Analysis of longer-term safety profile of the hepatitis B virus core inhibitor ABI-H0731 in an open label extension study

Abstract

Background: ABI-H0731 (731) is a first-generation hepatitis B virus core inhibitor in development for the treatment of chronic hepatitis B virus infection (cHBV). In the Phase 2 Studies 202 (NCT03577171) and 201 (NCT03576066), patients (pts) with cHBV were randomized to receive blinded placebo (Pbo) or 731 in combination with a nucleos(t)ide reverse transcriptase inhibitor (NrtI) for 24 weeks (wks). Following completion of these studies, eligible pts were able to enter the open-label extension Study 211 (NCT03780543) and receive 731+NrtI for up to 100 wks. Here we report longer-term integrated safety data across the Phase 2 program. Methods: Safety was assessed by treatment-emergent adverse events (AEs) and lab abnormalities. This integrated analysis compares safety data in pts who received 24 wks of Pbo+NrtI to those who received 731+NrtI presented by incidence in 24-wk observation intervals. Results: 40 pts received 24 wks of Pbo+NrtI in Studies 201 or 202, and 95 pts received 731+NrtI in Studies 201, 202 and/or Study 211. Overall, at baseline, the mean (SD) age was 43 (12) years, 56% were male, 87% were Asian, and mean (SD) ALT was 34 (38) U/L; 26% were treatment naïve and 43% were on tenofovir disoproxil fumarate, 22% on tenofovir alafenamide and 10% on entecavir. The mean (SD) duration of exposure to Pbo+NrtI was 24 (4) wks and to 731+NrtI was 65 (17) wks. Most AEs were Grade 1 or 2 and the number of pts with AEs during the first 24 wks of treatment with 731+NrtI was similar to Pbo+NrtI (Table). A single SAE of Grade 3 suicidal ideation unrelated to study drug led to study drug discontinuation. There were no Grade 4 AEs or deaths. There were 15 AEs of rashes reported by 11 pts receiving 731+NrtI, all of which were Grade 1 (10 pts, 1 of which led to study drug discontinuation at 27 wks) or Grade 2 (1 pt); the median (range) time to first rash was 4 (1-61) wks and duration of rash was 3 (0.3-17) wks. Most lab abnormalities were Grade 1 or 2. The Grade 3 lab abnormalities observed in more than 1 pt in the 731+NrtI group included elevated AST and ALT, observed in 3 pts total (3%) which were transient or isolated and without changes in direct bilirubin or viral antigens. Conclusion: 731 exhibits a favorable safety and tolerability profile in pts with cHBV who have now been treated with 731+NrtI for 1-1.5 years. Fewer AEs and lab abnormalities have been observed with the extended duration of therapy. The data support the differentiated safety profile and continued development of 731.