The US Food and Drug Administration has granted Fast Track designation to GSK's bepirovirsen for treating chronic hepatitis B, marking a significant regulatory milestone for what the company describes as the only single agent in Phase 3 development showing potential for clinically meaningful functional cure response when combined with oral nucleoside/nucleotide analogs.
The designation was requested based on bepirovirsen's potential to address an unmet medical need for chronic hepatitis B patients, given the low functional cure rates achieved with currently available treatments. The triple-action investigational antisense oligonucleotide is designed to recognize and destroy genetic components of the hepatitis B virus that lead to chronic disease.
Mechanism of Action and Clinical Approach
Bepirovirsen operates through three distinct mechanisms: inhibiting viral DNA replication in the body, suppressing hepatitis B surface antigen (HBsAg) levels in the blood, and stimulating the immune system to increase chances of a durable and sustained response. The drug specifically recognizes RNA used by hepatitis B virus to replicate in infected liver cells and stimulates an immune response through Toll-like receptor 8, helping the immune system achieve durable clearance of HBV from circulating blood.
Phase 2b Trial Results Support FDA Decision
The Fast Track application was supported by data from the phase 2b B-Clear and B-Sure trials, which evaluated efficacy, safety, and durability of response in people with chronic hepatitis B. Results from B-Clear were published in The New England Journal of Medicine in November 2022.
The randomized, investigator-unblinded B-Clear trial involved 457 participants with chronic HBV infection, including 227 receiving nucleotide analog therapy and 230 not receiving such therapy. Participants were required to be at least 18 years old with documented chronic HBV infection for more than 6 months and an HBsAg level greater than 100 IU per milliliter.
The study employed a 3:3:3:1 randomization ratio with participants receiving weekly subcutaneous injections of bepirovirsen at 300 mg for 24 weeks, 300 mg for 12 weeks then 150 mg for 12 weeks, 300 mg for 12 weeks then placebo for 12 weeks, or placebo for 12 weeks then 300 mg for 12 weeks.
Efficacy Outcomes and Safety Profile
Bepirovirsen at 300 mg per week for 24 weeks resulted in 9-10% of participants achieving HBsAg and HBV DNA loss for 24 weeks after treatment discontinuation, with similar results observed in participants receiving nucleotide analog therapy and those not receiving such therapy. Among those receiving nucleotide analog therapy, primary outcome events occurred in 9% of group 1 participants, 9% in group 2, 3% in group 3, and 0% in group 4. Among participants not receiving nucleotide analog therapy, primary outcome events occurred in 10%, 6%, 1%, and 0% respectively.
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. Investigators noted that patients with low baseline hepatitis B surface antigen levels were identified as most likely to benefit from bepirovirsen treatment.
Ongoing Clinical Development
The B-Sure trial is investigating long-term efficacy and durability of response, following B-Clear participants for an additional 33 months. This study includes criteria for stopping nucleotide analog therapy to evaluate potential for functional cure in patients who successfully discontinue all medication while continuing to demonstrate no serologic evidence of hepatitis B surface antigen or HBV DNA.
A confirmatory phase 3 program, B-Well, is currently ongoing. Investigators have pointed to the possibility of enhanced efficacy through patient selection according to baseline characteristics, combination therapies, or both approaches.
