FDA Panel Endorses Novel Hepatitis Vaccine Efficacy, Not Safety

Miriam E. Tucker

November 16, 2012

SILVER SPRING, Maryland — A federal advisory panel has voted to support the effectiveness but not the safety of a novel hepatitis B vaccine for adults aged 18 to 70 years.

At a meeting yesterday, the US Food and Drug Administration (FDA) Vaccines and Related Biological Products Advisory Committee voted 13 to 1 with no abstentions that immunogenicity data were sufficient to support the effectiveness of Dynavax Technologies Corporation's Heplisav.

However, the panel voted 8 to 5 with 1 abstention that the safety data presented by the company were not adequate to support safety of the product.

The panel's main concerns were that the safety database was too small to detect rare adverse events, that the vaccine hadn't been studied in sufficient numbers of ethnic minority populations, and that it hadn't been studied in combination with the administration of other adult vaccines. Dynavax had planned to address these concerns in post-licensure studies.

New Adjuvant Boosts Response

Heplisav differs from currently licensed hepatitis B vaccines in its adjuvant, a toll-like receptor 9 agonist that elicits hepatitis B surface antigen (HBs)-specific antibodies against the hepatitis B virus. Current hepatitis vaccines use alum as an adjuvant, which stimulate a more general inflammatory response to mechanical disruption of cell membranes and is therefore less specific for anti-HBs production.

As a result, Heplisav provides improved seroprotection with 2 doses given 1 month apart as opposed to the 3 doses given at 0, 1, and 6 months that current hepatitis vaccines require. This feature is expected to improve adherence, according to Dynavax chief medical officer J. Tyler Martin, MD.

Heplisav was also designed to overcome the problem of the reduced immunogenicity seen with current hepatitis B vaccines among several groups of high-risk adults for whom the vaccine is recommended, including older adults, men, obese individuals, smokers, people with diabetes, and those who are immunocompromised.

Phase 3 immunogenicity data came from 2 pivotal clinical trials in which a total of 2680 adults were randomly assigned to receive Heplisav and 892 the currently licensed Engerix-B (GlaxoSmithKline). The safety population included those subjects plus others from additional supportive trials, for 4425 participants randomly assigned to Heplisav and 1420 to Engerix-B.

In the trials, both vaccines were given at 0 and 4 weeks, and either Heplisav or placebo was administered at 24 weeks.

Data analyses by both Dynavax and the FDA showed that Heplisav met the prespecified endpoints of noninferiority in seroprotective antibody responses compared with Engerix-B, and superior and earlier responses were seen in many cases. Seroprotection rates of 90% or greater against hepatitis B were evident at 8 weeks after the second dose of Heplisav, according to FDA reviewer Alexandra B. Worobec, MD.

Safety Data Deemed Insufficient

Safety analyses showed no statistically significant differences between Heplisav and Engerix-B in local and systemic solicited adverse events or deaths, and laboratory investigations did not reveal any clinically significant differences between the 2 groups. Nonfatal serious adverse events occurred with similar incidence between groups, FDA reviewer Lorie Smith, MD, said.

However, although not statistically significant, there were numerically greater numbers of Heplisav patients with evidence of autoimmunity including thyroid disorders, and a handful of rare serious events among Heplisav recipients, including 1 case each of Wegener's granulomatosis, Tolosa-Hunt syndrome, and Guillain-Barre syndrome.

According to Dr. Smith, 20 instances of thyroid diseases and abnormal thyroid laboratory results were reported in 17 Heplisav subjects (0.4%) compared with 3 events in 3 Engerix-B subjects (0.2%).

Melinda Wharton, deputy director of the National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention, Atlanta, Georgia, voted yes for efficacy but no for safety. She said she was "glad to see work being done" on a hepatitis B vaccine that is more immunogenic in populations that don't respond optimally to current vaccines.

"That said, I don't think the safety database is sufficiently large to support a recommendation for use in the general adult population, given that this vaccine contains a new adjuvant," she explained.

Committee chairman Robert Daum, MD, voted no on both efficacy and safety. "I'm concerned that there are not enough data in different ethnic groups to be sure that the immunogenic responses are adequate. I'm also concerned that there were no data presented about giving other vaccines simultaneously.... If this were a pediatric vaccine we'd be jumping up and down about that.... I don't see this as a separate visit vaccine," said Dr. Daum, professor of pediatrics and microbiology and molecular medicine at the University of Chicago, Illinois.

Bruce Gellin, MD, MPH, director of the National Vaccine Program Office of the US Department of Health and Human Services, also voted yes for efficacy and no for safety, but he proposed a compromise in which the vaccine might be licensed initially for use specifically in populations at increased risk for hepatitis B for whom current vaccines are less effective.

That way, the benefit-risk ratio might be more in favor of the vaccine, and more data on efficacy and safety could be collected before expanding the indication to the general adult population. "Rather than the entire population, it could be targeted initially to the population where it is most needed," he said.

Advisory panels to the Food and Drug Administration are vetted for conflicts of interest. In this case, no waivers were required for any members.