Washington Editor

WASHINGTON - With FDA advisors scheduled to vote today on Dendreon Corp.'s autologous cancer vaccine, Provenge (sipuleucel T), some signs are pointing to the probability of another trial to confirm past efficacy.

The active cellular immunotherapy product, which targets the prostate cancer antigen prostatic acid phosphatase (PAP), is designed to treat men with asymptomatic metastatic androgen independent prostate cancer (AIPC). One of many therapeutic cancer vaccines in development, some observers may be watching the advisory committee meeting for clues as to the future of similar products. To date, none have been approved.

Provenge is the first cellular-based therapeutic cancer vaccine to go before an FDA panel, and the agency is asking members of its Cellular, Tissue and Gene Therapies Advisory Committee to cover a range of issues that speak to its approvability.

The agency, which typically follows the advice of its panels, is scheduled to complete its review by May 15.

For Seattle-based Dendreon, the impact of a yea or nay vote is obvious: how quickly can Provenge get to market, if at all. Questions swirling around the biologics license application center on the product's effectiveness and safety, according to an FDA document released ahead of today's meeting. Of note, it failed to achieve the primary endpoint of time to disease progression, as well as all secondary measures, in the principal Phase III study underlying the company's submission.

Analyst Maged Shenouda of UBS wrote in a research note that he continues to believe that the FDA will require additional data "before final approval." Dendreon submitted the final portion of its rolling biologics license application for Provenge in November, three months after beginning the application process. (See BioWorld Today, Aug. 25, 2006.)

The agency's efficacy concerns are focused on the survival benefit found only in a 127-patient trial, called D9901, which FDA reviewers labeled a clinically meaningful survival difference that compares favorably with other therapeutic options in that disease.

An analysis showed a statistically significant 23 percent difference in three-year survival rates favoring Provenge over placebo (p=0.0046), and the median survival time in Provenge-treated patients was 25.9 months compared to 21.4 months in the placebo arm, a statistically significant difference of 4.5 months (p=0.012). In comparison, the chemotherapeutic agent Taxotere (docetaxel, Sanofi-Aventis Group), has produced a survival improvement of about two and a half months in prostate cancer patients.

But the reviewers cautioned that the persuasiveness of those results is limited because survival was neither a primary nor secondary endpoint in the study. In addition, the trial's small size raises the possibility that the finding could have occurred by chance, and the potential confounding effect of subsequent chemotherapy on survival cannot be ruled out, they said.

It's also worth noting that the survival benefit was far less in a second Phase III study with 98 patients, known as D9902A - 19 months on average. Already a larger study, called D9902B or IMPACT for "Immunotherapy for Prostate AdenoCarcinoma Treatment," is under way to further evaluate Provenge, with survival its primary endpoint. Time to progression is a secondary endpoint.

With regard to safety, the FDA reviewers highlighted concerns related to strokes. Collective findings from multiple trials showed that 3.9 percent of Provenge patients had cerebrovascular events compared to 2.6 percent of those on placebo, an increased frequency cited as a potential safety signal.

Given those multiple question marks, Shenouda said he believes a confirmatory Phase III trial, likely the ongoing IMPACT study, "may be necessary for a regulatory approval." That trial is designed to include 500 patients. He expects interim data sometime next year, an analysis to be triggered when an undisclosed number of deaths are reached, but final data aren't expected until 2010.

As of Dec. 31, Dendreon had about $121.3 million in cash, cash equivalents and short- and long-term investments. On Wednesday, its stock (NASDAQ:DNDN) gained 60 cents to $5.22, a 13 percent run-up.