Clinically meaningful rates of functional cure in virologically suppressed patients with chronic hepatitis B infection treated with bepirovirsen: B-Well phase 3 trials

초록

Background and aims: Functional cure (FC), hepatitis B surface antigen (HBsAg) loss and hepatitis B virus (HBV) DNA < lower limit of quantification (LLOQ) 24 weeks off therapy, is the treatment goal in chronic HBV infection. Bepirovirsen (BPV), an antisense oligonucleotide, is the first anti-HBV therapy in global Phase 3 trials with FC as the primary outcome. Method: B-Well 1 and 2 are global double-blind Phase 3 trials. Noncirrhotic adults with nucleos(t)ide analogue (NA)-suppressed chronic HBV infection (HBV DNA <90 IU/mL) and HBsAg > 100–≤ 3000 IU/mL were randomised 2:1 to BPV 300 mg or placebo (PBO) weekly for 24 weeks. Participants (pts) discontinued NAs at Week 48, if eligible. The primary outcome was FC response rate at Week 72 for all pts; defined as HBsAg not detected (qualitative; < 0.05 IU/mL) and HBV DNA < LLOQ (< 20 IU/mL or target not detected) 24 weeks after discontinuing all HBV treatment. Key secondary outcomes included FC response rate for pts with baseline HBsAg ≤ 1000 IU/mL. Safety was assessed via adverse event (AE) and laboratory monitoring. Results: The full analysis set comprised 650 BPV and 328 PBO pts in B-Well 1 and 570 BPV and 286 PBO pts in B-Well 2. Pts were 71% male, mean age approximately 49 years, 68% Asian, 8% HBeAg positive, and 63% had baseline HBsAg ≤ 1000 IU/mL. No PBO pts achieved FC. Among BPV pts with baseline HBsAg ≤ 3000 IU/mL, 20% and 19% achieved FC in B-Well 1 and B-Well 2, respectively (p < 0.001 vs PBO). In BPV pts with baseline HBsAg ≤ 1000 IU/mL, 25% in B-Well 1 and 28% in B-Well 2 achieved FC (p < 0.001 vs PBO). Most common AEs with BPV (pooled safety: BPV = 1223, PBO = 611) in Week 1–72 included injection site erythema (31%; PBO 2%), injection site pain (23%; PBO 5%) and alanine aminotransferase (ALT) increase (23%; PBO 4%). ALT increases were transient and generally occurred in Week 5–10; 6% of BPV pts had ALT ≥ 10x upper limit of normal (vs PBO <1%). No cases were adjudicated as meeting drug-induced liver injury criteria. Few AEs were serious (BPV 7%; PBO 4%) or led to permanent treatment discontinuation (BPV 3%; PBO < 1%). Two deaths unrelated to study treatment occurred in the BPV arm. Conclusion: 24-week BPV treatment induced clinically meaningful and statistically significant FC rates versus PBO in virologically suppressed pts with chronic HBV infection, with an acceptable safety profile, showing the potential for BPV to be a first-in-class finite therapy for FC. Funding: GSK (202009/NCT05630807; 219288/NCT05630820). [for the B-Well Study Group].