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GUILFORD ANNOUNCES GLIADEL® WAFER PHASE III LONG-TERM SURVIVAL RESULTS IN PRIMARY BRAIN CANCER
Risk of Dying Over 3-4 Years Reduced 27% in Patients With High-Grade Malignant Glioma
BALTIMORE, MD, September 19, 2002 Guilford Pharmaceuticals Inc. today announced that it has completed an assessment of long-term survival in a Phase III clinical trial of GLIADEL® Wafer (polifeprosan 20 with carmustine implant) used at the time of initial surgery for patients with a high-grade malignant glioma. The results demonstrate that GLIADEL® Wafer reduces the risk of dying over 3-4 years after wafer implantation by 27% (p=0.017, unstratified log-rank test). GLIADEL® Wafer was used as an adjunct to conventional therapy, which consists of surgical removal of the tumor followed by radiation therapy.
"These data provide evidence of a long-term survival benefit when GLIADEL® Wafer is used during the initial surgical treatment of patients with a high-grade malignant glioma," remarked Craig R. Smith, M.D., Chairman and Chief Executive Officer. "In reviewing the data we used the same statistical analysis applied by the FDA in their prior review of our supplemental New Drug Application (sNDA). We believe this additional step is critical to our ongoing communication with the FDA and are pleased to announce further progress of this program."
Supplemental New Drug Application
In April 2001 Guilford submitted a supplemental New Drug Application (sNDA) to the United States Food and Drug Administration (FDA) seeking approval to expand the labeled indication for GLIADEL® Wafer to include use during initial surgery in patients with a high-grade malignant glioma.
In March 2002 Guilford received a non-approvable letter from the FDA concerning its supplemental New Drug Application. According to the FDA´s analysis, the hazard ratio for GLIADEL® Wafer treatment was 0.77, indicating a 23% reduction in the risk of dying with GLIADEL® Wafer treatment relative to placebo treatment, but the reduction in the risk of dying was not statistically significant (p=0.08, unstratified log-rank test). While the FDA made other points to support its conclusion, the non-approvable letter did not raise any issues concerning the safety or manufacturing of GLIADEL® Wafer.
In response to the non-approvable letter, Guilford met with the FDA´s review team to discuss possible responses to the non-approvable letter. Guilford proposed that it make best efforts to obtain an additional two years of follow-up through August 16, 2002 on as many of the 58 patients still alive in June 2000 as possible in the hope that the additional data would be responsive to FDA´s concerns regarding the survival benefit associated with GLIADEL® Wafer treatment.
Phase III Clinical Trial Design
The Phase III clinical trial was a randomized, double-blind, placebo-controlled study conducted at 38 centers in 14 countries. A total of 240 adult men and women undergoing initial surgical resection of a high-grade malignant glioma were enrolled and randomly assigned to receive implantation of either GLIADEL® Wafers or placebo wafers into the resection cavity followed by radiation therapy. Patients were enrolled in the trial from December 1997 to June 1999. The primary end-point for the trial was survival estimated by the Kaplan-Meier method and compared using the log-rank test. Follow-up for the Phase III clinical trial was completed in June of 2000, one year after enrollment of the last patient in the trial, and the results were presented at the Society for Neuro-Oncology meeting in November 2000.
Long Term Follow Up Results
Complete follow-up was obtained on 239 patients (99.6%) out of a total of 240 patients enrolled in the trial (one patient was lost to follow-up). By the end of the long-term follow-up protocol in August 2002, 228 patients were known to have died. Of the 11 patients known to be alive, 9 received GLIADEL® Wafer and 2 received placebo. During the 3-4 years of follow-up, the hazard ratio for GLIADEL® Wafer treated patients relative to placebo treated patients was 0.73 (95% CI: 0.56 to 0.95), indicating a reduction in the risk of dying of 27% (p=0.017, unstratified log-rank test). Pre-specified Cox proportional hazards models were used to estimate the treatment effect of GLIADEL® Wafer after accounting for the effects on survival of known prognostic factors (age, Karnofsky Performance Scores, and tumor type) or known sources of survival variability (country of treatment) and the results of the Cox models supported the results obtained from the log-rank test.
"Guilford has provided these data to the FDA for discussion," remarked Dr. Smith. "We look forward to working closely with the FDA to facilitate their review of the data."
About GLIADEL® Wafer
GLIADEL® Wafer is the only marketed cancer treatment capable of delivering chemotherapy directly to the site of a brain cancer, minimizing drug exposure to other areas of the body.
GLIADEL® Wafer is a small, white to off-white dime-sized wafer comprised of a biodegradable polymer (polifeprosan 20) incorporating 7.7 mg. of carmustine (BCNU), a chemotherapeutic agent usually administered intravenously to treat a malignant glioma. Up to eight GLIADEL® Wafers can be implanted in the cavity created when a surgeon removes a brain tumor. There, they slowly dissolve, releasing BCNU directly to the tumor site in high concentrations, while minimizing drug exposure to other areas of the body. GLIADEL® Wafer is currently indicated for use as an adjunct to surgery to prolong survival in patients with recurrent glioblastoma multiforme (GBM) for whom surgical resection is indicated.
About Primary Brain Cancer
Primary brain cancers are tumors that originate from cells normally found in the brain. The most common type of malignant primary brain cancer is a malignant glioma which is derived from the supporting cells in the brain called glial cells. The most common types of malignant glioma are glioblastoma multiforme (GBM), anaplastic astrocytoma, and oligodendroglioma. Glioblastoma multiforme is one of the most rapidly progressive and fatal forms of cancer. According to the American Brain Tumor Association, there are approximately 36,000 primary brain cancers diagnosed in the United States each year. Approximately 18,000 of these are malignant gliomas of which 8,000 are GBMs. Even with aggressive conventional treatment the typical patient with a high-grade malignant glioma lives less than one year after diagnosis. Guilford estimates that about 3,000 - 4,000 patients undergo re-operation for recurrent malignant glioma each year in the United States and approximately 8,000 12,000 patients undergo an initial resection of a high-grade malignant glioma.
Guilford Pharmaceuticals Inc. is a fully integrated pharmaceutical company that discovers, develops and markets novel pharmaceutical products targeting the hospital and neurological markets.