) and liver chemistry abnormalities were uncommon.

"BMS-663068 was generally well tolerated across all arms, with no related serious adverse events or adverse events or adverse events leading to discontinuation and no dose-related safety signals," the researchers concluded.

10/10/14

References

C Brinson, J Lalezari, GH Latiff, et al. HIV-1 Attachment Inhibitor Prodrug BMS-663068 in Antiretroviral-Experienced Subjects: Week 24 Subgroup Analysis. IDWeek 2014. Philadelphia, October 8-12, 2014. Abstract 540.

J Lalezari, GH Latiff, C Brinson, M Lataillade, et al. Safety Profile of HIV-1 Attachment Inhibitor Prodrug BMS-663068 in Antiretroviral-Experienced Subjects: Week 24 Analysis. IDWeek 2014. Philadelphia, October 8-12, 2014. Abstract 1574.

Other Source

Bristol-Myers Squibb. Bristol-Myers Squibb Presents Data from Multiple New Studies at IDWeek 2014 Showcasing Continued Innovation in Virology. Press release. October 3, 2014.