The question of whether cerebrovascular accidents signal potential safety problems with Dendreon's cellular-based therapeutic cancer vaccine Provenge will be one of the issues confronting FDA's Cellular, Tissue and Gene Therapies Advisory Committee during its March 29 meeting.

The company is seeking approval of Provenge (sipuleucel-T) for treating men with asymptomatic, metastatic, androgen-independent prostate cancer. Sipuleucel-T consists of peripheral blood mononuclear cells obtained from a patient and activated in vitro with a recombinant fusion protein. The product is infused intravenously into the patient to stimulate his immune system to fight the cancer. Provenge, which is the first therapeutic cancer vaccine to reach FDA, has a May 15 user date (¹ Also see "Dendreon's Provenge Therapeutic Cancer Vaccine Has A May 15 PDUFA Date" - Pink Sheet, 16 January, 2007.).

FDA is asking the committee to consider whether CVA events seen in clinical trials constitute a safety signal. In a safety review of data from three randomized studies involving AIPC patients, Dendreon found that 17 of 345 (4.9%) subjects receiving sipuleucel-T had CVAs, compared to three of 172 (2.6%) of those receiving a placebo. This represents a threefold increase by odds ratio (p=0.092) and an absolute increase of 2.8%.

Seven deaths among the 345 (2%) sipuleucel-T patients were attributed to CVAs, compared to two deaths among the 172 (1.2%) placebo patients - an absolute increase of 0.8%. "Although these differences did not reach statistical significance, the increased CVA frequency is a potential safety signal," CBER says in briefing material prepared for the committee.

The efficacy claim for Provenge also is raising questions at CBER. The committee is being asked to discuss "the persuasiveness of the efficacy evidence," since the BLA is based on two trials that did not meet any primary or secondary endpoints.

The primary basis for the claim is study D9901, which did not meet its primary objective of prolonged time to objective disease progression or any other pre-specified efficacy endpoint. The estimated median time to disease progression was 11 weeks in the treatment arm and 9.1 weeks in the placebo arm. The 1.9 week difference did not reach statistical significance, CBER noted. Because of the poor showing, a second companion trial (D9902A) with similar selection criteria and baseline characteristics was terminated early, so it was underpowered to meet the primary objective.

Dendreon is making an efficacy claim on the basis of a three-year survival analysis that found the median survival time for patients in the treatment arm of D9901 was 25.9 months compared to 21.4 months for the placebo arm. The 4.5 month difference reached statistical significance (p=0.01) by log rank test. However, the survival analysis was conducted as a follow-up safety review and its methodology was not pre-specified in the trial protocol.

Patients in the treatment arm of D9902A also had higher median survival times than those in the placebo arm - 19 months, compared to 15.7 months. While Provenge provided a higher median survival time in both studies, CBER's clinical review points out that participants in both arms of D9901 had about a six-month longer survival time than those in D9902A. "These observations increase the possibility that the survival difference in D9901 might be attributable to chance," CBER noted.

The center also will seek input on manufacturing issues with Provenge, especially the lack of consistency in the make-up of the product, as well as on how to conduct immune monitoring during future studies, whether antigen presenting cell function is the primary mode of action and whether CD54 expression is a measure of APC activation.

On March 28, Sanofi-Aventis announced it was getting into the therapeutic cancer vaccine race, acquiring a global license to develop and commercialize Oxford BioMedica's therapeutic cancer vaccine TroVax ( ² Also see "Sanofi Gains Therapeutic Cancer Vaccine TroVax In Deal With Oxford BioMedica" - Pink Sheet, 28 March, 2007. ).

- Cathy Dombrowski (c.dombrowski@elsevier.com)

FDA Raises Safety, Efficacy Concerns About Dendreon’s Cancer Vaccine Provenge

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