Dynavax Technologies Corporation has received a complete response letter (CRL) from the FDA regarding its biologics license application (BLA) for Heplisav-B (hepatitis B vaccine, recombinant [adjuvanted]) for the immunization of adults 18 years of age and older against hepatitis B infection. The FDA issues CRLs to communicate that the agency has completed a review cycle of an application and requires additional information for continued review and approval.
The CRL seeks information on several topics, including clarification regarding specific adverse events of special interest (AESIs); a numerical imbalance in the number of cardiac events in one study (HBV-23); new analyses of the integrated safety data base across different time periods; and post-marketing commitments. In the CRL, the FDA acknowledged that it has not yet completed its review of responses received from Dynavax in early October, including those pertaining to AESIs and the numerical imbalance in cardiac events. The responses included independent expert consultation supporting the company’s opinion that the imbalance was driven by an unexpectedly low number of events in the comparator arm.
Heplisav-B is an investigational hepatitis B vaccine for adults that combines hepatitis B surface antigen with a Toll-like receptor 9 agonist to enhance the immune response. The vaccine is administered in two doses over one month.
The occurrence of autoimmune diseases, including Wegener’s granulomatosis, led the FDA to place a clinical hold on a study of Heplisav-B in 2008. At that point, Merck, which held the license to the product, walked away. The agency brought up the link again when it first rejected the vaccine in 2012. In 2016, the vaccine’s prospects have waxed and waned as a phase 3 success was followed by the FDA delaying its decision, scrapping an advisory committee meeting, and asking for additional information.
Dynavax is looking for a partner with deep pockets to help prepare for another try at gaining regulatory approval.
Hepatitis B infection can become chronic, leading to cirrhosis, hepatocellular carcinoma, and death. In the United States, the Centers for Disease Control and Prevention estimates that approximately 20,000 hepatitis B infections continue to occur annually, with the majority occurring in adults. There is no cure for hepatitis B infection, and disease prevention through effective vaccination is critical to reducing the spread of the disease. Currently marketed hepatitis B vaccines are administered in three doses over a six-month schedule. Results of a published Vaccine Safety Datalink study showed that only 54% of adults completed the currently available three-dose hepatitis B vaccine series in one year.