Bepirovirsen Shows Promise in Phase III for Chronic Hepatitis B

GSK shared results from its dual Phase III B-Well 1 and B-Well 2 trials evaluating bepirovirsen for chronic hepatitis B.

The trials showed that bepirovirsen led to significantly higher rates of functional cure compared with the standard treatment for people with chronic hepatitis B. The global, randomized studies tested bepirovirsen alongside nucleos(t)ide analogues, the current standard of care.

Chronic hepatitis B is a viral infection that can cause long-term liver inflammation, cirrhosis and liver cancer. Current oral antiviral treatments can suppress the virus but typically require lifelong use and rarely achieve a functional cure. A functional cure is defined as a lasting loss of hepatitis B surface antigen (HBsAg) and undetectable viral DNA after a defined treatment period.

Because sustained HBsAg loss has been associated with a lower risk of cirrhosis and liver cancer and improved long-term outcomes, it is widely considered the best available surrogate for durable immune control of chronic hepatitis B.

HBsAg loss is typically rare with existing antivirals, but when achieved, it is usually maintained after treatment stops.

Bepirovirsen is an experimental antisense oligonucleotide, a short piece of synthetic genetic material designed to bind hepatitis B virus RNA and reduce the production of viral proteins such as HBsAg. GSK is developing it to help the immune system better control the infection and potentially allow treatment to be stopped.

The two trials, called B-Well 1 and B-Well 2, were global, multi-center, randomized, double-blind, placebo-controlled Phase III trials conducted in 29 countries. The studies enrolled more than 1,800 adults with chronic hepatitis B who were on stable nucleos(t)ide analogue therapy and had baseline HBsAg levels of 3,000 IU/mL or lower. Participants received either bepirovirsen or placebo in addition to standard treatment.

The primary endpoint in both trials was the proportion of patients achieving a functional cure, defined as loss of HBsAg and undetectable hepatitis B virus DNA for at least 24 weeks after completing a finite course of therapy.

A key secondary endpoint assessed sustained HBsAg loss in patients with lower baseline HBsAg levels.

GSK reported that both studies met their primary endpoints, with significantly higher rates of sustained HBsAg loss after treatment discontinuation in the bepirovirsen plus standard-of-care group compared with standard of care alone. The company also observed consistent effects across key secondary endpoints, including in patients with lower baseline HBsAg levels.

Safety and tolerability in the Phase III program were reported to be consistent with what was previously observed for bepirovirsen in earlier-stage studies.

Bepirovirsen is licensed from Ionis Pharmaceuticals and targets the hepatitis B virus RNA to reduce viral protein expression. GSK is developing it as a potential time-limited backbone therapy and as part of future combination regimens aimed at achieving a functional cure.

There are now more than a few companies reporting sustained HBsAg loss with finite treatment approaches. At the 2025 AASLD meeting, Brii Biosciences presented data from its Phase II ENSURE study showing that 42% of patients who responded to its therapeutic vaccine BRII-179 maintained HBsAg loss 24 weeks after completing combination therapy, compared with 8% of non-responders. These findings support the potential for a durable functional cure in selected patients.

Other RNA-targeting approaches are also advancing. AusperBio is developing the antisense oligonucleotide AHB-137 in Phase II and Phase III studies in China and globally, reflecting broader interest in ASO-based strategies for chronic hepatitis B.

Beyond RNA suppression, early clinical programs are exploring ways to directly inactivate or eliminate viral DNA reservoirs in liver cells. This includes gene editing approaches such as Precision BioSciences’ PBGENE-HBV, which is being evaluated in a global Phase I/II study.

GSK said it plans to begin global regulatory submissions for bepirovirsen in the first quarter of 2026.

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