Heplisav-B, Dynavax Technology’s experimental hepatitis B vaccine, was recommended for licensing at a meeting of the US Food and Drug Administration’s (FDA’s) Vaccines and Related Biological Products Advisory Committee on July 28.
The committee voted 12 yes, 1 no, and 3 abstain that the available data support administration of Heplisav-B to adults aged 18 years and older.
Much of the praise was for Heplisav’s shorter schedule: it is given twice over 1 month instead of rivals’ three doses over 6 months, important because of the low percentage of patients who currently complete all three doses.
The FDA does not have to follow the advice of its advisory panels but typically does.
Last November, the FDA rejected Dynavax’s marketing application for the vaccine for the second time in 3 years.
Although pivotal trials have shown that Heplisav-B is effective, its safety profile is not as clear, according to an FDA review released before the meeting.
A surprise finding from a clinical trial showed there were more deaths and serious heart problems, including myocardial infarction, among patients who received that vaccine than those given a rival product, Endrix B, according to the FDA report, but the numbers were small and hard to assess.
However, “After excluding deaths that were due to overdose or injury, 0.29% of Heplisav (16 subjects) and 0.14% of Engerix-B (4 subjects) recipients experienced fatal (severe adverse events),” according to the report.
The company has proposed a postmarketing study of 40,000 patients, primarily to address the imbalance in cardiac events.
Darcie Everett, MD, PhD, with the Division of Viral Products in the FDA, reported that Dynavax has proposed that Kaiser Permanente in northern and southern California use electronic health record databases to conduct the postmarketing study, for which Dynavax will supply Heplisav-B free of cost.
The study will compare the incidence rates of cardiac events in 20,000 Heplisav B recipients with the rates in 20,000 recipients of other monovalent hepatitis B vaccines. The cohorts will followed for up to 13 months after the first vaccination.
Recruitment is expected to be completed in 1 year. “Thus the final results may be available 3 to 3½ years after study initiation,” she said.
Immediacy of the post-licensure study is one of the main concerns of the panel.
Committee member Janet Englund, MD, professor in pediatrics at the University of Washington in Seattle, said she was also concerned that the population that might be tested in the postmarketing study may not be the same population in which severe cardiac events would most likely occur.
“I don’t want to see 20,000 people between 20 and 40,” she said. “I want to see 20,000 people between 50 and 70.”
Benefit vs Risk
Gregory Poland, MD, professor of medicine and director of the Vaccine Research Group at the Mayo Clinic, chaired the safety evaluation and adjudication committee for two of the three pivotal trials for Heplisav-B.
He told the committee, “I believe Heplisav provides me as a clinician with a critical tool that will move to the protection of more adults in the US.
“While the impressive success of the hepatitis B vaccine in children could create the perception that a new hepatitis B vaccine isn’t needed, it’s a far different story in adult medicine,” he said. “Acute cases are increasing in adults.”
Heplisav has several advantages. These include rapid induction of “almost 90% by 8 weeks and nearly all by 12-plus weeks,” which will help protect those at higher risk as well as healthcare workers; reliable induction of immunity; and a shortened immunization schedule.
Common sense suggests that people are more likely to follow the two-dose, 1 month schedule, he noted, which is crucial for full protection.
“From my perspective, the safety profile of Heplisav is similar to Endrix, which is reassuring. The results from a clinical trial showed similar rates of local and systemic postinjection reactions, adverse events, and serious adverse events. Rates of death were similar when excluding drug overdose.”
He attributed the imbalance seen in myocardial infarction to chance.
“Nonetheless, we all know that rare events, coincidental or not, may occur with wider use,” he said, and added his support for a rigorous postmarketing study, as proposed.
Many of the committee members said the possible link with cardiac events will likely remain unclear, and in the end, the vote came down to weighing the benefits against the risk.
Almost all of the public comment portion of the meeting was positive concerning the vaccine.
However, Megan Polanin, PhD, a senior fellow at the National Center for Health Research in Washington, DC, said, “The clinical trials have raised serious concerns about safety for some patients.
“Asians living in the United States account for more than half of the 1 million Americans living with chronic hepatitis. Chronic infection is responsible for most HBV-related morbidity and mortality. Clearly Asians are not adequately represented in the company’s pivotal trials.”
She said that because so few Asians were included in the study, there is no way to know whether they would be affected differently by the vaccine.
The US Centers for Disease Control and Prevention estimates that up to 2.2 million people in the United States have chronic hepatitis B virus infection and that about 786,000 people worldwide die each year from hepatitis B virus–related liver disease. There is no cure for hepatitis B, and disease prevention through more effective vaccines is critical to reducing the spread of the disease.
By Marcia Frellick
- Read Dynavax Technologies’ press release here.