Second-Generation Investigational HIV-1 Maturation Inhibitor Demonstrates Positive New Phase IIa Results, Supporting Continued Development

Bristol-Myers Squibb Company

today announced additional Phase IIa proof-of-concept data for BMS-955176, a novel investigational agent designed to prevent the maturation of HIV-1. The study findings, which are being presented in a late-breaking oral presentation at the 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention in Vancouver, confirmed the antiretroviral activity of BMS-955176 when administered with atazanavir (± ritonavir) and support further development of the second-generation HIV-1 maturation inhibitor. BMS-955176 is designed to inhibit one of the last steps of the HIV-1 viral lifecycle, resulting in the release of immature non-infectious HIV-1 particles. As part of a multi-part proof-of-concept study, a two-drug combination of BMS-955176 (80 mg) plus atazanavir (unboosted) had a maximum median change in HIV-1 RNA of -2.23 log10 c/mL from baseline through study discharge (Day 42). The standard of care (SOC) control of atazanavir 300 mg and ritonavir 100 mg plus tenofovir disoproxyl fumarate 300 mg plus emtricitabine 200 mg in a fixed dose combination had a maximum median change in HIV-1 RNA of -2.39 log10 c/mL from baseline through study discharge (Day 42). In addition, a lower dose of BMS-955176 (40 mg) plus atazanavir and ritonavir had a similar maximum median change in HIV-1 RNA of -2.20 log10 c/mL. Length of therapy for all treatment groups was 28 days. Study endpoints included change in HIV-1 RNA from baseline to Day 28 and from baseline to the end of the study (Day 42) and safety. "The BMS-955176 data provide further compelling evidence of its potential as a second-generation maturation inhibitor that suppresses HIV-1 in a novel way," said Douglas Manion, M.D., Head of Specialty Development, Bristol-Myers Squibb. "The 25 years we have spent fighting this disease have given us the expertise to help address the unmet needs in HIV treatment and we are committed to developing improved solutions for treatment-experienced patients." Study Design and Results In Part B of the Phase IIa, randomized, multi-part trial, antiviral activity and safety of BMS-955176 administered with atazanavir ± ritonavir were evaluated and compared to a standard of care regimen of atazanavir and ritonavir plus tenofovir disoproxil fumarate/emtricitabine after 28 days of therapy. The study included 28 HIV-1, subtype B-infected patients with HIV-1 RNA ≥5000 c/mL and CD4+ T-cell counts ≥200 cells/µL who were randomized 2:2:2:1 to four treatment groups: BMS-955176 40 mg plus atazanavir 400 mg; BMS-955176 40 mg plus atazanavir 300 mg and ritonavir 100 mg; BMS-955176 80 mg plus atazanavir 400 mg; and a SOC control of atazanavir 300 mg and ritonavir 100 mg plus tenofovir disoproxyl fumarate 300 mg plus emtricitabine 200 mg in a fixed dose combination. Study endpoints included change in HIV-1 RNA from baseline to Day 28, change in HIV-1 RNA from baseline to the end of the study (Day 42) and safety. A summary of the data is below. BMS-955176 (40mg QD)+ATV (400mg QD) BMS-955176 (40mg QD)+ATV (300mg QD)+RTV (100mg QD) BMS-955176 (80mg QD)+ATV (400mg QD) Tenofovir disoproxil fumarate (300mg QD)+emtricitabine (200mg QD) (fixed-dose combination) +ATV(300mg QD) +RTV (100mg QD) N 8 8 8 4 Maximum decline in HIV-1 RNA (log10 c/mL); median (min, max) -1.86 (-1.49, -2.37) -2.20 (-1.24, -3.52) -2.23 (-1.87, -2.68) -2.39 (-1.83, -3.04) Median decline in HIV-1 RNA (log10 c/mL) on Day 29 (min, max) -1.66 (-1.19, -2.04) -1.99 (-1.04, -3.32) -2.18 (-1.53, -2.68) -2.22 (-1.83, -2.84) There were no deaths, serious adverse events or adverse events leading to discontinuation. In addition, bilirubin levels were lower for patients receiving BMS-955176 plus unboosted atazanavir compared to patients receiving BMS-955176 40 mg plus boosted atazanavir or the standard of care. The most common adverse events (≥10%) across treatment groups included increased bilirubin levels (58%), headache (50%) and abnormal dreams (38%). These study findings follow data reported in February at the 2015 Conference on Retroviruses and Opportunistic Infections (CROI), which showed that as monotherapy, BMS-955176 demonstrated strong antiviral activity against HIV-1 regardless of naturally occurring changes in the Gag polyprotein that were not responsive to first-generation maturation inhibitor bevirimat. Taken together, data from Part A and Part B of the Phase IIa proof-of-concept study support the further evaluation of BMS-955176 in novel treatment regimens such as nucleos(t)ide- and booster-sparing regimens to address key unmet needs for HIV-1 treatment-experienced patients. Two Phase IIb studies have started in 2015: a traditional dose-finding study in treatment-naive patients and a second Phase IIb study to evaluate a nucleos(t)ide- and booster-sparing regimen in treatment-experienced patients. As one of the final steps in the HIV-1 lifecycle, maturation occurs when the virus breaks connections between structural proteins. The structural proteins are able to then undergo changes, resulting in the production of fully mature infectious virus particles that are subsequently released from cells, with the ability to infect new CD4+ cells. BMS-955176 is designed to inhibit the last cleavage step in the HIV-1 maturation process, which then blocks the virus from becoming mature and infectious. Globally, there are 34 million people infected with HIV-1. Significant treatment advances over the last twenty years have helped many infected by the disease live longer. However, patients living with HIV-1, particularly those who are treatment-experienced, can develop resistance to existing therapies due to a variety of factors. According to the U.S. Department of Health and Human Services, data has shown that suboptimal adherence and drug intolerance/toxicity, for example, accounted for 28% to 40% of virologic failure and regimen discontinuations. Novel therapies with low potential for cross-resistance can help address this challenge. About Bristol Myers-Squibb's HIV Portfolio For more than 20 years, Bristol-Myers Squibb has focused on delivering innovative medicines to help meet the needs of patients living with HIV-1. Our goal is to help individuals living with HIV-1 to live longer and healthier lives by achieving and maintaining viral suppression, and by managing challenges associated with treatment resistance. We are investigating new ways to attack the HIV-1 virus, and studies are ongoing for innovative treatments including the HIV-1 maturation inhibitor and an HIV-1 attachment inhibitor (BMS-663068).