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FDA advisory panel considers HEPLISAV effective; finds safety data insufficient
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The FDA’s Vaccines and Related Biological Products Advisory Committee today voted that, while the HEPLISAV hepatitis B vaccine effectively prevents infection in adults, its safety has yet to be adequately evaluated to warrant use in the general population.
Dynavax Technologies Corp. seeks approval for HEPLISAV, a recombinant vaccine that includes hepatitis B surface antigen and 1018 immunostimulatory sequence (ISS), a Toll-like receptor 9 agonist developed by the company to increase immunogenicity. The company proposed the treatment for patients aged 18 to 70 years at a 0.5-mL dose including 20 mcg of the recombinant surface antigen and 3,000 mcg of 1018 ISS, to be administered intramuscularly in two doses set 1 month apart.
Dynavax presented results from two multicenter, randomized clinical trials. In the first trial, HBV-10, 2,415 patients aged 18 to 55 years received either a two-dose HEPLISAV regimen with a placebo administered at 24 weeks (n=1,809) or a three-dose regimen of Engerix-B (GlaxoSmithKline) administered at weeks 0, 4 and 24 (n=606). In the second trial, HBV-16, 2,452 patients aged 40 to 70 years received either HEPLISAV (n=1,969) or Engerix-B (n=483).
Study results indicated HEPLISAV’s noninferiority to Engerix-B, with HBV seroprotection (SPR) rates of 90% or more within 8 weeks of the second dose. In HBV-10, SPR was 95.0% at 12 weeks for HEPLISAV recipients, compared with 81.1% at 28 weeks in the Engerix-B group. In HBV-16, SPR was 90.0% for HEPLISAV at week 12 compared with 70.5% for Engerix-B at week 32. No clinically significant differences were observed in response to HEPLISAV according to age or sex.
The committee voted nearly unanimously (13-1) that the presented data on immunogenicity sufficiently indicated the vaccine’s effectiveness in preventing HBV. “I’m concerned that there’s not enough data from different ethnic groups to be sure the immunogenetic response is adequate,” committee chair and sole dissenter Robert Daum, MD, CM, director of the infectious diseases section of the pediatrics department at the University of Chicago MRSA Research Center, said. “I’m also concerned about [the lack of] data presented about other vaccines that would be given simultaneously.”
Safety data taken from the phase 3 trials indicated no significant differences between the vaccines with regard to adverse events, deaths (one each occurred in the HEPLISAV and Engerix groups in study HBV-16) or laboratory investigations. Commonly reported events included nasopharyngitis (10.1% of HEPLISAV recipients), headache (6.9%) and back pain (3.4%), all of which occurred at similar rates among Engerix-B recipients. Incidence of serious adverse events also was similar between the treatments.
When asked whether the safety data supported the proposed indication, most committee members disagreed (5-8, with 1 abstention). Several members indicated a need for further evaluation incorporating a larger cohort with a more diverse ethnic makeup, as 83.0% of HEPLISAV recipients were white and 96.2% were non-Hispanic. Like Daum, others expressed concern about concomitant vaccine administration, which Dynavax indicated would be addressed post-approval.
MemberBruce Gellin, MD, director of the National Vaccine Program Office, suggested that the indication be shifted from the general population to patients who could not benefit from available products.
“It’s a way to introduce the vaccine to a broader population than the few that have been studied, and gain more experience, but at the same time to provide a product that has real benefits for people for whom the existing products don’t,” he said.
Daum concluded the meeting by suggesting that most of the committee had a favorable impression of the vaccine, despite the negative safety vote. “I think we’ve had a very difficult discussion today,” he said. “I think there’s a lot of enthusiasm around the table that this is a very promising vaccine approach. We’re not happy with where the adjuvant safety database is; nevertheless, this is a very promising adjuvant.”