The Safety, Pharmacokinetics, and Antiviral Activity of ABI ‐4334, A Novel Next‐Generation Hepatitis B Capsid Assembly Modulator

Novel, well-tolerated, short-term therapeutics for chronic hepatitis B virus infection (cHBV) are needed. ABI-4334 is a next-generation capsid assembly modulator that targets the HBV core protein. The safety, tolerability, and pharmacokinetics of ABI-4334 in healthy volunteers and participants with cHBV and antiviral effects in participants with cHBV were examined in two Phase 1 studies. Study 101 was a placebo-controlled study of healthy volunteers that included four single-ascending dose cohorts and two once-daily multiple-ascending dose cohorts randomized 6:2 (ABI-4334:placebo), and one crossover food-effect cohort randomized 3:3 (fed:fasted). Study 102 was a randomized, blinded, placebo-controlled study where participants with cHBV were randomized 8:2 (ABI-4334 [2 dose cohorts]:placebo). Overall, 54 healthy volunteers and 20 participants with cHBV were included in Studies 101 and 102, respectively. Most participants (75%) in Study 102 were hepatitis B e antigen (HBeAg) negative and generally had lower baseline HBV DNA and pregenomic RNA (pgRNA) levels. ABI-4334 was well tolerated, with no treatment-emergent serious adverse events (AEs) or treatment-emergent AEs leading to study discontinuation. The mean ABI-4334 plasma half-life ranges were comparable across doses in both studies. Following multiple-dose administration in participants with cHBV, the steady-state mean plasma half-life ranged from 17.5 to 27.5 h. HBV DNA declines were observed in both HBeAg-positive (n = 3) and -negative (n = 13) participants across doses. Reductions in pgRNA were observed in participants with detectable pgRNA at baseline. ABI-4334 was well tolerated, with pharmacokinetics and antiviral results supporting the continued development of ABI-4334 as a monotherapy or component of novel combination regimens for cHBV. Trial Registration: Study 101 (NCT05569941). Study 102 (NCT06384131).