FDA Issues CRL for Dynavax's HEPLISAV-B Four-Dose Regimen in Hemodialysis Patients

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Dynavax is currently reviewing FDA feedback and strategizing a meeting to discuss their HEPLISAV-B 4-dose regimen for hemodialysis patients, determining the path forward toward approval.

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The FDA issued a Complete Response Letter (CRL) on Dynavax Technologies Corporation supplemental Biologics License Application (sBLA) for a 4-dose HEPLISAV-B vaccine regimen for adults undergoing hemodialysis because of insufficient data to fully assess the effectiveness or safety of the regimen.

The sBLA relied on data from the phase 1 HBV-24 study in 119 hemodialysis patients and supportive trials conducted in adults with chronic kidney disease or undergoing hemodialysis. The CRL cited issues with the HBV-24 data, including destroying data source documents for nearly half of the enrolled subjects and insufficient participant numbers for safety evaluation. However, the decision does not affect HEPLISAV-B's existing approval for preventing hepatitis B infection in adults.1

The European Commission previously approved the 4-dose HEPLISAV-B regimen for adult hemodialysis patients in October 2023, which remains unaffected by the FDA's decision.

Study Data and Limitations

Among patients undergoing hemodialysis, the administration of 4 doses of HepB-CpG was well tolerated and resulted in the induction of notably high concentrations of anti-HBs and seroprotection in a significant majority of recipients.2

The 119 participants undergoing hemodialysis were followed for a median duration of 47.4 weeks, 75 constituted the per-protocol population. By week 20, the seroprotection rate, or the percentage of individuals with antibodies to hepatitis B surface antigen (anti-HBs) equal to or exceeding 10 mIU/mL, reached 89.3%. Additionally, 81.3% of participants displayed anti-HBs levels equal to or surpassing 100 mIU/mL. The geometric mean concentration of anti-HBs was 1061.8 mIU/mL. Throughout the study, HepB-CpG exhibited excellent tolerability, with no observed safety issues.2

The original methods were that participants would be administered 4 doses of HepB-CpG (HEPLISAV-B), comprising 20 mcg rHBsAg and 3000 mcg CpG 1018, a Toll-like receptor 9 agonist, at intervals of 0, 4, 8, and 16 weeks, remaining under observation for 68 weeks.2

Limitations to consider include that patients undergoing hemodialysis often have lower responses to vaccines and require higher doses for protection. The study population, with a median age of 59 and a significant portion having diabetes, had a notable mortality rate of 12%. The study lacked direct comparisons with other vaccines, potentially limiting the assessment of its superiority. Additionally, compliance with the vaccine schedule was a concern, with a significant portion of participants not completing all doses. The absence of a comparator group also raised the possibility of a healthier participant bias.2

What's Next

"We remain confident in the data generated to support HEPLISAV-B vaccination for adult hemodialysis patients. All key data collected in HBV-24 were verified against original source documents during the conduct of the trial," said Rob Janssen, MD, Chief Medical Officer of Dynavax, in a statement.1 "We are reviewing the agency's feedback and intend to request a meeting with the FDA to evaluate options for providing additional data to support the four-dose regimen for this vulnerable patient population in the US."

This CRL underscores forward-looking statements regarding future engagements with the FDA and potential outcomes, acknowledging associated risks and uncertainties. They are contingent upon factors such as follow-up study availability and costs, FDA's receptiveness, and uncertainties in realizing desired results.

References
1. DYNAVAX. Dynavax Provides Regulatory Update on sBLA for Four-Dose HEPLISAV-B® Regimen for Adults on Hemodialysis in the U.S. Published May 14, 2024. Accessed May 14, 2024. https://investors.dynavax.com/news-releases/news-release-details/dynavax-provides-regulatory-update-sbla-four-dose-heplisav-br
2. Awad A, Ntoso A, Connaire J, et. al. An open-label, single-arm study evaluating the immunogenicity and safety of the hepatitis B vaccine HepB-CpG (HEPLISAV-B®) in adults receiving hemodialysis. ScienceDirect. Published June 8, 2021. Accessed May 14, 2024. https://doi.org/10.1016/j.vaccine.2021.05.003
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