Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: a randomised, placebo-controlled phase 1 trial

Background

Therapies with novel mechanisms of action against hepatitis B virus (HBV) infection
are being explored with the goal of achieving a functional cure (sustained off-treatment
response) without requiring lifelong therapy. We aimed to evaluate the pharmacokinetics,
safety, and antiviral activity of ABI-H0731, an investigational inhibitor of the HBV
core protein.

Methods

This phase 1, randomised, placebo-controlled study was done in two parts. In part
1, healthy adults without hepatitis B aged 18–65 years at one clinical research centre
in New Zealand (eight participants per dose cohort) were randomly assigned (3:1) to
receive single oral doses of ABI-H0731 (100, 300, 600, or 1000 mg) or matching placebo,
or once-daily or twice-daily doses of ABI-H0731 800 mg or matching placebo for 7 days.
In part 2, adults aged 18–65 years at clinical research centres in New Zealand, Australia,
the UK, Hong Kong, Taiwan, and South Korea with chronic HBV (12 participants per dose
cohort) were randomly assigned (5:1) to receive ABI-H0731 (100, 200, 300, or 400 mg)
or matching placebo once daily for 28 days. In part 2, participants were required
to have HBeAg-positive or HBeAg-negative chronic HBV infection, with serum HBV DNA
concentrations of at least 2 × 10
⁴ IU/mL (HBeAg-positive) or 2 × 10
³ IU/mL (HBeAg-negative) and serum alanine aminotransferase concentrations less than
seven times the upper limit of normal. Both parts used simple randomisation, with
study participants, site personnel, and study monitors masked to treatment assignments.
The primary study objective was dose-related safety and tolerability of ABI-H0731
in healthy volunteers and in participants with chronic HBV infection, assessed in
all treated participants. Key secondary assessments included pharmacokinetic analyses
and virological responses. This study is registered with
ClinicalTrials.gov, identifier
NCT02908191 and is completed.

Findings

48 [61%] of 79 healthy volunteers were enrolled in the single-ascending or multiple-ascending
dose phase of part 1 between Nov 16, 2016, and Jan, 27, 2017. 38 [55%] of 69 HBV-infected
participants were enrolled in part 2 between June 15, 2017, and March 15, 2018. All
adverse events were non-specific and of mild or moderate intensity apart from a single
HBV-infected participant given the 400 mg dose who developed a severe (grade 3) maculopapular
rash and terminated treatment. Overall, the most frequent adverse events of any grade
among the 74 participants who received ABI-H0731 were headache (11 [15%]), influenza-like
illness (seven [9%]), and dizziness (six [8%]); the most frequent adverse events considered
treatment-related were rash (four [5%]) and dizziness (three [4%]). In part 1, ABI-H0731
reached maximum plasma concentrations (T
_max) in 2·50–4·17 h; the mean plasma half-life (t
_1/2) was 23·5–28·4 h. In part 2, mean maximum HBV DNA declines from baseline were 1·7
log
₁₀ IU/mL in the 100 mg dose cohort, 2·1 log
₁₀ IU/mL in the 200 mg dose cohort, and 2·8 log
₁₀ IU/mL in the 300 mg dose cohort. Across dose cohorts, serum HBV RNA declines correlated
with HBV DNA declines.

Interpretation

No pattern of treatment-emergent adverse events was observed at ABI-H0731 doses up
to 300 mg in individuals with chronic hepatitis B. ABI-H0731 was rapidly absorbed
and exhibited a plasma half-life supportive of once-daily dosing. Dose-dependent decreases
in serum HBV DNA and RNA concentrations are consistent with the proposed mechanism
of action.