Treatment with bepirovirsen led to sustained clearance of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA for 24 weeks after the end of treatment for adults with chronic HBV in the phase 2b B-Clear study.
The study results were presented at the annual meeting of the American Association for the Study of Liver Diseases and were simultaneously published in The New England Journal of Medicine.
Currently, nucleoside/nucleotide analogue (NA) therapy is the recommended first-line therapy for patients with chronic HBV because it can inhibit viral replication.
However, fewer than 5% of patients have HBsAg loss after 12 months of NA therapy, which underscores the need for therapies that can achieve a “functional” cure, largely defined as sustained, undetectable levels of HBV DNA and HBsAg in the blood, with or without generation of protective antibodies against HBsAg, the researchers noted.
Bepirovirsen is a potential first-in-class antisense oligonucleotide that targets all HBV messenger RNA and acts to decrease levels of viral proteins.
The phase 2b B-Clear study enrolled 457 patients with chronic HBV; 227 were receiving NA therapy, and 230 were not.
Participants were randomly assigned to receive weekly subcutaneous injections of bepirovirsen 300 mg for 24 weeks; bepirovirsen 300 mg for 12 weeks, then 150 mg for 12 weeks; bepirovirsen 300 mg for 12 weeks, then placebo for 12 weeks; or placebo for 12 weeks, then bepirovirsen 300 mg for 12 weeks (groups 1, 2, 3, and 4, respectively).
The composite primary outcome was HBsAg level below the limit of detection and HBV DNA level below the limit of quantification maintained for 24 weeks after the end of bepirovirsen treatment, without newly initiated antiviral medication.
Bepirovirsen 300 mg weekly for 24 weeks (group 1) led to HBsAg and HBV DNA loss in 9% of patients receiving NA therapy and 10% of patients not receiving NA treatment, which was sustained for 24 weeks after the last dose.
For groups 2, 3, and 4, HBsAg and HBV DNA loss occurred in 9%, 3%, and 0%, respectively, of patients receiving NA therapy and 6%, 1%, and 0%, respectively, of patients not receiving NA treatment.
Patients with low baseline HBsAg levels (< 1,000 IU/mL) responded best to treatment with bepirovirsen. Among patients who received bepirovirsen 300 mg weekly for 24 weeks, the primary outcome was achieved by 16% of patients taking NA therapy and by 25% of patients not taking NA therapy.
Although a “relatively low percentage” of patients overall achieved the primary outcome, the study “indicates the possibility of enhanced efficacy with the selection of patients according to baseline characteristics (low HBsAg level at baseline), with combination therapies, or both,” the researchers wrote.
Adverse events with bepirovirsen included injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase (ALT) levels. Increases in ALT levels, which were more common in those not receiving NA therapy than in those receiving NA therapy (41% vs. 17%), led to two serious adverse events.
On the basis of phase 2b data, GlaxoSmithKline (GSK) plans to advance bepirovirsen into phase 3 development, according to a news release.
Further pursuit of bepirovirsen therapy is “certainly warranted, with the use of a dose of 300 mg per week for at least 24 weeks; indeed, the duration of therapy might be dictated best by HBsAg levels at baseline,” Jay H. Hoofnagle, MD, director of the liver disease research branch at the National Institute of Diabetes and Digestive and Kidney Diseases, wrote in an editorial in the New England Journal of Medicine.
Several critical questions remain, including whether HBsAg negativity will persist beyond 24 weeks, wrote Dr. Hoofnagle, who was not involved in the study.
It’s a question GSK is addressing in the B-Sure trial, which will follow participants for an additional 33 months, the study noted.
Other questions include when NA therapy can be safely stopped, what other factors predict response, and whether RNA therapy–induced loss of HBsAg materially improves long-term outcomes, Dr. Hoofnagle wrote.
“Bepirovirsen is just one RNA-based HBV therapy now being pursued. Several other antisense RNAs as well as the more malleable small interfering RNA molecules (‘-sirans’) are currently in early-phase clinical trials. A new era in the control of hepatitis B may be at hand with these most modern of therapies for this most ancient disease,” Dr. Hoofnagle noted.
The B-Clear study was supported by GSK. Several authors have disclosed relationships with the company. A complete list of author disclosures is available with the original article. Dr. Hoofnagle has disclosed no relevant financial relationships.
A version of this article first appeared on.