Safety and pharmacodynamics of the GALNAC-siRNA AB-729 in subjects with chronic hepatitis B infection

Abstract

Background: AB-729 is an RNA interference (RNAi) therapeutic that targets hepatocytes using a covalently conjugated N-Acetylgalactosamine (GalNAc) technology that enables subcutaneous (SC) delivery. In preclinical models AB-729 reduces all HBV transcripts, resulting in inhibition of viral replication and reductions in hepatitis B surface antigen (HBsAg). Here we report preliminary safety and pharmacodynamic (PD) results following administration of AB-729 in subjects with chronic hepatitis B (CHB) from an ongoing first-in-human study. Methods: Part 1 examined single doses of AB-729 or placebo in healthy subjects. In Part 2 non-cirrhotic, HBeAg positive or negative CHB subjects currently taking nucleos(t)ide antiviral (NA) therapy with HBV DNA below the limit of quantitation and ALT up to 5xULN received single doses of AB-729 60mg, 90mg, or 180mg. Assessments included safety and PD through at least 12 weeks post-dose. Part 3 is evaluating multiple dose regimens of AB-729 for 6 months at varying dose levels/intervals. Results: There have been no serious adverse events (AEs) or discontinuations due to AEs to date. In Part 2, 19 AEs were observed among the 16 CHB subjects dosed, most of which were mild. 11/19 were assessed as related; of which 7 were mild to moderate injection-related AEs (mostly pain). At 180mg, there were two transient Grade 1 ALT elevations and one unrelated Grade 3 ALT/AST elevation in the context of acute gastroenteritis. ALT/AST levels remained normal or at the same grade (in one subject) as pre-study levels for all subjects in the 60mg and 90mg cohorts. Following single dose AB-729, continuous declines in mean HBsAg were observed through 12 weeks post-dose (Figure). At Week 12, HBsAg declines ranged from -0.62 to -2.14 log10 (60mg), -0.79 to -1.87 log10 (90mg) and -0.69 to -1.62 log10 (180mg). Evaluation of AB-729 60mg at dosing intervals of every 4 weeks and every 8 weeks is ongoing, and available safety and PD data will be reported. Conclusion: AB-729 was generally safe and well tolerated following single SC doses, with no clinically relevant ALT/AST changes in the 60mg and 90mg cohorts. Robust mean declines in HBsAg were observed following single doses of 60mg, 90mg and 180mg in CHB subjects that continued through 12 weeks post single dose, supportive of a dosing interval of monthly or less frequently in multiple dose studies.