Antiviral activity and safety of the hepatitis B core inhibitor ABI-H0731 administered with a nucleos(t)ide reverse transcriptase inhibitor in patients with HBeAg-positive chronic hepatitis B infection in a long-term extension study

Abstract

Background and aims: ABI-H0731 (731) is a first-generation HBV core inhibitor in development for the treatment of chronic hepatitis B infection (CHB). In the Phase 2a studies 202 and 201, treatment naïve (TN) and virally suppressed (VS) HBeAg-positive patients (pts) with CHB were randomized 1:1 to 731 or placebo (Pbo) with NrtI in a blinded manner for 24 weeks. The combination of 731+NrtI was well tolerated and demonstrated faster and greater reductions in HBV DNA and pgRNA than NrtI alone. Following study completion, eligible pts entering an open-label extension study 211 received 731+NrtI for up to an additional 76 weeks. Here we report the updated data from study 211 through the current last reported observation. Method: For TN pts, HBV DNA was measured by COBAS TaqMan 2.0 (LLOQ = 20 IU/mL) and pgRNA by an in-house quantitative PCR assay (LLOQ = 135 U/mL). For VS pts, HBV DNA was measured by an inhouse semi-quantitative PCR assay (LLOD = 5 IU/mL) and pgRNA by an in-house semi-quantitative RT-PCR assay (LLOD = 5 IU/mL). For all pts, quantitative HBeAg and HBsAg were measured by Abbott Architect (LLOQ = 0.11 IU/mL and 0.05 IU/mL, respectively) and HBcrAg by Lumipulse G (LLOD = 1 kU/mL). Safety was assessed by adverse events (AEs) and laboratory parameters. Results: Of the 23 TN pts from study 202, median (range) treatment duration 57 (36–83) weeks, 21 pts have DNA declines to <100 IU/mL and 6 pts have pgRNA declines to <500 U/mL. Declines of ≥1 log or at <LLOQ in HBeAg, HBcrAg and HBsAg have been observed in 6, 8 and 3 pts, respectively. Of the 43 VS pts from study 201, median (range) treatment duration 58 (30–81) weeks, 34 and 21 pts have now achieved DNA and pgRNA <5 IU/mL, respectively. In addition, 29 pts have HBeAg <5 IU/mL, 27 pts have HBcrAg <500 kU/mL and 4 pts have HBsAg <1000 IU/mL. During the first 24 weeks of study 211, AEs were reported by 47% (31/66) pts, most of which were Grade 1 or 2. There were no SAEs or AEs leading to study drug discontinuation. The only AE reported by >5% was upper respiratory tract infection (4 pts, 6%). Most laboratory abnormalities were Grade 1 or 2. Transient or intermittent Grade 3 elevations in ALT were observed in 2 pts (3%), both of whom continue on study drug. Conclusion: Results from the ongoing Phase 2a extension study demonstrate continued declines in HBV DNA, pgRNA and viral antigens in pts treated with 731+NrtI. 731 continues to exhibit a favorable safety and tolerability profile in pts treated for over 1 year. The data support the continued development of 731.