FDA Issues CRL for HEPLISAV-B in Adults on Hemodialysis

Rob Janssen, MD

Credit: LinkedIn

The US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) in response to Dynavax’s supplemental Biologic License Application (sBLA) to include a 4-dose HEPLISAV-B vaccination [Hepatitis B Vaccine (Recombinant), Adjuvanted] regimen for adults on hemodialysis.¹

Announced on May 14, 2024, the CRL stated the application did not provide sufficient data to support the full evaluation of effectiveness or safety of a 4-dose regimen of HEPLISAV-B. Dynavax noted the CRL has no impact on the approved indication for HEPLISAV-B in the US, the European Union, and Great Britain, for the prevention of infection caused by all known subtypes of hepatitis B virus (HBV) in adults 18 years of age and older, nor does it affect the approval from the European Commission in October 2023 for the 4-dose HEPLISAV-B regimen in adults on hemodialysis.¹

"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," Rob Janssen, MD, Chief Medical Officer of Dynavax, said in a press release.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 U.S."

A vaccine that combines hepatitis B surface antigen with Dynavax's proprietary Toll-like Receptor (TLR) 9 agonist to enhance the immune response, HEPLISAV-B first earned FDA approval in 2017 for the prevention of infection caused by all known subtypes of hepatitis B virus in adults ≥ 18 years of age.² However, prior to this decision, the vaccine received a pair of CRLs in 2013 and again in 2016.^3,4

The first CRL requested further safety evaluation and additional data from Dynavax's process validation program as well as clarifying information on the manufacturing controls and facilities related to the assurance of the quality of the commercial product, further citing concerns about rare autoimmune events. The second CRL, however, did not request additional clinical trials or voice concerns about rare serious autoimmune events and was attributed to completion of the review cycle before the Agency could fully assess Dynavax’s response.^3,4

The sBLA included clinical immunogenicity and safety data from the phase 1 HBV-24 study of a 4-dose regimen of HEPLISAV-B in 119 adults undergoing hemodialysis.¹ Final immunogenicity data were announced on January 7, 2021, and demonstrated a seroprotection rate of 89.3% with high levels of anti-HBs antibodies. Interim safety data showed HEPLISAV-B was well tolerated with no observed safety concerns.⁵

Additionally, 5 supportive clinical trials of HEPLISAV-B in adults with chronic kidney disease (CKD) or undergoing hemodialysis were included in the sBLA. However, the CRL stated that the data from HBV-24 were insufficient due to the destruction of data source documents by a third-party clinical trial site operator for approximately half of the subjects enrolled in the trial. It also noted the total number of subjects in the single-arm HBV-24 study was deemed to be insufficient to evaluate safety of the 4-dose regimen.¹

According to the release, Dynavax plans to meet with the FDA to assess options to provide additional data in support of a 4-dose HEPLISAV-B regimen in this patient population.¹

References:

^{1. Dynavax. Dynavax Provides Regulatory Update on sBLA for Four-Dose HEPLISAV-B® Regimen for Adults on Hemodialysis in the U.S. 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. Dynavax. Dynavax Announces FDA Approval of HEPLISAV-B(TM) for Prevention of Hepatitis B in Adults. November 9, 2017. Accessed May 13, 2024. https://investors.dynavax.com/news-releases/news-release-details/dynavax-announces-fda-approval-heplisav-btm-prevention-hepatitis}

^{3. Dynavax. Dynavax Receives FDA Complete Response Letter on HEPLISAV(TM) Biologic License Application. February 25, 2013. Accessed May 13, 2024. https://investors.dynavax.com/news-releases/news-release-details/dynavax-receives-fda-complete-response-letter-heplisavtm}

^{4. Dynavax. Dynavax Receives Complete Response Letter from U.S. Food and Drug Administration for Biologics License Application for HEPLISAV-B. November 14, 2016. Accessed May 13, 2024. https://investors.dynavax.com/news-releases/news-release-details/dynavax-receives-complete-response-letter-us-food-and-drug}

^{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 13, 2024. https://investors.dynavax.com/news-releases/news-release-details/dynavax-announces-final-immunogenicity-and-interim-safety}