FDA Grants Fast Track Designation for Bepirovirsen for Chronic Hepatitis B

The US Food and Drug Administration (FDA) has granted Fast Track designation to GSK’s bepirovirsen for the treatment of chronic hepatitis B.¹

According to the press release, the designation was requested based on the potential for bepirovirsen to address an unmet medical need for chronic hepatitis B given the low functional cure rates in currently available treatments.¹

A triple-action investigational antisense oligonucleotide, bepirovirsen is the only agent in phase 3 development that has shown the potential to achieve clinically meaningful functional cure response when combined with oral nucleoside/nucleotide analogs. It is designed to recognize and destroy genetic components of the hepatitis B virus leading to chronic disease. Bepirovirsen inhibits the replication of viral DNA in the body, suppresses the level of hepatitis B surface antigen (HBsAg) in the blood, and stimulates the immune system to increase the chances of a durable and sustained response.¹

The Fast Track application was supported by data from the phase 2b trials B-Clear and B-Sure, which evaluated the efficacy, safety, and durability of response of bepirovirsen in people with chronic hepatitis B. Results from B-Clear were published in The New England Journal of Medicine in November of 2022.^1,2

A randomized, investigator-unblinded trial involving participants with chronic HBV infection, B-Clear assessed the efficacy and safety of 12- and 24-week bepirovirsen treatment in participants either receiving stable nucleotide analog therapy or not receiving nucleotide analog therapy. The primary efficacy outcome was HBsAg and HBV DNA loss for 24 weeks after the discontinuation of bepirovirsen treatment in the absence of newly initiated antiviral treatment.²

For inclusion, patients were required to be ≥ 18 years of age with documented chronic HBV infection for > 6 months and an HBsAg level > 100 IU per milliliter. In total, the intention-to-treat population comprised 457 participants, including 227 receiving nucleotide analog therapy and 230 not receiving nucleotide analog therapy.²

Participants were randomly assigned in a 3:3:3:1 ratio to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4).²

Bepirovirsen at a dose of 300 mg per week for 24 weeks resulted in 9-10% of participants having HBsAg and HBV DNA loss for 24 weeks after the end of bepirovirsen treatment, with similar results observed in participants receiving nucleotide analog therapy and those not receiving nucleotide analog therapy. Among those receiving nucleotide analog therapy, a primary outcome event occurred in 6 (9%) participants (95% CI, 0-31) in group 1, in 6 (9%; 95% CI, 0-43) in group 2, in 2 (3%; 95% CI, 0-16) in group 3, and 0 (0%; post hoc CI, 0-8) in group 4. Among participants not receiving nucleotide analog therapy, a primary outcome event occurred in 7 (10%; 95% CI, 0-38) participants, 4 (6%; 95% CI, 0-25), 1 (1%; post hoc CI, 0-6), and 0 (0%; post hoc CI, 0-8), respectively.²

During weeks 1-12, adverse events, including injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase levels, were more common with bepirovirsen than with placebo.²

Of note, patients with low baseline hepatitis B surface antigen levels were identified as the most likely to benefit from treatment with bepirovirsen. Investigators pointed out the possibility of enhanced efficacy with the selection of patients according to baseline characteristics, with combination therapies, or both.²

Long-term efficacy and durability of response are being investigated in the B-Sure trial, which follows participants from the B-Clear study for an additional 33 months and includes criteria for stopping NA therapy to evaluate the potential for functional cure in patients who successfully stop all medication and continue to demonstrate no serologic evidence of hepatitis B surface antigen or HBV DNA. A confirmatory phase 3 program, B-Well, is ongoing.¹

References:

1. ^{GSK. GSK receives US FDA Fast Track designation for bepirovirsen in chronic hepatitis B. Press Releases. February 12, 2024. Accessed February 13, 2024. https://www.gsk.com/en-gb/media/press-releases/gsk-receives-us-fda-fast-track-designation-for-bepirovirsen-in-chronic-hepatitis-b/}
2. ^{Yuen MF, Lim SG, Plesniak R, et al. Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection. N Engl J Med. doi:10.1056/NEJMoa2210027}