Bepirovirsen Achieves Clinically Meaningful Functional Cure Rates in Chronic Hepatitis B

Bepirovirsen (GSK/Ionis Pharmaceuticals), an investigational antisense oligonucleotide (ASO), has now become the first anti-hepatitis B (HBV) therapy to complete global phase 3 trials with functional cure (FC) as the primary outcome.¹

Results from the B-Well 1 (NCT05630807) and B-Well 2 (NCT05630820) trials, presented at the European Association for the Study of the Liver (EASL) Congress 2026 and simultaneously published in the New England Journal of Medicine, demonstrate that a finite 24-week course of bepirovirsen can achieve clinically meaningful and statistically significant FC rates, a finding with potentially transformative implications for a disease in which no approved finite therapy currently exists.

“These phase 3 data represent a major step forward in the search for a finite treatment for chronic hepatitis B,” said Seng Gee Lim, FRACP, FRCP, FAMS, MD, director of Hepatology at the Division of Gastroenterology and Hepatology, National University Health System, Singapore, in a statement provided by EASL. “For patients who currently face long-term therapy, achieving a functional cure after a defined course of treatment could fundamentally change expectations for care.”

Chronic hepatitis B (CHB) affects more than 250 million people worldwide and is responsible for approximately 56% of liver cancer cases globally, contributing to roughly 1.1 million deaths annually. Although nucleos(t)ide analogues (NAs) have transformed disease management by suppressing viral replication, they rarely eliminate hepatitis B surface antigen (HBsAg) and typically require lifelong administration, with FC rates of approximately 1% per year on treatment.²

B-Well 1 and B-Well 2 are global, multicenter, randomized, double-blind, placebo-controlled phase 3 trials conducted across 29 countries enrolling more than 1800 patients in total. Eligible participants were non-cirrhotic adults with NA-suppressed CHB (HBV DNA below 90 IU/mL) and baseline HBsAg between 100 and 3000 IU/mL, a population selected based on phase 2b data suggesting the greatest likelihood of response in lower-antigen patients.¹

Participants were randomized 2:1 to receive either subcutaneous bepirovirsen 300 mg weekly or placebo for 24 weeks, with NA therapy continued through week 48, after which eligible participants discontinued NAs. The primary outcome was functional cure (FC) response rate at week 72, defined as HBsAg not detected by qualitative assay (below 0.05 IU/mL) and HBV DNA below the lower limit of quantification (below 20 IU/mL or target not detected) 24 weeks after discontinuing all HBV treatment. A key secondary outcome evaluated FC in the subset of participants with baseline HBsAg at or below 1000 IU/mL.

The full analysis set comprised 650 bepirovirsen-treated and 328 placebo-treated participants in B-Well 1, and 570 bepirovirsen-treated and 286 placebo-treated participants in B-Well 2. The combined population was 71% male, with a mean age of approximately 49 years. Asian patients represented 68% of the cohort, 8% were HBeAg-positive, and 63% had baseline HBsAg at or below 1000 IU/mL.

Bepirovirsen Demonstrates Functional Cure

Bepirovirsen met the primary end point in both trials. Among participants with baseline HBsAg at or below 3000 IU/mL—the full enrolled population—20% of bepirovirsen-treated patients in B-Well 1 and 19% in B-Well 2 achieved FC at week 72, compared with no placebo-treated patients in either trial (P < .001 vs placebo for both). Efficacy was more pronounced in participants with lower baseline antigen burden. Among those with baseline HBsAg at or below 1000 IU/mL, 25% achieved FC in B-Well 1 and 28% in B-Well 2—both statistically significant vs placebo and both representing the key secondary end point. This pattern reinforces the emerging principle across the CHB drug development landscape that baseline HBsAg level is among the strongest predictors of response to HBsAg-targeting agents.

Safety and Tolerability

In the pooled safety analysis (bepirovirsen n = 1223; placebo n = 611) across weeks 1 through 72, the most frequently reported adverse events with bepirovirsen were injection site erythema (31%; placebo 2%), injection site pain (23%; placebo 5%), and alanine aminotransferase (ALT) elevation (23%; placebo 4%). ALT increases were transient and generally occurred between weeks 5 and 10, coinciding with the period of maximal HBsAg reduction.

Six percent of patients treated with bepirovirsen had ALT elevations of at least 10 times the upper limit of normal, compared with less than 1% in the placebo group. Importantly, no cases were adjudicated as meeting criteria for drug-induced liver injury. Serious adverse events were infrequent, occurring in 7% of bepirovirsen recipients versus 4% of placebo patients, and permanent treatment discontinuation due to adverse events was rare (bepirovirsen 3%; placebo below 1%). Two deaths occurred in the bepirovirsen arm; both were determined to be unrelated to study treatment.

“To conclude, ladies and gentlemen, bepirovirsen is a first-in-class 24-week finite therapy,” said Lim.

References

1. Hou JL, Lim SG, Buti M, et al. Clinically meaningful rates of functional cure in virologically suppressed patients with chronic hepatitis B infection treated with bepirovirsen: B-Well phase 3 trials. Presented at: EASL Congress; May 27-30; Barcelona, Spain.
2. Bepirovirsen accepted for priority review and granted Breakthrough Therapy Designation by the US FDA. GSK. Press release. April 28, 2026. Accessed May 28, 2026. https://www.gsk.com/en-gb/media/press-releases/bepirovirsen-accepted-for-priority-review-and-granted-breakthrough-therapy-designation-by-the-us-fda/