Two phase 1 studies of safety, tolerability, and pharmacokinetics of an EFdA prodrug (BRII-732) in healthy adult participants

BRII-732, a medoxomil carbonate prodrug of EFdA, is designed for once weekly dosing as part of combination antiretroviral therapy for HIV. Two single-center, randomized, double-blind, placebo-controlled phase 1 studies evaluated its safety, tolerability, and pharmacokinetics in 72 healthy adult participants. Study 1 assessed single doses (10-200 mg) and multiple weekly doses (10, 25 mg), while Study 2 investigated lower doses (≤2.5 mg) and relative bioavailability of tablet versus oral solution. In Study 1, the first single-dose cohort and the first multiple-dose cohort each enrolled four participants (three active; one placebo); the remaining cohorts each enrolled eight participants (six active; two placebo). In Study 2, each cohort enrolled eight participants (six active; two placebo). BRII-732 was well tolerated, with most TEAEs being mild and no SAEs, or withdrawals. Clinical laboratory tests, vital signs, and ECGs revealed no significant abnormalities. Plasma BRII-732 concentrations were largely below the limit of quantification, confirming efficient conversion to EFdA. Plasma exposures of EFdA increased near dose-proportionality, with a mean <i>t</i>_1/2 of 1.50-2.94 hours (≤10 mg) and 55-112 hours (25-200 mg). EFdA showed no accumulation in plasma after weekly dosing. Intracellularly, EFdA-TP demonstrated rapid formation, slow elimination (<i>t</i>_1/2: 194-227 hours), and meaningful accumulation after weekly dosing, with an estimated steady-state accumulation ratio of ~2.2-2.5. Tablet and solution formulations exhibited comparable systemic exposure. These studies highlight the favorable safety, tolerability, and pharmacokinetic profile of once weekly BRII-732 in healthy adult participants.