Members of FDA’s Vaccines and Related Biological Products Advisory Committee will weigh in Nov. 15 on whether a post-market observational study is sufficient to address lingering FDA concerns about the potential for autoimmune reactions to Heplisav (rHBsAg-1018 ISS), the hepatitis B vaccine from Dynavax Technologies Corp. that contains a novel adjuvant.

FDA did not formulate specific questions in its briefing materials for the panel, but rather said the meeting will focus on the adequacy of the safety and effectiveness data submitted to support licensing of the vaccine. Dynavax is seeking an indication to provide adults 18 to 70 years old with active immunization against all subtypes of hepatitis B virus infection.

Autoimmunity became a concern for Heplisav in 2008 when a participant in one of the vaccine’s Phase III trials developed Wegener’s granulomatosis, a rare inflammation of blood vessels. FDA put a clinical hold on the vaccine’s development program that cost Dynavax the partnership of Merck & Co. Inc. Also see "Merck Returns Heplisav To Dynavax After FDA Rules Vaccine Too Risky For Healthy Adults" - Pink Sheet, 19 December, 2008.. FDA allowed Dynavax to proceed with clinical trials 18 months later Also see "FDA Lifts Clinical Hold On Dynavax's Hep B Vaccine Heplisav, Narrows Population" - Pink Sheet, 10 September, 2009..

The Heplisav NDA is supported by two Phase III trials that evaluated the vaccine against the non-adjuvanted hepatitis B vaccine Energerix-B from GlaxoSmithKline PLC. “There did not appear to be a difference in the potential for autoimmunity between” the two, according to FDA briefing documents.

However, the agency noted that “the pre-licensure safety database for this vaccine with a new adjuvant may not have sufficient power to detect rare adverse events” and the only safety database for the adjuvant is from the Heplisav studies. Also hampering a clear picture of safety is the limited follow-up periods that the studies had as well as the facts that autoimmune diseases have a relatively low incidence in the general population and often have a non-specific initial presentation, FDA said.

The sponsor proposes to conduct an open-label, prospective, observational study to assess the incidence of medically significant adverse events, including autoimmune disease, in 5,000 individuals vaccinated with Heplisav, compared to 5,000 people vaccinated with Engerix-B. Participants will be followed for 12 months after the first injection.

Novel Adjuvant Increases Safety Questions

Adding to FDA’s uncertainty about Heplisav safety is the presence of the 1018 ISS adjuvant, which is a synthetic cytosine phosphoguanine oligodeoxynucleotide (CpG ODN) that interacts with the toll-like receptor 9 (TLR9) to stimulate immune response to the vaccine’s antigen.

FDA has been cautious about approving vaccines with adjuvants and currently, there is no other vaccine containing 1018 ISS licensed in the U.S. and available to provide a track record for the adjuvant’s safety.

There is “limited prior human experience” with 1018 ISS, the agency said. Reports in the literature about use of CpG 7909 in the context of cancer patients did not reveal autoimmune signals, FDA said, but noted the difficulty of interpreting the findings due to the heterogeneous populations studied.

Toxicity studies also failed to reassure agency reviewers. “Non-clinical investigations of the potential for CpGs or Heplisav to induce autoimmunity have been suboptimal given the lack of an appropriate mouse or well-characterized NHP models of human autoimmunity,” FDA said.

In both pivotal trials, two doses of Heplisav were non-inferior to three doses of Engerix-B in inducing immunogenicity to Hepatitis B as determined by a seroprotection rate of anti-HBsAG level ≥ 10 mIU/mL, FDA said. At least 90% of the Heplisav patients maintained seroprotective antibody levels against hepatitis B at 48 weeks, after two doses, FDA said.

Dynavax’s future plans include a supplemental application to add an indication for patients with chronic kidney disease Also see "Dynavax’s Heplisav Heads To Advisory Panel, But Will It Drudge Up Old Safety Issues?" - Pink Sheet, 28 August, 2012..

Dynavax Hepatitis B Vaccine Could Get Comparative Post-Market Autoimmunity Assessment

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