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 h, and area under the plasma concentration‐time curve increased dose proportionally. In Part B, Day 10 T max was 2 h, mean t ½ was 15.5–18.4 h, and exposure accumulated 1.7‐ to 3.1‐fold. In Part C, Day 14 T max was 1 h, 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.