Safety, tolerability, pharmacokinetics (PK), and antiviral activity of the capsid inhibitor (CI) AB-506 in healthy subjects (HS) and chronic hepatitis B (CHB) subjects

Abstract

Background: AB-506 is an oral, class II, selective HBV CI for the treatment of CHB with activity against genotypes A-H and nucleos(t)ide resistant variants in vitro. The objectives of this ongoing first-in-human study are to evaluate the safety, tolerability, PK, and antiviral activity of AB-506 in HS and HBV-DNA+ CHB subjects. Methods: In Part 1, 2 cohorts of HS were randomized 6:2 to receive single ascending doses of AB-506 from 30mg to 1000mg or placebo (PBO). In Part 2, 1 cohort of 12 HS was randomized 10:2 to receive AB506 400mg or PBO once daily (QD) for 10 days. In Part 3, two cohorts of 12 non-cirrhotic, HBV DNA+ subjects were randomized 10:2 to receive AB-506 or PBO for 28 days at either 160mg or 400mg QD. Safety, tolerability, PK, immune markers, viral sequence and antiviral activity were assessed. Results: No serious adverse events (AEs) were observed in HS; most AEs were mild and considered unrelated to AB-506. No clinically significant abnormalities in laboratory tests, ECGs, or vital signs were noted. CHB subjects were aged 22-59 years and were mostly female, Asian and genotype C or D. HBV DNA and HBV RNA responses by dose and e-antigen status are shown in Table 1. There was no viral breakthrough on treatment. Baseline substitutions at positions Y38, I105, and T109 were noted in 5, 4 and 2 of the 24 subjects respectively; one subject with I105T had no response to treatment. There were no serious AEs; most AEs were mild. 6 subjects across both cohorts had transient, reversible ALT elevations (2 Grade 2, 4 Grade 4), with 2 subjects discontinuing study drug per protocol on Days 23 and 24. Bilirubin, albumin, and INR values remained normal in all subjects; none met drug-induced liver injury (DILI) criteria. All had declining HBV DNA levels of >2 log10 on treatment, and none had unusual AB-506 exposures. One subject has had persistent HBeAg (>2.6 log10) and HBsAg (>1.4 log10) declines from baseline 8 months-post flare and was the only subject with increases from baseline in interferon gamma (IFN-γ) and other T cell activation markers that preceded the ALT flare. The other Grade 4 flare subjects had accompanying increases in IP-10, but no changes in IFN-γ. A novel, longer duration (28 day) study of AB-506 in HS is ongoing. Conclusion: AB-506 was generally safe and well-tolerated and robust antiviral effects were observed in CHB subjects. The ALT flares observed in CHB subjects may be immune-mediated and may lead to beneficial declines in HBV markers.