FDA Calls for More Data on HEPLISAV-B for Hemodialysis Patients

FDA Requests Additional Data for HEPLISAV-B in Hemodialysis Adults

The U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to Dynavax Technologies regarding their supplemental Biologic License Application (sBLA) for HEPLISAV-B. Specifically, the FDA requires more comprehensive data to fully evaluate the effectiveness and safety of a 4-dose regimen of this hepatitis B vaccine in adults undergoing hemodialysis.

The CRL, released on May 14, 2024, emphasizes that the existing data submitted by Dynavax were not sufficient for a thorough assessment. This feedback affects the proposed 4-dose regimen but does not impact the current approved use of HEPLISAV-B in the U.S., the European Union, and Great Britain for adults aged 18 and older.

Background and Past FDA Responses

HEPLISAV-B combines the hepatitis B surface antigen with Dynavax's proprietary Toll-like Receptor (TLR) 9 agonist to enhance immune response. The vaccine initially received FDA approval in 2017 for adults 18 and older to protect against all known subtypes of the hepatitis B virus (HBV). However, this 2024 CRL is not the first for HEPLISAV-B; the vaccine faced similar requests for additional data in 2013 and 2016.

The first CRL in 2013 asked for further safety evaluations and additional data to validate the manufacturing process. The 2016 CRL mainly focused on the completion of the review cycle, which prevented the FDA from thoroughly assessing Dynavax's response at that time.

Clinical Trial Data and Limitations

The current sBLA included clinical data from phase 1 of the HBV-24 study, which examined a 4-dose regimen of HEPLISAV-B in 119 adults undergoing hemodialysis. Final immunogenicity data, disclosed in January 2021, showed a seroprotection rate of 89.3% with significant levels of anti-HBs antibodies. Interim safety data indicated that HEPLISAV-B was generally well-tolerated with no major safety concerns.

The CRL pointed out that data from the HBV-24 trial were problematic due to the destruction of source documents by a third-party clinical trial site operator. Additionally, the single-arm study’s limited number of participants was considered insufficient for a robust safety evaluation.

Dynavax’s Response and Next Steps

In response to the FDA's feedback, Dynavax plans to request a meeting with the agency to explore ways to provide the additional data required. Rob Janssen, MD, Chief Medical Officer at Dynavax, expressed confidence in the existing data but acknowledged the need to meet the FDA's additional requirements.

“We remain confident in the data collected and are committed to addressing the FDA's feedback. Our goal is to ensure the 4-dose regimen of HEPLISAV-B becomes available to adults undergoing hemodialysis in the U.S.,” said Janssen in a press release.

Impact on Current Indications

Although the CRL affects the sBLA for the 4-dose regimen, it does not alter the current approved uses of HEPLISAV-B. The vaccine remains endorsed for preventing hepatitis B in adults aged 18 and older across the U.S., the EU, and Great Britain. In October 2023, the European Commission also approved the 4-dose regimen specifically for adults undergoing hemodialysis, which remains unaffected by the FDA’s latest decision.

The planned meeting between Dynavax and the FDA aims to chart a pathway for the vaccine's expanded use, addressing a critical need in the hemodialysis population who are particularly vulnerable to HBV infection.

Clinical Trials Supporting the sBLA

The sBLA also included data from five supportive clinical trials involving patients with chronic kidney disease (CKD) or those undergoing hemodialysis. Despite these additional trials, the FDA deemed the data from the HBV-24 study insufficient due to the issues with source documents and the limited sample size.

Moving forward, Dynavax intends to generate additional data to meet the FDA’s standards. This will involve addressing the shortcomings identified in the HBV-24 study, as well as potentially conducting new trials to bolster the evidence base for the 4-dose regimen.