B-Together Trial Demonstrates Efficacy of Bepirovirsen Followed By Peg-IFN for HBV

Key Takeaways

Sequential treatment with bepirovirsen and Peg-IFN showed modest efficacy in reducing HBsAg and HBV DNA levels below LLOQ in chronic HBV patients.
The trial involved 108 participants across 11 countries, all on stable nucleotide analogue therapy, excluding telbivudine.
Adverse events were common but mostly mild, with no serious liver injuries reported, indicating a manageable safety profile.
The study suggests potential benefits of sequential therapy in reducing post-treatment relapse, though efficacy varied between treatment arms.

The long-term durability of response will be evaluated in the B-Sure trial (NCT04954859), which will enroll patients with hepatitis B virus (HBV) from B-Together (NCT04676724).

Bepirovirsen (GSK) is an antisense oligonucleotide that induces sustained reductions in hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA below the lower limit of quantification (LLOQ) in certain patients. Knowing this, the authors of a study published in the Journal of Hepatology examined whether sequential 12- to 24-week-long treatment featuring bepirovirsen followed by 24 weeks of peginterferon (Peg-IFN, Pegasys; Genentech) could reduce the overall relapse rates and improve responses observed in the B-Clear trial (NCT04449029) 24 weeks following end of treatment.¹

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The multicenter, randomized, open-label phase 2b trial, B-Together (NCT04676724), aimed to assess the efficacy and safety of sequential treatment with bepirovirsen followed by Peg-IFN in patients with chronic HBV infection.² The trial was conducted from January 28, 2021, through February 2023, and enrolled a total of 108 adult patients across 52 health centers in 11 countries.^1,2 All participants were confirmed to have chronic HBV infection (HBsAg-positive) for at least 6 months prior to screening and were currently receiving stable nucleotide analogue (NA) therapy (defined as no changes to their NA regimen for at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study) except telbivudine (Tyzeka; Idenix Pharmaceuticals, Novartis).^1,2

Patients were randomly assigned to either treatment arm 1 (n = 55) or 2 (n = 53). All patients received the same treatment (300 mg of bepirovirsen once per week for 12 weeks, a loading dose on days 4 and 11, followed by 180 mcg of PegIFN once per week up to 24 weeks), except arm 1 required patients to complete treatment by week 48, whereas arm 2 was by week 36. Because of this, Peg-IFN treatment varied from a minimum of 12 weeks to a maximum of 24 weeks.^1,2

The primary efficacy outcome was the percentage of patients in each arm who achieved HBsAg and HBV DNA levels below the lower limit of quantification (LLOQ; HBsAg: 0.05 IU/ml, HBV DNA: 20 IU/ml) at every visit for 24 weeks after the planned end of sequential treatment. Secondary end points included efficacy of bepirovirsen and Peg-IFN sequential therapy on HBV biomarkers (HBsAg and HBeAg) and virus-specific antibody responses (anti-HBeAg status, anti-HBs); durability of virological response; and between-treatment comparison for the primary outcome.^1,2

Most participants had baseline HBsAg greater than 1000 IU per ml (n = 74 [69%]) and were HBeAg-negative (n = 80 [74%]). The primary outcome was achieved in approximately 9% (n = 5) and 15% (n = 8) of participants in arms 1 and 2, respectively (arm 1: 12% [95% CI 0%, 46%]; arm 2: 15% [95% CI 0%, 56%]). Additionally, about 13% (n = 7) and 15% (n = 8) in arms 1 and 2, respectively, achieved the alternative primary outcome.¹

Additionally, the investigators observed that at the end of bepirovirsen treatment, about 36% (n = 20) and 23% (n = 12) of patients in arms 1 and 2, respectively, had achieved HBsAg and HBV DNA below LLOQ, and among this group, 40% (n = 8, arm 1) and 42% (n = 5, arm 2) relapsed before the Peg-IFN end of treatment. At Peg-IFN end of treatment, 24% (n = 13, arm 1) and 17% (n = 9, arm 2) of participants had HBsAg and HBV DNA below LLOQ, and of these, 58% (n = 7, arm 1) and 0% (n = 0, arm 2) relapsed during follow-up.¹

Further, of the participants who were HBeAg-positive at baseline, 57% (n = 8, arm 1) and 7% (n = 1, arm 2) became anti-HBe-positive by the end of the bepirovirsen treatment period. At the end of the Peg-IFN treatment period, this changed to (56%, n = 9) and 11% (n = 1), respectively.¹

About the Trial

Trial Name: Study of Sequential GSK3228836 and Peginterferon Treatment in Participants With Chronic Hepatitis B (CHB) (B-Together)

ClinicalTrials.gov ID: NCT04676724

Sponsor: GlaxoSmithKline

Completion Date: February 17, 2023

The authors observed that the proportion of participants who experienced adverse events (AEs) in the bepirovirsen and Peg-IFN treatment windows was similar between treatment arms (arm 1: 95%; arm 2: 98%), with most AEs considered treatment-related. The most common observed AEs were injection-site erythema. There were few AEs that led to treatment discontinuation (4%; 3 during bepirovirsen and 1 during Peg-IFN treatment). Additionally, the safety profile of Peg-IFN was consistent with its approved product information. There were no reports of serious liver injury, clinically significant bleeding events, renal injury, or vascular injury associated with alternate complement pathway activation. A total of 9 serious AEs were reported in 8 participants, of which 5 occurred during bepirovirsen treatment (1 treatment-related) and 3 in the off-treatment period.¹

REFERENCES

1. Buti M, Heo J, Tanaka Y, et al. Sequential Peg-IFN after bepirovirsen may reduce post-treatment relapse in chronic hepatitis B. J Hepatol. 2025;82(2):222-234. doi:10.1016/j.jhep.2024.08.010

2. Study of Sequential GSK3228836 and Peginterferon Treatment in Participants With Chronic Hepatitis B (CHB) (B-Together). ClinicalTrials.gov identifier: NCT04676724. Updated Mau 2, 2024. Accessed February 14, 2025. https://clinicaltrials.gov/study/NCT04676724