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

## TL;DR

This study tested a new HIV drug (BRII-732) in healthy adults, finding it safe and effective with once-weekly dosing.

## Contribution

The study provides first-in-human data on the safety and pharmacokinetics of a once-weekly EFdA prodrug for HIV.

## Key findings

- BRII-732 was well tolerated with no serious adverse events in healthy participants.
- EFdA plasma levels increased dose-proportionally and showed no accumulation after weekly dosing.
- EFdA-TP intracellular levels accumulated significantly after weekly dosing, supporting once-weekly therapy.

## Abstract

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 t1/2 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 (t1/2: 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.