West Coast Editor
The start of more trials with Heplisav - including the expansion, as promised, of an ongoing Canadian Phase III study into sites in Germany - puts Dynavax Technologies Corp. in position to submit its biologics license application in the second half of next year for the hepatitis B virus vaccine, which targets Toll-like receptor 9.
"We're probably going to have the first CpG-based product approved of all," said Eduardo Martins, vice president of clinical development for Berkeley, Calif.-based Dynavax. "Personally, I have no doubts."
Enrollment in the pivotal study, known as PHAST (Phase 3 HeplisAv Short-regimen Trial) started in Germany at the middle of this month. Begun late last year in Canada, the study is enrolling participants 11 years through 55 years of age, and stacks a two-dose regimen of Heplisav against the conventional three-dose regimen of London-based GlaxoSmithKline plc's Engerix-B. Total sign-up in Canada and in Germany is expected to reach about 2,000 subjects.
Heplisav has entered a U.S. study - also enrolling patients ages 11 through 55 - and results from that work, plus the Phase III trials in Canada and Europe, along with lot-to-lot consistency trials (starting in the second half of this year), will help make up a safety database of about 4,000 subjects.
Dynavax also expects to launch a Phase II trial in patients with end-stage renal disease, recently cleared by Health Canada. That study will test two separate doses of Heplisav, enrolling adults ages 40 through 70 who have progressive loss of renal function (GFR less than or equal to 45 mL/min) and are either pre-dialysis or hemodialysis patients.
ESRD patients are notoriously hard to immunize. "There are other populations [in serious need of an HBV vaccine], such as patients with HIV and cirrhosis, but ESRD is the largest one," Martins said. An outbreak of HBV on a dialysis unit is "a disaster," he added. "It goes like a dry brushfire."
The idea is to get approval of Heplisav in relatively healthy patients, and then seek the supplemental indication of ESRD. In 2005, GSK won European marketing clearance of its HBV vaccine Fendrix for the high-risk group, but apparently was interested mainly in validating the monophosphoryl lipid A adjuvant that would be used in other medicines - all the more so after GSK bought the adjuvant's originator, Seattle-based Corixa Corp., for $300 million in cash, later the same year. (See BioWorld Today, May 3, 2005.)
Heplisav adds Dynavax's immunostimulatory sequence to HBV surface antigen to spark an immune response. "Imagine putting two things together and shaking the vial," Martins said. "That's Heplisav." In practice, of course, manufacture is not so simple, but the components of Heplisav are not chemically bound.
Dynavax also has the ragweed allergy immunotherapy Tolamba, which disappointed investors at the start of this year when interim data from a two-year Phase III trial called DARTT (Dynavax Allergic Rhinitis Tolamba Trial) showed no meaningful ragweed-specific allergic disease in any of the treatment or placebo groups. The drug is made of immunostimulatory sequences linked to Amb a 1, the purified major allergen of ragweed. It is designed to suppress the Th2 cells responsible for inflammation associated with the allergy. (See BioWorld Today, Jan. 9, 2007.)
"Tolamba is a different thing," Martins said. "[The two elements] are chemically linked. You get a very specific T-cell response."
In all three study arms of the Phase III trial there was a minimal change from baseline in the total nasal symptom score (TNSS), the primary efficacy endpoint. But a prespecified regional analysis found that DARTT sites in the Midwest - comprising more than half the study population - included patients with more pronounced ragweed symptoms, and that group had a "clinically meaningful" reduction of TNSS, Dynavax said. Phase II results have proven positive, too.
"We are defining [the path forward with Tolamba] right now," Martins said, and the company hopes to "devise a way to show the efficacy of the drug without the out-of-our-control type of glitches that we had in this last trial. Clearly, the traditional way in which we select patients - history and skin test alone - do not suffice."
Dynavax lost about a year's worth of development time as a result of the outcome of the Phase III trial. "Until December of last year, it was a neck-and-neck race with Heplisav," Martins said. "There are no efficacy issues" with the HBV vaccine, he said. "It's has been 100 percent in every single trial that we've had, and so far no safety issues whatsoever."
Farther back in the pipeline is a therapy for non-Hodgkin's lymphoma in Phase II trials and for metastatic colorectal cancer at the Phase I stage, plus a therapy for HBV, also in Phase I. Dynavax's preclinical asthma and chronic obstructive pulmonary disease program is partnered with London-based AstraZeneca plc, and an early stage influenza-vaccine bid is partly funded by The National Institutes of Health.
Symphony Dynamo Inc., of Rockville, Md., funds Dynavax's colorectal cancer trials and a preclinical hepatitis C virus push, but Dynavax has rights to pursue strategic partners for the efforts in which SDI and the NIH are involved.
Dynavax started the second quarter of this year with more than $100 million in cash. The company's stock (NASDAQ:DVAX) closed Wednesday at $4.06, down 5 cents.