Heplisav Seems Headed For Approval, But With More Robust Postmarketing Study

Safety of Dynavax's hepatitis B vaccine gets thumbs up from US FDA advisory committee, but panel remained concern that postmarketing proposal doesn't address questions about potential link to cardiovascular events.

Dynavax Technologies Corp. looks poised to finally get its hepatitis B vaccine Heplisav (rHBsAg-1018 ISS) to market, but it could require a more robust postmarketing plan than it has initially proposed to the US FDA.

During its July 28 review, the agency's Vaccines and Related Biological Products Committee voted 12 to 1 – with three abstentions – that the available data support the safety of Heplisav when administered to adults 18 years and older.

Although there was a consensus among the panel that the vaccine has demonstrated robust effectiveness, there was still a large degree of uncertainty as to whether myocardial infarctions were a safety signal caused by the vaccine. In the company's third pivotal trial of the vaccine, 0.3% of patients taking Heplisav reported events of myocardial infarctions versus 0.1% of those taking GlaxoSmithKline PLC's Engerix-B, a competitor hepatitis b vaccine.

Although the rates of myocardial infarctions were low for both arms, the rate for Heplisav was three times that of Engerix-B.

Although the rates are low for both arms, the rate for the Heplisav arm was three times that of the Engerix-B arm. Amid the uncertainty about the safety signal, several panelists called for a stronger postmarketing safety study to assess the risk.

Dynavax is proposing a retrospective cohort study consisting of 20,000 Heplisav recipients and 20,000 other hepatitis b vaccine recipients, with a follow-up in 13 months following the first dose of the vaccine. The study would compare the incidence rates of cardiac events, pre-specified immune-mediated diseases and herpes zoster, and would enroll patients at Kaiser Permanente Northern California.

Panelists said the proposal was not good enough, raising concerns about studying the vaccines in patients at high risk of cardiovascular events, the group for which are most concerned about the safety of Heplisav.

In spite of the concerns, most of the committee members felt there is a place for the vaccine on the market, with panelist Ofer Levy, a staff physician in the Division of Infectious Diseases at Boston Children’s Hospital, calling Heplisav "super effective." Levy, however, ultimately abstained from the vote.

"Clinical studies of Heplisav-B have shown that the vaccine provides increased rates of seroprotection," Dynavax CEO Eddie Gray said in a statement. "In addition, the two-dose regimen offers the potential to increase patient compliance, which physicians and advocates agree is essential to preventing more cases of hepatitis B and achieving the public health goal of eradication. We look forward to completing our ongoing discussions with the FDA regarding an appropriate post-marketing commitment as it finalizes its review."

Heplisav has a Prescription Drug User Fee Act (PDUFA) date of Aug. 10, 2017. The vaccine is hoping to finally make it to market after picking up two complete response letters. (Also see "Heplisav Vaccine Postmarketing Study Might Overcome FDA Safety Worries At Panel" - Pink Sheet, 26 Jul, 2017.)

More Robust Postmarketing Study Needed

Kathryn Edwards, a Vanderbilt University School of Medicine professor and chair of the advisory committee, said she was "pretty dismayed" about the proposed pharmacovigilance postmarketing proposal.

"I think it needs to be more comprehensive, I think it needs to think about how patients will be allocated, how patients will be followed, how the vaccine will be distributed, whether it will only be able to be accomplished it one setting," Edwards said. "It really needs a lot more information and details to allow me to feel comfortable with a 'yes' [vote]."

Edwards ultimately did vote yes, noting she felt the two-dose regimen would "immunize many more people effectively."

Other panelists agreed that the study needs to be more focused on myocardial infarctions.

"If you do a study of 20,000 or 40,000 people, something else is going to show up," said Jay Hoofnagle, director of the Liver Disease Research Branch at the National Institutes of Health (NIH), who also voted "yes."

"I think what has been found so far needs to be addressed directly and have a focused study rather than a global study."

"I would favor approving the vaccine as long as what was known about the myocardial infarctions was actually included in the labeling," Baylor's Milton Packer said.

Virtually every panelist stressed the importance of having a robust postmarketing pharmacovigilance plan.

There were, however, differences among the panelists in their views on how plausible the risk of cardiovascular events is linked to the vaccine.

University of California, San Diego Professor Mark Sawyer said there is a "reasonable chance" that the myocardial infarction signal is "spurious." Ruth Lynfield, medical director at the Minnesota Department of Health, agreed that the relationship is doubtful.

Other panelists were not as certain.

"We are not going to know the answer on the myocardial infarction," said Milton Packer, a distinguished scholar in cardiovascular science at the Baylor University Medical Center. "We are just not going to know."

Packer – who was one of the most verbal panelists at the meeting given his experience as a cardiologist – abstained from the vote about safety, expressing his dislike of the way the question was phrased. He said that an approval is ultimately decided by a risk/benefit decision, which doesn't mean that a product is risk-free.

"It is hard to answer a question whether available data support the safety," Packer said.

"I would favor approving the vaccine as long as what was known about the myocardial infarctions was actually included in the labeling," he added. "That way, you allow the uncertainty to be fully expressed in public. I don't understand why we have to reach decisions about certainty when uncertainty is the only reality."

University of Maryland epidemiology and biostatistics Mei-Ling Ting Lee also abstained from voting, as she raised concerns that she couldn't make a calculation about the link based on the data available.

Pam McInnes, deputy director of the National Center for Advancing Translational Sciences at NIH, was the lone "no" vote. She said the causal interpretation of myocardial infarctions is limited, adding that the link requires further study and that she is not confident about the sponsor's postmarketing proposal.

"As somebody who now has to make a decision in how I feel about this, I think that this really could be a real observation," McInnes said. "And I can't come up with a construct to discern that. So this gives me pause."

Several panelists also agreed that the postmarketing study should be conducted at more than one site rather than the single Kaiser Permanente.

Exceptional Efficacy

None of the panelists expressed any concern about the efficacy. Nearly every committee member lauded the vaccine's effectiveness in its response, while noting that the committee agreed back in 2012 that Heplisav does indeed work.

"If you look at the data and compare it to that of the vaccines we have now, it's not even close," Levy said. "It blows them out of the water. The number of doses is huge. And getting stronger immune responses is huge."

Current hepatitis B vaccines on the market in the US include GSK's Engerix-B, Merck & Co. Inc.'s Recombivax HB, and GSK's combination vaccine Twinrix, which includes a hepatitis A vaccine component. Although Engerix-B and Recombivax HB are approved for infants and children as well as adults, the currently approved vaccines have three-dose regimens.

Panelists agreed that the two-dose regimen would increase compliance among patients.

"We need this vaccine to save lives, and we can't wait 10 years to get something like this," said Janet Englund, a professor of pediatrics at the University of Washington. "I think we have to judge this as a risk versus benefit. … I think FDA has a history of helping design postmarketing trials. They know how to do that, and we should empower them."