Dendreon Announces Plans to Submit Application for FDA Approval
Update September 14, 2005
Dendreon Corporation announced plans to submit a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) to market Provenge®, the Company’s investigational immunotherapy for the treatment of advanced prostate cancer.
This decision follows a pre-BLA meeting in which the Company reviewed safety and efficacy data with the FDA from its two completed Phase 3 clinical trials of Provenge in patients with advanced prostate cancer. The outcome of these discussions determined that the survival benefit observed in the D9901 study in conjunction with the supportive data obtained from study D9902A and the absence of significant toxicity in both studies is sufficient to serve as the clinical basis of a BLA submission for Provenge.
As reported earlier this year, the final three-year follow up of the D9901 Phase 3 study of Provenge in 127 men with asymptomatic, metastatic, androgen-independent prostate cancer showed a median survival benefit of 21 percent or 4.5 months and a three-fold improvement in survival at 36 months for patients who were randomized to receive Provenge compared to placebo.
Final three-year follow up of the D9902A Phase 3 study of Provenge in 98 men with asymptomatic, metastatic, androgen-independent prostate cancer showed a 20 percent improvement in median survival for patients who were randomized to receive Provenge compared to placebo. In addition, at the three-year final follow up, the percentage of patients alive in the Provenge-treated group was substantially greater than the percentage of patients alive who received placebo.
In both studies, as in previous studies, Provenge was well tolerated with the most common adverse events reported being fever and chills lasting for one to two days.
PCRI Insights November, 2003 vol. 6, no. 4
In the October 2001 issue, Insights presented two articles by researchers from the Dendreon Corporation dealing with dendritic cell-based therapy that uses the body’s own immune system (primarily, antigen presenting cells (APCs), to treat men suffering from late-stage Androgen-Independent Prostate Cancer (AIPC). In the articles, Dendreon researchers predicted that prostate cancer could be the first cancer to benefit from an APC-based therapy. At that time, several vaccines for various cancers had reached Phase II clinical trials. Provenge®, an investigational vaccine developed by Dendreon Corporation, was the farthest along, having reached to Phase III testing, the D9901 trial. The following is a summary of the results to date and a review of the current pivotal trial as excerpted from recent news releases.
Clinical Trial Design and Data
In June 2003, Eric Small, M.D., principal investigator of the study and professor of medicine and urology at the University of California San Francisco, presented the results from the D9901 trial at the American Society of Clinical Oncology annual meeting.
The D9901 trial involved 127 men with late stage, metastatic AIPC, 82 of whom received Provenge®. The primary endpoint for the study was the time to objective disease progression. Comparison of the Provenge®-treated group to the placebo group using the Kaplan-Meier method revealed a clinical benefit in the Provenge® treated patients (p=0.061) that approached but did not achieve the pre-specified primary endpoint of the study (p = 0.05).
However, according to information supplied by Dendreon, analysis of the data for pre-specified variables revealed Gleason score as the single most important predictor of response to Provenge®. In patients with a Gleason score = 7 who received Provenge®, the likelihood of remaining progression free and free of cancer-related pain while on study was over twice that of men who did not receive Provenge®. In addition, those patients receiving Provenge® whose disease had not progressed six months after randomization, had a greater than eight-fold advantage in progression-free survival compared to those patients who received placebo (35.9% versus 4%). In contrast, the benefits of Provenge® therapy were not seen in patients with a Gleason score = 8.
“Gleason grade is the most powerful prognostic factor driving virtually all algorithms for pathologic outcome and clinical prognosis,” said Paul Schellhammer, M.D., professor and chief of urology at Eastern Virginia Medical School. “The majority of patients newly diagnosed with hormone resistant prostate cancer [AIPC] are graded in the 6 or 7 category. That Provenge® provided a statistically significant benefit for this cohort is a very encouraging finding.”
Immune response data collected from the D9901 trial showed that Provenge® treatment induced a highly significant T-cell mediated immune response compared to placebo (p=0.0003), with Provenge®-treated patients demonstrating an eight-fold increase in T-cell proliferation compared to placebo, Dendreon reported. In addition, among men treated with Provenge®, those with a Gleason score = 7 developed a median change in T-cell mediated immune response seven-fold greater than that seen in Provenge®-treated men with a Gleason score = 8 (p=0.0065). These results are consistent with, and support the biologic rationale of, the data from the D9901 Phase III Trial.
In September 2003, Dendreon announced preliminary survival data from D9901 that showed a median survival of 26.3 months in the patients randomized to Provenge® compared to 19.3 months in patients randomized to placebo who never received active therapy; a survival difference of seven months. Of the patients who were randomized to placebo and then had progression of their disease, 75% went on to receive active therapy in a crossover salvage protocol that accompanied the D9901 trial. The median survival in the patient population who received salvage Provenge® was 23.9 months.
“AIPC is a highly aggressive disease, with a survival time normally in the range of 15 to 19 months,” said Dendreon CEO, Mitchell H. Gold. “ And while this trial was not designed, nor powered, to measure survival, a potential survival benefit of seven months is substantial and meaningful for asymptomatic, metastatic AIPC patients who have failed all treatment options and have no other available therapy.”
Pivotal Trial Currently Underway
Provenge® is currently in a pivotal double blind, placebo-controlled Phase 3 trial, D9902B, seeking to confirm previous results that indicate the product may delay progression of disease and the development of disease-related pain. Dendreon has received a Fast Track designation for Provenge® from the FDA in addition to a positive assessment under the Special Protocol Assessment provision indicating that D9902B may serve as the basis for a Biologics License Application for Provenge®.
To be eligible for the Provenge® D9902B study, patients must have metastatic PC that has progressed following ADT and have a Gleason score = 7. Patients must also be free of PC-related pain. Information on Dendreon’s clinical trials is available at www.dendreon.com.