Antiviral activity, pharmacokinetics and safety of the second-generation hepatitis B core inhibitor ABI-H2158 in Phase 1b study of patients with HBeAg-positive chronic hepatitis B infection

Abstract

Background and aims: The HBV core protein plays an integral role in multiple steps of the HBV lifecycle. ABI-H2158 is a second-generation HBV core inhibitor in development for the treatment of chronic hepatitis B infection. Here we report the antiviral activity, pharmacokinetics (PK) and safety from a Phase 1b study in which patients (pts) were treated with ABI-H2158. Method: In each cohort, 9 pts (7 active, 2 placebo [Pbo]) were randomized in a blinded manner to receive either ABI-H2158 100, 300 or 500 mg or Pbo once daily for 14 days. Eligible pts were males or females aged ≥18 and ≤65 years, HBV treatment naive, HBeAg positive with HBV DNA ≥2 × 105 IU/mL and Metavir F0-F2. HBV DNA, pgRNA, HBeAg, HBsAg and HBcrAg were measured on Days 1, 8 and 15. PK was assessed on Days 1 and 14. Safety was evaluated by treatment-emergent adverse events (AEs) and laboratory parameters. Results: Across the cohorts, the mean (range) age of pts was 36 (19– 51) years, with the majority being male (59%), Asian (96%) and HBV genotype C (59%). At baseline, the mean (range) HBV DNA was 8.0 log10 (4.7–9.1) IU/mL, pgRNA was 6.8 log10 (5.2–7.9) U/mL and ALT was 40 (14–124) U/L. Change in HBV DNA and pgRNA from baseline to Day 15 and PK data are shown in the Table 1. AEs were reported for 38% (8/21) of pts receiving ABI-H2158 and 50% (3/6) receiving PBO. The majority of AEs were Grade 1; none were Grade 3 or 4, serious or led to treatment discontinuation. Headache was the only AE reported by more than 1 pt receiving ABI-H2158 (2 pts). Graded laboratory abnormalities were observed in 71% (15/21) of pts receiving ABI-H2158 and 50% (3/6) receiving Pbo, the majority of which were Grade 1. Transient increases in ALT were observed in 24% (5/21) of pts receiving ABI-H2158 (all Grade 1) and in 33% (2/6) receiving Pbo (1 Grade 1; 1 Grade 3). Conclusion: Results from this Phase 1b study demonstrate that ABIH2158 has potent antiviral activity and a favourable safety profile when administered once daily for 14 days supporting further evaluation in combination with nucleos(t)ide analogues in Phase 2.