The second-generation hepatitis B virus (HBV) core inhibitor (CI) ABI-H2158 is associated with potent antiviral activity in a 14-day monotherapy study in HBeAg-positive patients with chronic hepatitis B (CHB)

Abstract

Background: The HBV core protein plays an integral role in multiple steps of the HBV life cycle. ABI-H2158 is a 2nd generation, potent and selective HBV CI, being developed for the treatment of patients (pts) with CHB. In vitro, ABI-H2158 exhibits enhanced inhibitory potency over 1st generation CIs against both viral replication (EC90 = 69 ng/mL) and surrogate markers (pgRNA, HBeAg and HBsAg) of cccDNA biosynthesis (EC90 = 242-288 ng/mL) in Primary Human Hepatocytes (PHH) infection assays. Here we report the safety and antiviral activity from the initial cohort of pts treated with ABI-H2158 100 mg or placebo. Methods: Sequential cohorts of 9 pts are planned to be enrolled in the ABI-H2158-101 study. Each cohort will be randomized to receive ABI-H2158 or placebo (7:2) QD for 14 days in a blinded manner. Eligible pts include males and females aged >18 and <65 years, HBV treatment-naive, HBeAg+, with HBV DNA >2x105 IU/mL and F0-F2 fibrosis. Safety will be assessed by adverse events (AEs) and laboratory parameters. Pharmacokinetics are performed on Day 1 and 14. HBV DNA, RNA, HBeAg, HBsAg and HBcrAg are measured on Day 1, 8 and 15. Results: Dosing in the 1st cohort (100 mg) has been completed. Overall, the mean age of pts was 36 years [range 19–49], with the majority being male (n=7), Asian (n=8) and HBV genotype C (n=7). In pts receiving ABI-H2158, mean declines from Baseline to Day 15 in HBV DNA and RNA levels were 2.3 log10 IU/mL [range 1.7 – 3.0] and 2.1 log10 IU/mL [range 1.5 - 2.7] respectively. No serious AEs, dose limiting toxicities or premature discontinuations were reported. Three pts reported a total of 5 mild, drug-related AEs that recovered without intervention; dizziness, fatigue, rash, headache and upper abdominal pain. Treatment emergent laboratory abnormalities were infrequent, mild and transient, with no ALT elevations Grade >1 severity. Day 14 plasma ABI-H2158 Cmax and AUC0-24hr were 3,390 ng/mL and 46,100 hr*ng/mL, respectively. A second cohort receiving 300 mg QD is ongoing. Conclusion: Results from the initial 100 mg low dose of ABIH2158 cohort demonstrated potent antiviral activity, a favourable safety profile when administered for 14 days, and support once daily dosing in CHB patients. Data from additional cohorts may be presented if available at the time of the conference.