The mid-game turnaround late last month by FDA panel members considering Dendreon Corp.'s cancer immunotherapy Provenge (sipuleucel T) has armchair bookies debating chances for approval by the May 15 PDUFA data, as other firms with similar products rode Dendreon's coattails.

Members of the Cellular, Tissue and Gene Therapies Advisory Committee voted 13-4 in favor of substantial evidence of the autologous therapy's efficacy, but ambivalence wasn't hard to find.

Dendreon has major chips on Provenge against asymptomatic, metastatic, hormone-refractory prostate cancer, a product that emerged from Dendreon's Antigen Delivery Cassette technology. Provenge deploys a recombinant form of prostatic acid phosphatase, an antigen found in 95 percent of prostate cancers.

At the start of 2006, the company let go about 15 percent of its work force from early stage research and development programs and general functions, freeing resources for new manufacturing and marketing jobs ahead of Provenge's hoped-for clearance.

Dendreon based the biologics license application on data from the rather small D9901A Phase III trial (127 patients), supplemented with results from the second Phase III study, called D9902A. The improvement in overall survival shown in the first trial was achieved by way of a secondary statistical analysis, which more than a few observers expected the FDA might doubt.

For Provenge, the marketed drug to beat is Taxotere (docetaxel), a chemotherapeutic for breast cancer and non-small-cell lung cancer from Sanofi-Aventis Group. Taxotere won approval in May for prostate cancer and has achieved a survival improvement of about two and a half months.

Will existing data take Dendreon all the way to the May 15 finish line with Provenge? The question is tricky. Officials at the firm point to survival benefit that increased over time in D9901A - 4.5 months compared to placebo (p=0.012), plus a 23 percent difference in three-year survival rates that favor Provenge over placebo (p=0.0046).

Survival is the key cancer endpoint, no doubt, but skeptics noted that it was measured in a post hoc analysis of Study D9901A, and Provenge missed the primary endpoint of time to progression in that trial as well as D9902A. But experts concede the surrogate might not be altogether valid, particularly with a biologic such as Provenge, which packs an efficacy punch at the end of the course of therapy (three administrations per month). In such a scenario, the farther-out survival endpoint becomes more valuable.

The FDA panel turned out much less jittery about Provenge's safety than some expected, voting 17-0 in favor. Serious adverse events between the placebo and Provenge arms proved similar, except that more cerebrovascular accidents (CVAs) showed up in the Provenge arm (5.4 percent vs. none). But when all available data were put together - including numbers from an ongoing study called D9902B - CVAs were found in 3.9 percent of Provenge patients versus 2.6 percent of those who got placebo, not shocking in an older, sick patient sector. In any case, Dendreon plans to get a better bead on CVA risk through a 3,000-patient safety trial that will assess results every six months for three years.

Panelists also seemed to brush aside the fact that both of the finished trials let patients get second-line chemotherapy and cross over from Provenge to chemotherapy - that is, patients in the Provenge placebo arm (given a frozen version at low doses) who showed objective disease progression could switch to the actual drug, and chemo was allowed.

More patients in the placebo group got chemo after progression than patients on Provenge (63 percent as compared to 53 percent), but an FDA check on the timing of the chemo in both patient groups led to the agency finding that survival was not significantly affected.

Importantly, the panel's advisors gave their blessing to Provenge only after FDA reviewers changed their question from whether the data backing Dendreon's BLA establishes the efficacy of Provenge to whether it provides "substantial evidence" of its efficacy.

Still, Cell Genesys Inc. (which has a prostate cancer immunotherapy called GVAX in Phase III for prostate cancer) took a 20 percent ride on the panel meeting's outcome, and Favrille Inc. (with a Phase III active immunotherapy product known as FavId for non-Hodgkin's lymphoma) rose almost as high. Genitope Corp., developing MyVAX in non-Hodgkin's lymphoma and leukemia, gained 12 percent. Last summer, Genitope lost almost half its stock value when the firm disclosed that the Phase III trial with MyVAX would last longer than expected.

For Dendreon, analysts at Lazard Capital Markets "continue to believe that a post-hoc analysis of two small trials will be insufficient for approval on May 15," wrote Joel Sendek in a research report. However, Lazard forecasts approval in 2009 if positive interim survival data emerge in the middle of next year from the ongoing D9902B trial (also known as IMPACT for "Immunotherapy for Prostate AdenoCarcinoma Treatment"). The study is expected to complete enrollment later this year.

Dendreon CEO Mitchell Gold said during a conference call with investors that D9902B "has been enrolling very well," with about 400 patients aboard. Typically they are added more slowly at the start of such studies, he pointed out, and Dendreon is "clearly on the upper end of the hockey stick, as far as enrollment goes.

Needham & Co. disagreed with Lazard, and predicted (with Gold) that the FDA would decide on Provenge by May 15, calling "increasingly likely" the possibility that regulators will clear Provenge with a Phase IV marketing commitment, though another approvable letter that demands further work is "still a possible outcome."

Dendreon's stock proved volatile - let's say jumpy - last week. But the gain through Provenge, if and when it happens, could be satisfying for Dendreon investors. About 55,000 potential patients await a safe drug that works well, and Needham estimated peak sales at $750 million.

Gold posited similar patient numbers in the U.S., and told investors during a conference call that the numbers in Europe "are not much different," though he was not certain about the patient population size in Asia. Although Dendreon aims to launch Provenge in the U.S., targeting urology and urologic oncology, but the firm will seek a partner for the overseas market.

"[We need] about 98 reps for the U.S. market, but if you look at the sales force as a whole, including the medical science liaisons and other support staff, it's about 125 individuals, which is something that I think is very easily managed," Gold said.