Genitope Corp. revealed that cancer vaccine MyVax missed its primary endpoint in a pivotal Phase III trial, failing to improve progression-free survival compared to control in patients with follicular B-cell non-Hodgkin's lymphoma (NHL).

Yet Dan Denny, Genitope's chairman and CEO, said during a conference call that he was "delighted" to give the final report on the "successful" trial and plans to use the data to file a biologics license application with the FDA.

Denny's optimism stemmed primarily from a pre-specified analysis showing that 39.5 percent of patients receiving MyVax mounted an immune response to the drug, and those patients demonstrated a statistically significant improvement in progression-free survival compared to the nonresponders and the control group (p<0.01 for both). The survival benefit didn't carry over into the overall trial population, Denny said, because of higher than expected survival in the control arm, which received the carrier protein KLH and the adjuvant GM-CSF.

Analysts were not convinced.

"We find management's optimism to be both outrageous and completely unwarranted," Jonathan Aschoff of Brean Murray, Carret & Co. wrote in a report.

Aschoff went on to note that Genitope pretreated all patients in the trial with chemotherapy and then randomized only those who had maintained at least a partial response for six months, potentially biasing the trial by selecting the healthiest patients. Additionally, the KLH and GM-CSF may have contributed to the response seen in the treatment arm as well as the control arm, raising questions about what role MyVax played, he said.

"MyVax simply does not work and, in our view, has absolutely no chance of reaching the market," he wrote, adding that the best possible outcome would be an approvable letter requesting another Phase III trial.

RBC Capital Markets analyst Jason Kantor was similarly pessimistic. He called the subgroup analysis "fundamentally flawed" because nonresponders to the drug fared worse than the control arm and can't be separated from responders. "A therapy that provides a benefit to 40 percent of patients but causes a worse outcome for the other 60 percent is illogical," if the two groups can't be prospectively identified, he wrote.

Kantor also noted that the survival benefit in the responder subgroup could be attributable to those patients having healthier immune systems to begin with, rather than to their treatment with MyVax. "With a single Phase III trial and failed primary endpoint, MyVax has little or no hope of getting FDA approval," he concluded.

Investors seemed to agree. They pushed shares of Fremont, Calif.-based Genitope (NASDAQ:GTOP) down $1.77, or 68 percent, to close at 82 cents on Friday. Interestingly, although the Phase III data were released after the market closed on Thursday, the company's shares dropped $1.44 late Thursday ahead of the news.

Genitope is certainly not the only company to face a late-stage setback with a therapeutic cancer vaccine, as CancerVax Corp., Antigenics Inc. and many others can attest. Yet the biotech industry seems to be getting closer to that elusive first FDA approval for the space.

Dendreon Corp. nearly pulled it off this summer, gaining a thumbs up from an FDA advisory committee for prostate cancer vaccine Provenge (sipuleucel T) before the agency dashed the company's hopes with a request for additional data. Provenge had missed its primary endpoint of time to disease progression in two Phase III trials, but later analyses showed overall survival benefits. (See BioWorld Today, June 1, 2007.)

An interim analysis for Dendreon's ongoing Phase III trial is expected in mid to late 2008, and positive findings could pave the way to approval. In the interim, three U.S. congressmen have urged an investigation into why the FDA didn't approve Provenge in the first place. (See BioWorld Today, Dec. 17, 2007.)

Also expected by mid-2008 are Phase III data on two additional NHL cancer vaccines: Favrille Inc.'s Specifid (formerly FavId) and Biovest International Inc.'s BiovaxID. Both products differ from MyVax, primarily in the way they are manufactured and in their trial designs.

While MyVax is a recombinant product manufactured in mammalian cells, Specifid is a recombinant product manufactured in insect cells. Data presented at this month's American Society of Hematology conference demonstrated that, in preclinical studies, the insect-generated approach resulted in a more immunogenic response.

Additionally, Favrille founder and chief scientific officer Daniel Gold told BioWorld Today that the Specifid Phase III trial uses pretreatment with Rituxan (rituximab, Genentech Inc. and Biogen Idec Inc.) rather than chemotherapy, includes patients who achieve responses or stable disease in pre-treatment, continues dosing indefinitely and does not include KLH in the control arm.

Favrille expects to report Phase III Specifid data by July 2008.

Meanwhile, BioVest reiterated on Friday that BiovaxID is a hybridoma-produced rather than recombinant product, and that it has demonstrated an 80 percent immune response in previous trials. The Biovax ID Phase III data are expected in April 2008.

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