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CROI 2014: HIV Attachment Inhibitor BMS-663068 Shows Good Safety and Efficacy in Phase 2b

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Combination therapy using a novel HIV attachment inhibitor demonstrated good safety and effectiveness, offering the promise of a new antiretroviral class that may be particularly beneficial for people with extensive resistance to current drugs, according to a report at the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) this week in Boston.

HIV treatment combines medications from different antiretroviral classes that interfere with different steps of the viral 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.

Jay Lalezari from Quest Clinical Research in San Francisco presented findings from study AI438011, a randomized, controlled Phase 2b trial evaluating the safety and efficacy of Bristol-Myers Squibb's attachment inhibitor BMS-663068 in treatment-experienced people with HIV.

BMS-663068 is a pro-drug that is metabolized in the body to the active agent BMS-626529, which binds to the gp120 protein on the HIV-1 envelope and blocks interaction between the virus and host cells. BMS-663068 interferes with conformational or shape changes that enable HIV to bind to CD4 cell surface receptors. Unlike maraviroc, BMS-663068 works regardless of CCR5 or CXCR4 co-receptor tropism.

Because of its novel mechanism of action, BMS-663068 has a unique resistance profile and is active against HIV strains that are resistant to other antiretrovirals. An early proof-of-concept study showed that 8 days of BMS-663068 monotherapy led to HIV viral load reductions of 1.2 to 1.7 log copies/mL.

This multinational study included 253 treatment-experienced participants with HIV viral load of at least 1000 copies/mL and CD4 T-cell counts greater than 50 cells/mm3. A majority (about 60%) were men, about one-third were white, and the median age was 39 years. The study had sites in middle-income countries including South Africa, raising the proportion of women, non-whites, and younger people compared to most antiretroviral drug development trials. Two-thirds had HIV subtype B.

Participants had rather advanced disease, with a mean CD4 count of approximately 230 cells/mm3 and nearly 40% having less than 200 cells/mm3. Many had failed first- or second-line ART. About half had at least 1 major mutation conferring resistance to at least 1 widely used antiretroviral class. However, they were required to still be sensitive to raltegravir (Isentress), tenofovir (Viread, also in some coformulations), and atazanavir (Reyataz). They also underwent screening at baseline to see if they were sensitive to BMS-626529.

Participants were randomly allocated to 5 treatment arms. 4 groups received BMS-663068 at doses of 400 or 800 mg twice-daily, or 600 or 1200 mg once-daily. A control group received ritonavir-boosted atazanavir. Everyone also took tenofovir and raltegravir. A subset of 32 patients took part in an optional lead-in monotherapy sub-study in which BMS-663068 was taken alone for 7 days.

Results

  • In the monotherapy sub-study, viral load decreased by an average of 0.7 to 1.5 log copies/mL by day 8.
  • There was a small rise in HIV RNA around day 2, which Lalezari said could be due to the virus accumulating in plasma when it is unable to enter cells.
  • At week 24, all BMS-663068 arms demonstrated similar efficacy -- defined as HIV RNA <50 copies/mL -- in a modified intent-to-treat analysis:

o   400 mg twice-daily: 80%;

o   800 mg twice-daily: 69%;

o   600 mg once-daily: 77%;

o   1200 mg once-daily: 72%;

o   Atazanavir control arm: 75%.

  • Response rates were higher in an observed or as-treated analysis: 87%, 81%, 78%, 84%, and 86%, respectively.
  • Response rates were comparable regardless of baseline BMS-626529 susceptibility.
  • CD4 T-cell gains were similar in all arms.
  • BMS-663068 was generally well-tolerated at all doses and there were no signals of safety issues.
  • There were a total of 15 serious adverse events and 4 treatment discontinuations for this reason in the BMS-663068 arms, but none were deemed related to the study drug.

"Through week 24, response rates were similar across all BMS-663068 arms and with atazanavir/ritonavir in treatment-experienced, HIV positive subjects," the researchers summarized. "BMS-663068 was generally well tolerated across all arms without any dose-response safety signal," they added. "These results support the continued development of BMS-663068."

Lalezari concluded by saying that as an activist, he wanted to thank Bristol-Myers Squibb for working to bring forth a new HIV drug with a new mechanism of action. "There's room for this drug in our armamentarium," he said.

3/6/14

Reference

J Lalezari, GH Latiff, C Brinson, et al. Attachment Inhibitor Prodrug BMS-663068 in ARV-Experienced Subjects: Week 24 Analysis. Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 86.

Other Source

Bristol-Myers Squibb. Bristol-Myers Squibb Presents Promising Phase IIb Data for Novel, Investigational Attachment Inhibitor for HIV-1 Infected Treatment-Experienced Patients. Press release. March 5, 2014.