From Bristol-Myers Squibb:

48-Week Analysis of Investigational HIV-1 Attachment Inhibitor Paves Way for Phase III Trial Initiation

Phase III trial now underway for novel therapy for heavily treatment-experienced HIV-1 patients

Binding directly to the HIV virus, BMS-663068 is the first investigational antiretroviral designed to prevent initial viral attachment to host CD4+ T cells and entry into host immune cells

Wednesday, February 25, 2015 8:30 am EST

"Today, due to tremendous advancements in therapy, many patients living with HIV are able to remain healthier and live longer; however, this means that they are usually exposed to multiple therapies over time, and may often develop drug resistance"

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced data from a Phase IIb trial of investigational compound BMS-663068, designed as an HIV-1 attachment inhibitor, in treatment-experienced HIV-1 patients. In the study, which compared BMS-663068 to a pharmacoenhanced protease inhibitor (Reyataz (atazanavir sulfate) and ritonavir), virologic response rates (HIV-1 RNA <50 c/mL) and immunologic reconstitution were similar across the BMS-663068 and Reyataz/ritonavir arms of the trial through 48 weeks. Specifically, 61-82% of BMS-663068 patients had HIV-1 RNA levels <50 c/mL, compared to 71% of Reyataz/ritonavir patients at week 48 (mITT FDA snapshot analysis). HIV-1 RNA levels <50 c/mL typically indicate virus replication is undetectable.

Treatment with BMS-663068 resulted in no dose response safety signals, no treatment discontinuations related to adverse events (AEs), and no treatment-related serious adverse events over the course of the trial. The most common AEs were headache (2% in the 800 mg cohort) and abdominal pain (2% in 1200 mg cohort).

Due to the positive results seen thus far, a Phase III clinical trial of the attachment inhibitor among heavily treatment-experienced patients began on Monday, February 23, 2015. For the purposes of the Phase III trial, heavily treatment-experienced patients are defined as individuals who can no longer formulate a viable regimen (standard three-course treatment regimen) due to accumulation of drug resistance, past intolerabilities or antiretroviral contraindications.

“The attachment inhibitor clinical development program exemplifies our commitment to focusing on patients living with HIV who have high unmet needs,” said Douglas Manion, M.D., head of Specialty Development, Bristol-Myers Squibb. “This development is representative of a continued effort at Bristol-Myers Squibb to find innovative approaches to fighting this disease.”

The Phase IIb study results, presented yesterday at the 22nd Conference on Retroviruses and Opportunistic Infections (CROI), highlight the novel mechanism of action of the investigational prodrug BMS-663068, which when converted into its active moiety BMS-626529, is designed to bind directly to the HIV gp120 protein, and prevents initial viral attachment to the host CD4+ T cell and entry into the host immune cell.

“Today, due to tremendous advancements in therapy, many patients living with HIV are able to remain healthier and live longer; however, this means that they are usually exposed to multiple therapies over time, and may often develop drug resistance,” said Jacob Lalezari, M.D., Director of Quest Clinical Research and an Assistant Clinical Professor of Medicine at the University of California-San Francisco/Mount Zion Hospital. “Treatment-experienced patients represent an important patient subset, for whom ongoing research and development of new drug classes is being actively pursued.”

Study Design

This ongoing, active-controlled Phase IIb trial, which expands on a previous 24-week analysis presented at CROI last year, randomized 254 treatment-experienced HIV-1 infected patients into four BMS-663068 cohorts. The first cohort (n=43) received 400 mg twice daily (n=43), the second received 800 mg twice daily (n=39), the third received 600 mg once daily (n=45), and the fourth received 1200 mg once daily (n=42). A control group received Reyataz (atazanavir sulfate) and ritonavir, 300/100 mg once daily (n=41). Within the control group and each of the treatment arms, treatment also included raltegravir (400 mg twice daily), in addition to tenofovir disoproxil fumarate (300 mg once daily). The primary study endpoints addressed the proportion of subjects with HIV-1 RNA <50 c/mL at week 24; efficacy and safety at week 48 were assessed as secondary endpoints.

A second study assessing drug-drug interactions between the attachment inhibitor prodrug BMS-663068 with darunavir and ritonavir or in combination with darunavir and ritonavir plus etravirine also was presented at CROI this year. Findings showed that BMS-663068 can be co-administered with darunavir and ritonavir, etravirine alone, as well as darunavir and ritonavir plus etravirine, without dose adjustment. Skin rash (Grade 1–2) was reported in 28.3% of patients in the study, and was considered related to etravirine and darunavir/ritonavir, not to BMS-663068.

Study Design

In this open-label, single-sequence, multiple-dose, three-cohort study in 42 healthy patients, BMS-663068 was administered at 600 mg twice daily (n=14), darunavir and ritonavir at 600 mg/100 mg twice daily (n=14), and etravirine at 200 mg twice daily (n=14). Compared to BMS-663068 administered twice daily alone, co-administration with darunavir and ritonavir increased BMS-626529 maximum serum concentration (C_max) by ~50%, the concentration of drug in blood plasma against time (AUC_tau) by ~60%, and the drug transfer between compartments (C₁₂) by ~90%, respectively. These results are consistent with CYP3A inhibition by ritonavir.

Consistent with CYP3A induction by etravirine, the administration of etravirine decreased BMS-626529 C_max, AUC_tau, and C₁₂ each by ~50%. Darunavir and ritonavir plus etravirine increased BMS-626529 C_max, AUC_tau, and C₁₂ by ~50%, ~30%, and ~30%, respectively, consistent with RTV inhibition of CYP3A predominating over the induction of etravirine. Additionally, BMS-626529 caused minimal changes to the pharmacokinetics parameters of either darunavir and ritonavir, etravirine or darunavir and ritonavir plus etravirine.

About Bristol-Myers Squibb’s HIV Research Portfolio

For more than 20 years, Bristol-Myers Squibb has focused on the discovery, development and delivery of innovative medicines to help meet the needs of patients living with HIV-1. Today, at least one in every three U.S. patients with HIV is prescribed a Bristol-Myers Squibb therapy, and current studies are ongoing for a range of new treatments in addition to BMS-663068, including an HIV-1 maturation inhibitor (BMS-955176).

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

Bristol-Myers Squibb Forward Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that clinical trials of BMS-663068 will support regulatory filings, or that BMS-663068 will receive regulatory approval in the United States, or if approved, that it will become a commercially successful product. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2014, in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.