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Dynavax hep B vaccine may be sunk once more by safety issues

July 27, 2017

An FDA advisory committee will meet on Friday to once again explore the safety and efficacy of an investigational adult hepatitis B vaccine called Heplisav-B, and safety issues are likely to be front and center.

The Vaccines and Related Biological Products Advisory Committee (VRBPAC) will decide whether the vaccine, manufactured by Dynavax Technologies Corporation in Berkeley, Calif., merits a recommendation for approval for active immunization against all subtypes of hepatitis B virus infection in adults ages 18 and older.

Heplisav-B combines recombinant hepatitis B with a proprietary adjuvant and is administered in two doses over a 1-month period. The vaccine is designed to enhance the body’s immune response to the hepatitis B virus, which can lead to cirrhosis of the liver, cancer, and death.

To date, more than 10,000 adults have received the vaccine throughout 11 clinical trials, including three pivotal phase III studies that compared Heplisav-B with a rival product called Engerix-B, according to FDA briefing documents published earlier this week

Study results showed there were more deaths and serious heart problems in patients given Heplisav-B than in those given Engerix-B; however, overall numbers and rates of such cardiac events were low.

“Heplisav was shown to have a robust immune response in healthy adults 18-70 years of age in Studies DV2-HBV-10 and-16. Heplisav met pre-specified noninferiority criteria to an active comparator vaccine, Engerix-B, in these two phase III clinical trials,” noted the documents.

“Regarding safety, there appear to be imbalances in deaths and SAEs [severe adverse events] of MI [myocardial infarction] in DV2-HBV-23, and imbalances in AESIs [adverse events of special interest] in DV2-HBV-16 and -23 (the studies that prospectively evaluated these events). Numbers and rates of events are low, and the lack of prospectively defined monitoring and evaluation of cardiac events limits the causal interpretation of these observations.”

Heplisav-B has twice been rejected by the FDA on the basis of unresolved safety concerns. The question then becomes whether panel members will endorse a vaccine with efficacy similar to a marketed product but with arguably greater risks.

In 2012, an FDA advisory committee voted 13-1 in support of the efficacy of the vaccine but questioned its safety and the lack of information on the effects among certain minorities. Additionally, VRBPAC voted 5-8, with one abstention, against the safety of the drug in adults ages 18 to 70.

The committee will now focus on the pharmacovigilance plan — specifically on the adequacy of the pre-licensure safety data to support licensure of Heplisav.

Dynavax proposed to conduct a retrospective observational study among hepatitis B vaccinees ages 18 or older enrolled in Kaiser Permanente Northern California to compare:

  • Rates of pre-specified immune-mediated events in Heplisav recipients with the rates in concurrent recipients of other hepatitis B vaccines
  • Rates of three-point Major Adverse Cardiovascular Events (MACE) in Heplisav recipients using self-controlled risk-interval methods
  • Rates of medical events other than immune-mediated or MACE in Heplisav recipients using self-controlled risk-interval methods

In addition to this post-marketing study, Dynavax proposed routine pharmacovigilance and a pregnancy registry.

Friday’s meeting is scheduled to include FDA committee presentations regarding the immunogenicity, safety, and statistical analysis of acute myocardial infarction risk.

The FDA is not bound to follow the advice of its advisory panels but typically does so.

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