1282. Safety, Tolerability, and Pharmacokinetics of BRII-732, A Medoxomil Carbonate Prodrug of Islatravir in Healthy Adult Subjects

Abstract Background BRII-732, a prodrug of islatravir (ISL), is potent HIV-1 nucleotide reverse transcriptase translocation inhibitor. Following oral absorption, BRII-732 rapidly converted to ISL, which metabolized intracellularly the active metabolite, ISL triphosphate (ISL-TP). Single doses as low 0.5 mg significantly suppressed RNA by more than 1.0 log at day 7 in treatment-naive adults with infection. Current development work designed provide optimal drug exposure enable once weekly (QW) dosing, be part combination antiretroviral therapy improved patient convenience and treatment adherence. Methods This was Phase 1, randomized, double-blind, placebo-controlled study consisting healthy adult subjects enrolled five single ascending dose two multiple cohorts. The objectives were assess safety, tolerability, PK profiles plasma; ISL-DP ISL-TP human PBMCs. orally administered fasted state using an solution formulation. Safety-related assessments included physical examinations, ECGs, vital signs, AEs, standard clinical laboratory tests. Results or generally safe well-tolerated when subjects. There no Grade ≥ 3 SAEs, drug-related AEs leading withdrawal graded lymphocyte abnormalities. post administration detectable level (LLOQ = ng/mL) systemic circulation 0.5h. Dose proportional increases observed over range 10 200 BRII-732. No meaningful accumulation plasma after QW doses. exposures PBMC cells increased dose-dependently. Approximately 1.7-2.0 fold ratios for are consistent long terminal half-lives 110-150 hours. Conclusion Safety, tolerability including administrations supports further therapy. Disclosures David A. Margolis, MD MPH, Brii Biosciences: Stocks/Bonds Ji Ma, PhD, Michael Watkins, PharmD, Yujin Wang, M.Sc., Chetana Trivedi, B.A., Chi-Chi Peng, Xuelian Wei, Lijie Zhong, Kamlesh Patel, Jean-Luc Girardet, PhD MBA, Annalise VonderEmbse, Li Yan, Zhi Hong, Ownership Interest Lianhong Xu, Stocks/Bonds.