Abstract

Background: In the Phase 2b B-Clear study (209668), bepirovirsen (BPV; an antisense oligonucleotide) 300 mg for 24 weeks (wks) achieved sustained HBsAg and HBV DNA loss (<lower limit of quantification [LLOQ] for 24 wks off BPV therapy) in 9% of participants (pts) who remained on nucleos[t]ide analogs (NA); end of BPV response rates were higher (26%), but some pts relapsed during follow-up. Response was higher in pts with lower baseline HBsAg (≤3000 vs ≤1000 IU/mL: 12% vs 16%). The B-Together study assessed if sequential therapy with BPV and pegylated interferon (PegIFN) can improve on the BPV efficacy rates observed in B-Clear.

Methods: B-Together was a Phase 2b, multicenter, randomized, open-label study. Patients on stable NA therapy were eligible if they had HBsAg >100 IU/mL, HBV DNA <90 IU/mL, ALT ≤2x upper limit of normal and no contraindication to receive PegIFN. Pts were randomized 1:1 to receive BPV 300 mg once weekly (QW; plus loading dose on Days 4 and 11) for 24 (Arm 1) or 12 (Arm 2) wks. Post BPV end, eligibility was assessed to receive up to 24 wks of PegIFN 180 mcg QW, with 24 (Arm 1) or 36 (Arm 2) wks follow-up post PegIFN end. Pts continued NA therapy throughout the study. Primary endpoint: proportion of pts with HBsAg and HBV DNA <LLOQ for 24 wks after planned end of sequential treatment, in the absence of newly initiated antiviral therapy (rescue therapy). Safety was assessed by adverse event (AE) monitoring.

Results: The study enrolled 108 pts (n: Arm 1=55; Arm 2=53). Baseline characteristics were similar between arms and to those in B-Clear. The primary endpoint was achieved by 5 (9%) pts in Arm 1 and 8 (15%) pts in Arm 2 (Figure); all responders had baseline HBsAg ≤3000 IU/mL. Only BPV responders benefited from Peg-IFN treatment, through prevention of relapse off-treatment (relapse rate B-Together vs B-Clear: Arm 1: 58% vs 63%; Arm 2: 0% vs 75%). The proportion of pts experiencing AEs was similar in both arms (Arm 1: 52 [95%]; Arm 2: 52 [98%]). Serious AEs were reported in 8 (7%) of pts (during BPV: 5 [5%]; during PegIFN: 0; follow-up period: 3 [3%]). BPV did not appear to adversely influence the safety profile of subsequent PegIFN.

Conclusion: Sequential therapy with BPV and PegIFN results in an improved off-treatment response vs BPV alone (B-Clear), which appears to be driven by prevention of relapse in BPV responders. There were no new safety signals of concern.

Funding: GSK (study 209348)