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Dynavax Tumbles on Heplisav Delay; More Safety Data Needed

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By Jennifer Boggs
Managing Editor

Hopes for a resubmitted Heplisav application by the end of this year were dashed Monday, after Dynavax Technologies Corp. said a recent meeting with the FDA indicated that an additional safety study would be required before the agency would consider approving the hepatitis B vaccine.

Also nixed was the possibility of submitting a new application seeking initial use of Heplisav in restricted patient populations, such as subjects with chronic kidney disease (CKD), or limiting the vaccine to patients older than 40. Upon discussion with the FDA, that approach "did not address the fundamental issue of a shortfall in the safety database," noted Dynavax CEO Eddie Gray on a Monday morning conference call.

The firm will continue seeking approval for the broad indication – as immunization of adults, ages 18 through 70, against infection by all known subtypes of hepatitis B and for vaccinating patients with CKD. It will just take longer than expected.

Shares of the Berkeley, Calif.-based biotech (NASDAQ:DVAX) dropped 43.3 percent, closing Monday at $1.40, down $1.07, on news of the delay, as well as unanswered questions concerning the scope and cost of the anticipated safety study.

Gray, who replaced longtime Dynavax CEO Dino Dina last month, said the firm was still digesting information from the FDA meeting and was only just starting to design a protocol for a safety study to resolve outstanding issues. He later apologized for sounding "a bit like a cracked record" in response to repeated questions on duration and trial cost.

The best he could offer was a rough ballpark estimate. "The FDA reasonably understands that a safety study designed to include, say, 30,000 patients is not economically feasible for a small company like Dynavax," he told investors, stating that the scale likely would be more along the lines of what was suggested during last year's Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting. VRBPAC gave a thumbs-down to Heplisav largely due to what committee members called an insufficient safety database. (See BioWorld Today, Nov. 16, 2012.)

Gray did not specify further, but VRBPAC member Edgar Marcuse, associate medical director at Seattle Children's Hospital, suggested during the adcom that a trial enrolling 8,000 to 10,000 patients might suffice.

Gray was equally cagey on trial duration, saying only in response to an analyst's probing that "I think it's fair to say we don't think it's going to be a 60-day follow-up."

More information will be forthcoming, he assured. Still, Gray cautioned, "I don't think you should make any assumptions about the study design right now."

The FDA's demand for additional safety data is in line with both the VRBPAC vote and the complete response letter received earlier this year.

Panelists and reviewers primarily were concerned with the Toll-like receptor 9 agonist used as an adjuvant in the vaccine, specifically the possibility that it was linked to rare autoimmune events. Heplisav testing had even been suspended by the FDA at one point after a single case of Wegener's granulomatosis cropped up in the active drug arm. (See BioWorld Today, Feb. 26, 2013.)

If there's a silver lining to Monday's news it's that the immunogenicity data for Heplisav still appear acceptable. The "spirit and tone of the interactions with the FDA" suggest support for the vaccine, Gray said.

The adjuvant is designed to help the vaccine be more immunogenic in populations that don't normally respond optimally to current vaccines. So building a large safety database for Heplisav also will go a long way toward validating the underlying technology, he added.

Dynavax tested Heplisav in more than 4,800 patients, with data showing noninferiority, superiority and safety in comparison to the marketed hepatitis B vaccine, Engerix-B, from GlaxoSmithKline plc. Final data reported last year in CKD patients showed that the vaccine protected 90 percent vs. 82 percent in the Engerix-B arm, so the firm had hoped the agency might be willing to a near-term filing in the CKD subset. (See BioWorld Today, July 21, 2012.)

Despite the setback, Gray said the firm is optimistic going forward. "In my view, the outcome of the meeting was clear and followed, I think predictably, the themes expressed by VRBPAC last November."

He warned, however, that the company would have to engage in "financial discipline." Dynavax had about $105.4 million on its balance sheet as of March 31.

In the meantime, a marketing authorization application for Heplisav continues through the review process in Europe. At this time, Dynavax's European strategy, which it has said likely would involve seeking a partner, has not changed.

Heplisav previously was partnered with Whitehouse Station, N.J.-based Merck & Co. Inc., but that deal dissolved in 2009 following the clinical hold. (See BioWorld Today, March 19, 2008, Aug. 7, 2008, Dec. 22, 2008, and Sept. 11, 2009.)

Its troubles with the hepatitis B vaccine didn't end there. In 2011, Dynavax experienced another setback, this time in manufacturing, when it reported problems with lot-to-lot consistency. (See BioWorld Today, July 22, 2011.)