FDA Issues Complete Response Letter to sBLA for Four-Dose Heplisav-B Regimen in Adults on Hemodialysis


In the Complete Response Letter to Dynavax, the FDA stated that the supplemental Biologic License Application based on findings from the Phase I HBV-24 trial lacked sufficient data to support a full evaluation of the efficacy or safety of a four-dose Heplisav-B regimen in adults on hemodialysis.

Image credit: Destina | stock.adobe.com

Image credit: Destina | stock.adobe.com

Dynavax’s supplemental Biologic License Application (sBLA) for a four-dose Heplisav-B vaccination [Hepatitis B Vaccine (Recombinant), Adjuvanted] regimen for adults on hemodialysis has been issued a Complete Response Letter (CRL) by the FDA.1 In the CRL, the agency stated the sBLA—based on findings from the Phase I HBV-24 trial—lacked sufficient data to support a full evaluation of the efficacy or safety of a four-dose Heplisav-B regimen in this patient population. However, the CRL will not affect the previously approved indications for Heplisav-B in the United States, Great Britian, and the European Union.

"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 press release. "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."1

In November 2017, Heplisav-B became the first and only two-dose hepatitis B virus (HBV) vaccine recombinant to gain FDA approval for the prevention of infection caused by all known subtypes of HBV.2 Heplisav-B is an adult HBV vaccine combining the hepatitis B surface antigen with Dynavax's proprietary toll-like receptor 9 agonist. Heplisav-B was the first new HBV vaccine to be approved in the United States in more than a quarter-century and was the first approved HBV vaccine to use a two-dose regimen instead of the traditional three-dose regimen.2

Approximately half of adults fail to complete the three-dose HBV vaccine regimen within one year despite a six-month dosing period.3 HBV is a significant cause of acute and chronic liver disease around the world. If left untreated, the infection can lead to cirrhosis, hepatocellular carcinoma, and death. Despite effective vaccines to protect against HBV, there were 887,000 deaths worldwide in 2015 attributed to the disease, which is believed to have a global prevalence rate of approximately 3.7%.4

The open-label, single-arm HBV-24 trial analyzed the new four-dose regimen of Heplisav-B in in 119 patients with end-stage renal disease undergoing hemodialysis and who have not previously received an HBV vaccine. The study was designed to analyze the immunogenicity of Heplisav-B at study week 20 and safety over the duration of the 68-week trial.

Final immunogenicity data announced in January 2021 showed a seroprotection rate of 89.3% with high levels of anti-HBs antibodies. Interim safety data showed Heplisav-B was well tolerated with no newly identified safety concerns.5

The sBLA also included data from five supportive clinical trials of Heplisav-B in adults with chronic kidney disease or who are undergoing hemodialysis. In the CRL, the FDA said these data were insufficient because the data source documents for approximately half of the trial participants were destroyed by a third-party clinical trial site operator. The agency further stated that the total number of participants in the trial was insufficient to analyze the safety of the four-dose regimen.1


1. Dynavax Provides Regulatory Update on sBLA for Four-Dose HEPLISAV-B® Regimen for Adults on Hemodialysis in the U.S. News release. Dynavax. May 14, 2024. Accessed May 14, 2024. https://prnmedia.prnewswire.com/news-releases/dynavax-provides-regulatory-update-on-sbla-for-four-dose-heplisav-b-regimen-for-adults-on-hemodialysis-in-the-us-302144529.html

2. Dynavax Announces FDA Approval of HEPLISAV-B(TM) for Prevention of Hepatitis B in Adults. News release. Dynavax. November 9, 2017. Accessed May 14, 2024. https://investors.dynavax.com/news-releases/news-release-details/dynavax-announces-fda-approval-heplisav-btm-prevention-hepatitis

3. Nelson J, et al. Compliance with multiple-dose vaccine schedules among older children, adolescents and adults: results from a Vaccine Safety Datalink Study. American Journal of Public Health. 2009;99:S2.

4. Kwon JY, Daoud N, Ghoz H, Yataco ML, Farraye FA. Efficacy of a two-dose hepatitis B vaccination with a novel immunostimulatory sequence adjuvant (Heplisav-B) on patients with chronic liver disease: a retrospective study. Transl Gastroenterol Hepatol. 2023 Jan 25;8:8. doi: 10.21037/tgh-22-12. PMID: 36704654; PMCID: PMC9813651.

5. Dynavax. Dynavax Announces Final Immunogenicity and Interim Safety Results from Clinical Trial Evaluating HEPLISAV-B in Patients Undergoing Hemodialysis. January 7, 2021. Accessed May 14, 2024. https://investors.dynavax.com/news-releases/news-release-details/dynavax-announces-final-immunogenicity-and-interim-safety

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