Up to 36 months durability of functional cure in response to bepirovirsen therapy in B-Clear On-NA responders: results from the B-Sure study

초록

Background and aims: Bepirovirsen (BPV) is an unconjugated antisense oligonucleotide in Phase 3 development for the treatment of chronic hepatitis B virus (HBV) infection. In the Phase 2b study BClear (NCT04449029), a subset of participants (pts) on nucleos(t)ide analogues (NAs) achieved a virological response at the end of BPV treatment, which was sustained for 24 weeks. Pts who had a complete (CR) or partial (PR) response at the end of the B-Clear (parent) study were eligible for the B-Sure long-term durability study (NCT04954859; ongoing). Here we present up to 45 months of follow-up data on the durability of response for B-Clear On-NA CRs and PRs enrolled in B-Sure. Method: CR was defined as hepatitis B surface antigen (HBsAg) < 0.05 IU/mL and HBV DNA < lower limit of quantification (LLOQ; < 20 IU/mL), and PR as 0.05 ≤ HBsAg < 100 IU/mL and HBV DNA < LLOQ, both for 24 weeks off BPV in B-Clear. If eligible, pts discontinued NA 3 months (mo) into B-Sure (≥ 9 mo from their last BPV dose) and were followed further to determine achievement of functional cure (FC; sustained HBsAg < 0.05 IU/mL and HBV DNA < LLOQ at 24 weeks off all HBV treatment) and durability of response off all HBV therapy. Adverse events (AEs) were recorded at each visit. Results: In total, 44 pts (14 CRs, 26 PRs and 4 non-responders) were enrolled into B-Sure. Of the 14 CRs, 10 (71%) discontinued NAs 3 mo after rollover into B-Sure; 8/10 (80%) maintained a CR to 6 mo post– NA cessation, thus achieving FC; 8/8 (100%) have maintained 24 mo FC, 7/7 (100%) 30 mo FC and 1/1 (100%) 36 mo FC (follow-up ongoing). Of the 26 PRs, 22 (85%) discontinued NAs 3 mo after rollover into B-Sure. 2/22 (9%) achieved delayed FC at 6 post–NA cessation and have maintained FC for 30 mo. 5/22 (23%) maintained PR status at 6 mo post–NA cessation and 1/22 (5%) at 36 mo post–NA cessation; all 4 losses of PR beyond 6 mo post–NA cessation were due to HBV DNA reversion. Among 22 PRs who discontinued NAs,13 (59%) had restarted NA therapy by 18 mo post–NA cessation. Of all pts who discontinued NAs, 4 had alanine aminotransferase (ALT) ≥ 2x upper limit of normal (ULN) and 1 had ALT > 5x ULN; 1 of those did not restart NA. Post–NA cessation, no pts reported AEs of severe ALT flare. There was no indication that prior use of BPV had any latent adverse effects. Conclusion: FC is achieved after BPV and discontinuation of all HBV treatments and durable for up to 36 months in B-Clear CRs enrolled in B-Sure, with no long-term safety signals reported. Funding: GSK (206882).