Bepirovirsen leads to functional cure in one fifth of people with long-term hepatitis B

One in five people with chronic (long term) hepatitis B who were treated with the investigational agent bepirovirsen were functionally cured and no longer needed to take daily antiviral therapy, according to late-stage study results presented last week at the European Association for the Study of the Liver (EASL) Congress in Barcelona and published in The New England Journal of Medicine.

Nucleoside/nucleotide antivirals such as tenofovir (Viread, Vemlidy) and entecavir (Baraclude) can control hepatitis B virus (HBV) replication indefinitely, but they rarely lead to a functional cure, indicated by sustained HBV DNA suppression and loss of hepatitis B surface antigen (HBsAg) for at least six months after the end of treatment. Achieving a functional cure lowers the risk of long-term complications including cirrhosis, liver cancer and liver-related death.

“These phase III data represent a major step forward in the search for a finite treatment for chronic hepatitis B,” presenter Professor Seng Gee Lim of the National University Health System in Singapore said in an EASL news release. “For patients who currently face long-term therapy, achieving functional cure after a defined course of treatment could fundamentally change expectations for care.”

Bepirovirsen, from GSK, is an antisense oligonucleotide that both interferes with HBV replication by binding to viral mRNA and stimulates an immune response, potentially enabling the immune system to control the virus. Bepirovirsen does not eliminate a form of HBV DNA hidden in the nucleus of liver cells, however, so it produces a functional cure rather than a so-called sterilising cure.

The phase III B-Well trials enrolled adults with chronic hepatitis B in 29 countries who were currently on stable antiviral therapy with a suppressed viral load (below 20). At study entry, about 40% were on entecavir and about 60% were taking various tenofovir formulations.

B-Well 1 (NCT05630807) included 981 participants and B-Well 2 (NCT05630820) included 857 people. In the combined study population, about 70% were men and the median age was approximately 50 years. Two thirds were Asian, a quarter were White, about 5% were Black and about 8% had Latino ethnicity.

The study had some important exclusion criteria that will impact use of bepirovirsen in the real world. Participants had not yet progressed to liver cirrhosis, and more than 90% had an alanine aminotransferase (ALT) liver enzyme level below the upper limit of normal, indicating minimal liver inflammation. HBsAg levels at baseline ranged up to 3000 IU/ml, with nearly two thirds having 1000 IU/ml or lower; people with very high levels were not included. People with hepatitis C, hepatitis D or HIV coinfection were also excluded.

Participants in both trials were randomly assigned to receive bepirovirsen or a placebo, administered by subcutaneous injection once weekly for 24 weeks after two initial loading doses, while staying on their antivirals. Eligible patients who maintained viral suppression, achieved undetectable HBsAg and had normal ALT stopped their antivirals at 48 weeks, with follow-up continuing through 72 weeks.

Results from the two trials were similar: 20% of B-Well 1 participants and 19% in B-Well 2 achieved a functional cure at 72 weeks in the bepirovirsen groups. In comparison, no one in the placebo groups achieved sustained viral suppression and HBsAg loss after stopping all treatment.

Functional cure rates were higher for people who started with lower HBsAg levels. Those who started with an HBsAg level below 1000 IU/ml had a functional cure rate of 26%, but this fell to just 5-10% for those with 1000 to 3000 IU/ml at baseline. People who experienced large ALT increases – an indicator of flaring liver inflammation – were also more likely to cured.

"Longer follow-up is needed to see if functional cure is durable, and alternative therapies are needed for people excluded from these trials."

These findings are a considerable improvement over those seen in a smaller phase IIb trial published in 2022. In that study, people who received various doses and durations of bepirovirsen, with or without antivirals, had an overall functional cure rate of about 10%.

Bepirovirsen was generally safe and well tolerated. While a majority of people reported some adverse events in both the treatment and placebo groups, serious adverse event rates were low (7% and 4%, respectively). However, severe (grade 3 or higher) adverse events were substantially more frequent in the pooled bepirovirsen groups compared with the placebo groups (16% vs 3%). Injection site reactions were the most common side effect overall, while elevated ALT was the most frequent severe event among bepirovirsen recipients (6%). Professor Lim suggested that substantial ALT elevation indicated that bepirovirsen was working well. Only 3% of bepirovirsen recipients stopped treatment due to adverse events.

“Today’s standard of care for chronic hepatitis B imposes a heavy burden on patients and healthcare systems, and rarely delivers a functional cure,” study first author Professor Jinlin Hou of the Guangdong Institute of Hepatology in China said in a GSK news release. “With recent guidelines now prioritizing functional cure, these new data could represent an important advance. Combined with improved testing and diagnosis, this innovation has the potential to improve the lives of millions living with chronic hepatitis B.”

Based on these data, bepirovirsen is now under review by the European Medicines Agency and the US Food and Drug Administration.

Given the low rates of functional cure using antivirals alone (around 3% after a decade of treatment) and pegylated interferon (around 10% after three years), the bepirovirsen results are “remarkable,” Professor Anna Lok of the University of Michigan Ann Arbor wrote in an accompanying editorial. “The B-Well trials represent a major step toward a functional cure for HBV infection, and bepirovirsen is an attractive option for selected patients.”

However, she added that longer follow-up is needed to see if functional cure is durable, and alternative therapies are still needed for people excluded from these trials, including those with cirrhosis or a very high baseline HBsAg levels. Ultimately, she wrote, “curative therapies must be simple, safe, accessible and affordable to benefit the 240 million persons worldwide who are living with chronic HBV infection.”