Safety, pharmacokinetics, and antiviral activity of ABI-H2158, a hepatitis B virus core inhibitor: a randomized, placebo-controlled Phase 1 study.

Treatment for chronic hepatitis B virus infection (cHBV) is mostly indefinite, with new finite-duration therapies needed. We report safety, pharmacokinetics, and antiviral activity of the investigational HBV core inhibitor ABI-H2158. This Phase 1a/b study (NCT03714152) had three parts: Part A, participants received a single ascending oral dose of ABI-H2158 (5-500 mg) or placebo; Part B, participants received multiple doses of ABI-H2158 300 mg once (QD) or twice (BID) daily or placebo, for 10 days; Part C, cHBV patients received ABI-H2158 (100, 300, or 500 mg QD or 300 mg BID) or placebo, for 14 days. Ninety-three participants enrolled. In Parts A/B, there were no serious adverse events (SAEs) or deaths, and all treatment-emergent AEs (TEAEs) were Grade 1. In Part C, two patients had Grade 3 TEAEs unrelated to ABI-H2158; there were no deaths, SAEs, or Grade 4 TEAEs. In Part A, median time to maximum ABI-H2158 plasma concentration (T max ) and mean terminal elimination half-life (t ½ ) were 1-4 and 9.8-20.7 hours, and area under the plasma concentration-time curve increased dose proportionally. In Part B, Day 10 T max was 2 hours, mean t ½ was 15.5-18.4 hours, and exposure accumulated 1.7- to 3.1-fold. In Part C, Day 14 T max was 1 hour, exposure accumulated 1.4- to 1.8-fold, and ABI-H2158 was associated with >2 log 10 declines in HBV nucleic acids. In conclusion, ABI-H2158 in cHBV patients following 14 days of dosing was well tolerated and demonstrated potent antiviral activity. Safety and pharmacokinetics supported future QD dosing.