August 4, 2017
By Mark Terry, BioSpace.com Breaking News Staff
Only days after a U.S. Food and Drug Administration (FDA) panel voted 12 to 1 to recommend Dynavax Technologies Corporation (DVAX)’s Heplisav-B hepatitis B vaccine, the FDA requested more information about the company’s post-marketing plans. Investors responded, and Dynavax shares dropped 11 percent after Thursday’s end-of-trading day.
On July 31, the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted 12 to 1 to recommend Haplisav-B in adults 18 years or older. Three members of the committee abstained. The committee also commented on the company’s design for a proposed post-marketing pharmacovigilance plan for the vaccine, which is the new sticking point.
There was never much concern about the vaccine’s efficacy, but there was concern over its safety profile. Regulators noted an imbalance of fatalities and cardiac events that have never been explained.
As a result, after further discussions after the committee vote, the FDA and Dynavax have decided that more time is needed to lock in details of the post-marketing study, particularly in light of an August 10 PDUFA date.
“Our conversation with the Agency was open and productive and confirmed our mutual understanding of the VRPBACs suggested requirements for the post-marketing study,” said Eddie Gray, Dynavax’s chief executive officer, in a statement. “We are working with our third-party providers to develop an appropriate study that addresses the advisory committee’s feedback. We now have clarity on the path forward and next steps required to complete the regulatory review of HEPLISAV-B. We plan to respond to the request for additional information expeditiously. We look forward to bringing this important vaccine to market to support the elimination of hepatitis B infection as a public health problem.”
The details remaining to be hammered out include the timeline for the final protocol submission, trial completion and final report deadline, the timeliness of bringing patients into the study, time points for data review, ways of controlling for potential study arm bias, and updated statistical analysis plan.
Dynavax is indicating it should be able to initiate the drug marketing plan with an approval by November 10, which is three months after the original PDUFA date.
The original post-marketing plan was to conduct observational electronic medical record review at Kaiser Permanente Northern California to compare 3-point MACE as well as pre-specified immune-mediated events. The evaluation would look at 20,000 patients who received Heplisav-B compared to 20,000 more who received a different hepatitis B vaccine.
The advisory panel had also suggested that full safety data should be in Heplisav’s label. This is typically undesirable, because doctors may choose against using the vaccine in high-risk patients as a result.
Dynavax is currently trading for $17. Shares traded for $9.25 on July 27 and spiked to $15.85 on July 31. It dropped on August 1 to $15.20, but has recovered somewhat, although pre-market trading had the shares down to $16.20.
Milton Packer, the only cardiologist on the advisory panel, a Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center at Dallas, wrote about the vaccine for STAT News today. He writes, “The vaccine works through a unique adjuvant—a substance that improves the body’s immune response to the virus. The advantages of the Dynavax vaccine were demonstrated in a randomized trial of more than 8,000 patients: About 5,600 received the new vaccine and about 2,800 received the existing standard hepatitis B vaccine. During the trial, though, 14 people in the Dynavax group had heart attacks compared to just one in the conventional vaccine group. Since the Dynavax group was twice as large, the heart attack risk was seven times higher with the new vaccine.”
The committee apparently spent quite some time trying to determine, based on available data, whether the heart attack risk was caused by the vaccine. The adjuvant used in it causes an inflammatory response for an unknown period. Inflammation causes atherosclerotic plaques in coronary arteries to rupture, which triggers most heart attacks. So a link was a possibility. But was it just a coincidence?
The available data couldn’t tell. They would need data in 50,000 people. Packer was one of the three committee members who abstained.
“Why did I abstain?” he writes. “Based on the available data, it was impossible for anyone to know if the increase in heart attack risk in the Dynavax group was real or spurious. So although the questions were fascinating and the discussions terrific, my vote wasn’t that complicated. There is a simple rule in life: if you don’t know, you should say you don’t know.”
