Up to 18 months' functional cure in response to bepirovirsen therapy in B-Clear On-NA responders: B-Sure third report

초록

Background and aims: Bepirovirsen (BPV) is an unconjugated antisense oligonucleotide currently in Phase 3 for the treatment of chronic hepatitis B virus (HBV) infection. Data from a Phase 2b study (B-Clear) indicated that a subset of participants (pts) achieved a response at the end of BPV treatment, which was sustained for 24 weeks. This occurred in pts on and not on nucleos(t)ide analogues (NA) (On-NA and Not-on-NA). 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 2.5-year follow-up data on the durability of response for B-Clear On-NA complete responders (CRs) and partial responders (PRs) who entered 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 HBsAg <100 IU/mL and HBV DNA <LLOQ at the end of B-Clear. If eligible, pts discontinued NA 3 months (mo) into BSure (≥9 mo from their last BPV dose) and were followed further to determine functional cure (FC) and durability of response off all HBV therapy. Adverse events (AEs) were recorded, with physical examinations and blood tests performed at each visit for safety and efficacy, including time from NA cessation to loss of response. Results: In total, 44 pts (11 CRs, 29 PRs and 4 non-responders) were enrolled into B-Sure; 33/44 (75%) were male, with a mean age of 53.8 years, and 24/44 (55%) were Asian. At entry into B-Clear, the majority of pts were hepatitis B e-antigen (HBeAg) negative (34/44 [77%]), 19/ 44 (43%) had HBV duration of ≥20 years and 32/44 (73%) had HBsAg ≤1000 IU/mL. Of the 11 CRs, 9 (82%) discontinued NAs 3 mo after rollover into B-Sure; 7/9 (78%) maintained a CR to 6 mo post–NA cessation, thus achieving FC, and all 7 maintained FC to 24 mo post– NA cessation. Of the 2 pts who did not achieve FC at 6 mo post–NA cessation, 1 had restarted NA therapy by 24 mo post–NA cessation. Of the 29 PRs, 23 (79%) discontinued NAs 3 mo after rollover into B-Sure. 3/23 (13%) achieved delayed FC 6 months post–NA cessation and were maintaining FC at 24 months post–NA cessation. 5/23 (22%) maintained PR status at 6 mo post–NA cessation, 3/23 (13%) at 9 mo post–NA cessation and 2/23 (9%) at 24 mo post–NA cessation; all 3 losses of PR beyond 6 mo post NA cessation were due to HBV DNA reversion. Among 23 PRs who discontinued NAs, 13 had restarted NA therapy by 24 mo post–NA cessation. Of all CRs/PRs who discontinued NAs, 5 had alanine aminotransferase (ALT) ≥2x upper limit of normal (ULN). After NA cessation, no pt who continued without needing to restart NA had an ALT increase of >5 × ULN. Post–NA cessation 3 pts reported AEs of ALT increased (2 with mild severity, 1 with moderate severity). There were no new safety signals. Conclusion: These data provide evidence of longer durability of FC observed with BPV.