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Adjuvant Bell 'Tolls' for DVAX: Heplisav Panel Thumbs Down

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By Randy Osborne
Staff Writer

The Toll-like receptor (TLR) 9 agonist used as an adjuvant in Dynavax Technologies Corp.'s Heplisav doomed the hepatitis B vaccine at an FDA advisory panel meeting, where members said knowledge of the drug's effects is neither broad nor diverse enough.

"Having a hepatitis B vaccine which is more immunogenic in populations that don't respond optimally to current vaccines is a good thing," said Melinda Wharton, member of the Vaccines and Related Biological Products Advisory Committee. "I'm glad to see this work being done. 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."

At the close of the meeting, Chairman Robert Daum said members "had a very difficult discussion today." As difficult as the talk may have been for panelists, it was worse for Berkeley, Calif.-based Dynavax.

Briefing documents posted by the agency earlier this week seemed to suggest an outcome positive for the company, but the vote turned out 8-5, with one abstention, against recommending approval based on the inadequacy of safety data.

Other voting on whether the immunogenicity proofs offered by Dynavax could justify approval totaled 13 "yes" votes, but Daum voted "no" on that matter, too, the lone negative ballot.

"I'm concerned that there are not enough data [from] different ethnic groups," he said, and numbers also fell short regarding outcomes when other vaccines are given simultaneously with Heplisav.

"If this were a pediatric vaccine, we would be extremely jumping up and down about that," Daum said, adding that the same level of concern should reach to adults. "We're giving simultaneous vaccines like TDAP [tetanus, diphtheria, pertussis] and flu, to name two, and Pneumococcus to name a third," he said. "I don't see [Heplisav] as a separate-visit vaccine."

Panelist Edgar Marcuse hailed the new adjuvant, but said the question "comes down to weighing the potential benefits vs. the potential risks," and the safety database on Heplisav is "too flimsy" to allow marketing clearance for general use.

Accepted for review in June with an assigned PDUFA date of Feb. 24, 2013, the Heplisav biologics license application seeks approval for immunizing adults 18 through 70 against infection caused by all known subtypes of hepatitis B virus, and for patients with chronic kidney disease (CKD).

Heplisav has been put into more than 4,800 patients so far. In March, Dynavax reported final data from a pivotal Phase III trial showing that the vaccine protected 90 percent of CKD patients compared to 82 percent of those receiving Engerix-B (GlaxoSmithKline plc) at the primary endpoint (p = 0.01), one month after the third dose of Heplisav and the eighth dose of Engerix-B.

More analysis showed Heplisav worked in more than twice as many patients at two months. Dynavax reported top-line data for the 516-patient trial in October 2011. In a separate trial, in CKD nonresponders on hemodialysis who failed to develop protection after two or more previous vaccination series with the licensed vaccines, new data showed a higher protection rate for Heplisav compared to Engerix-B and Fendrix (also GSK).

Autoimmune events have cropped up in Heplisav experiments, though none has been definitively linked to the vaccine. At one point, the FDA put a trial on clinical hold after a patient in the active-drug arm developed Wegener's granulomatosis.

"I would like to see a larger database, somewhere of the order of 8,000 to 10,000," said Marcuse, who also called for a more ethnically diverse population.

Committee member Trudy Murphy said the TLR9 adjuvant "really has enormous potential if it works well, and is safe for perhaps other vaccines," but also carries "implications for existing vaccines if it turns out we do have a safety signal down the line," since patients may stop trusting those, too.

Panelist Carol Tacket praised the kinetics of Heplisav, citing "a benefit to be had immediately, in terms of the rapidity of the immune response and the height of the immune response."

How much more clinical work must be done before approval and how much can be done after were topics at the end of the meeting.

"One strategy may be a focused effort on a higher-risk population, where the benefits of the vaccine would likely be greater," Wharton said. "I would be comfortable with doing more of the safety assessment post-licensure in that population" than among patients in general.

Daum said that although the panel was "not happy with where the safety database is, nevertheless this is a very promising adjuvant."

Analyst Phil Nadeau with Cowen and Co. called the panel's opinion "surprising, given that the FDA's own reviewers suggested that rare adverse events could be assessed through postmarketing studies." He predicted that the latest development would delay but not prevent approval of Heplisav.

Dynavax, which gained about 13 percent Tuesday after the briefing documents came to light, halted trading Thursday (NASDAQ:DVAX) at $4.63 because of the panel meeting.