Washington Editor

GAITHERSBURG, Md. - A majority of FDA advisors voted favorably on Dendreon Corp.'s autologous cancer immunotherapy, Provenge (sipuleucel T), following an examination of survival data on which the company relied for its biologics license application, and after the agency amended a question related to its efficacy.

"This is a historic day," CEO Mitchell Gold told BioWorld Today. "We've always believed in the role of Provenge in the cancer population."

Members of the Cellular, Tissue and Gene Therapies Advisory Committee voted 13-4 that there is substantial evidence of its efficacy, though a number of them conceded that they aren't yet fully convinced. FDA reviewers seemed equally torn.

"The discussion as a whole reflects the nature of the situation," Celia Witten, the director of the Office of Cellular, Tissue and Gene Therapies within the Center for Biologics Evaluation and Research (CBER), told reporters after the meeting. In other words, quick conclusions were hard to come by.

The product provides "a very strong suggestion of efficacy," said panel member Richard Alexander, who voted in favor of its effectiveness, but he added that the findings to support that belief aren't definitive. "I don't think it's 100 percent proven that it's efficacious," added fellow panelist Jeffrey Chamberlain, who also voted favorably.

In contrast, panelist Maha Hussain disagreed that "rushing to say this is OK now is of utmost urgency." There were suggestions of making Provenge available through an expanded access program, a sort of purgatory before approval, but Gold and others at Dendreon demurred on that proposal.

The FDA, which typically follows the advice of its panels, is scheduled to complete its review by May 15. Gold seemed bullish on Provenge's prospects in that final ruling, despite the conservative nature of the FDA these days, not to mention the political climate swirling around its every action. And given the uncertainty among agency's reviewers on the product's demonstrated efficacy to date, it seems hard to predict whether the FDA will approve it outright or down the road, after a larger study designed to more precisely measure its survival benefit generates data in a few years.

The ongoing Phase III study, called IMPACT, has accrued 400 of 500 planned patients, with data to be reported upon 360 events. But such a delay would assuredly prompt a good deal of consternation among advanced prostate cancer patients looking for more treatment options, some of whom spoke during the meeting's open public session. Each indicated a desire to use Provenge, even though the FDA questioned the strength of its efficacy as well as a safety signal related to strokes.

"We'll take the risk," said panelist Robert Samuels, a 13-year prostate cancer survivor who served as the committee's patient representative.

Not everyone has the stomach for such a possibility, though. "I wouldn't risk the stroke," said Steward Frazier, a 21-year prostate cancer survivor. "It's a trend that needs to be addressed." In the meantime, he told BioWorld Today that he'd prefer to continue to endure the negative side effects of the chemotherapeutic agent Taxotere (docetaxel, Sanofi-Aventis Group). But if the FDA approves Provenge, patients such as Samuels and Frazier would have another choice.

The FDA's dilemma stems from question marks on the relative strength of the data put forth by Dendreon. The Seattle company's vice president of clinical affairs, Mark Frohlich, said Provenge "conferred a large survival benefit which increased over time" in a 127-patient trial called D9901. Specifically, the study demonstrated a 4.5-month survival benefit for Provenge-treated patients compared to those on placebo (p=0.012), as well as a 23 percent difference in three-year survival rates favoring Provenge over placebo (p=0.0046).

Elizabeth Smith, Dendreon's vice president of regulatory affairs, labeled the survival endpoint "the most clinically relevant" measure of efficacy in cancer treatment, a declaration endorsed by FDA reviewers. "Overall survival is the most reliable cancer endpoint," said CBER's Ke Liu, "and usually the preferred endpoint."

But survival was measured in a post hoc analysis of Study D9901. In fact, it missed its primary endpoint of time to progression, as did a second Phase III trial known as D9902A. But admittedly, the jury is still out on the use of that surrogate. "Progression is difficult to measure," said Christopher Logothetis, a professor at MD Anderson Cancer Center who spoke on Dendreon's behalf. "Results are inconsistent."

That's especially true with a biologic such as Provenge, which exhibits a delayed effect near the tail end of its three administrations in a month as a single course of therapy, making distant endpoints such as survival more relevant.

Still, the FDA's concerns with Dendreon's survival conclusions cast a shadow of doubt on Provenge's benefit. Such "uncertainties exist regarding the persuasiveness" of the application, Liu said, because there are limitations in a post hoc analysis, not to mention the study's relatively small sample size as well as confounding factors such as patient crossovers and chemotherapy use.

However, Frohlich countered FDA worries that post-progression chemotherapy affects the survival results and added that Provenge's survival benefit was "not only clinically significant, but also statistically persuasive," meaning that the finding is "unlikely to be a false positive." In addition, he said multiple subsequent analyses found that no subpopulation contributed more heavily to the treatment effect than any other.

Nicole Provost, Dendreon's vice president of product development, pointed to increases in CD54 upregulation following the second and third doses of Provenge, suggesting "that the immune system may be responding" to treatment. She also linked the higher upregulation to survival, adding that the relationship persists after adjusting for prognostic factors.

Relative to safety worries related to strokes, the majority were not fatal and their event rate was similar to a comparison with a Medicare database of advanced prostate cancer patients. Panelists overwhelmingly supported its safety profile in a unanimous 17-0 vote, and Dendreon has proposed developing a pharmacovigilance plan with the FDA to monitor for strokes. Among other FDA worries, CBER's Keith Wonnacott said Provenge's manufacturing process has "implications for product quality and consistency," because the number of cells varies, as do the relative percentages of cells. In addition, agency reviewers and panelists expressed concern with the low numbers of minority patients enrolled in the studies, a concern in light of the stroke risk that's been raised. Only about 5 percent of the IMPACT study's recruited patients to date are of minority descent.

Trading of shares in Dendreon (NASDAQ:DNDN) was halted throughout the day.

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