Aventis and Genta Incorporated presented results of their Phase 3 trial of Genasense (oblimersen sodium) Injection in combination with dacarbazine (DTIC) versus dacarbazine alone at the Oncologic Drugs Advisory Committee (ODAC) of the U.S. Food and Drug Administration (FDA). In the absence of increased survival, the committee voted that the evidence presented today did not provide substantial evidence of effectiveness, as measured by response rate and progression-free survival, to outweigh the increased toxicity of administering Genasense for the treatment of patients with metastatic melanoma who have not received prior chemotherapy. While the advisory committee's recommendation is not binding, the FDA will consider it as the agency completes its Priority Review of the New Drug Application (NDA) for Genasense.

"We strongly believe in the potential of Genasense and what it represents to patients with advanced melanoma," said Dr. Raymond P. Warrell Jr., Genta's chairman and chief executive officer. "We are committed to its ongoing development and we will work closely with the FDA to determine the appropriate next steps."

"Advanced melanoma represents a significant unmet medical need. While disappointing, the committee's vote underscores the complexities of treating this devastating disease," said Frank Douglas, MD, PhD, executive vice president of Drug Innovation and Approval and a Member of the Board of Management at Aventis. "We will work with our partners at Genta to address any outstanding questions from the FDA."

Genta filed its NDA for Genasense in December 2003 and was granted Priority Review. An FDA response on the Genasense NDA is expected by June 8, 2004. The NDA for Genasense is based on results from a Phase 3 randomized trial of Genasense plus dacarbazine in patients with advanced melanoma. The study - the largest randomized trial ever conducted for advanced melanoma - enrolled patients at 139 sites in nine countries. Investigators randomly assigned 771 patients who had not previously received chemotherapy to either Genasense plus dacarbazine or dacarbazine alone. Patients who received Genasense in addition to dacarbazine showed significant improvement across clinical measures; a 51 per cent improvement in median progression-free survival (74 days vs. 49 days); an improvement in durable response rate of = 6 months, (13 patients vs. 5 patients); and a 72 per cent increase in overall anti-tumor response rate (11.7 per cent vs. 6.8 per cent).

During the meeting, the company also presented additional information on complete responders that were not part of the original NDA submission, and that have not been confirmed by the FDA. Six additional patients were identified who achieved complete responses in the follow-up period in the Genasense plus dacarbazine group, yielding a total of 11 complete responses. In this update, no additional complete responders were identified in the dacarbazine alone group.

In a randomized clinical trial in which patients received Genasense combined with dacarbazine (n=371) compared to dacarbazine alone (n=360), the most frequent serious adverse event occurring in = 5 per cent of patients was fever (5.9 per cent vs. 3.1 per cent, respectively); the most frequent Grade 3 or 4 adverse events occurring in = 5 per cent of patients were neutropenia (21.3 per cent vs. 12.5 per cent respectively), thrombocytopenia (15.6 per cent vs. 6.4 per cent), leukopenia (7.5 per cent vs. 3.9 per cent), anemia (7.0 per cent vs. 4.7 per cent), and nausea (7.0 per cent vs. 2.5 per cent).

Genasense inhibits production of Bcl-2, a protein made by cancer cells that is thought to block chemotherapy-induced apoptosis (programmed cell death). By reducing the amount of Bcl-2 in cancer cells, Genasense may enhance the effectiveness of current treatments for advanced melanoma. Genta and Aventis are pursuing a clinical development program with Genasense evaluating its potential to treat various forms of cancer.

Advanced melanoma is the most deadly form of skin cancer because it has spread throughout the body forming secondary tumors. The incidence of melanoma has increased more rapidly than any other cancer, and has more than doubled in the last 30 years. According to the American Cancer Society, more than 55,000 cases of melanoma will be diagnosed in the U.S. in 2004. Melanoma is the number one cause of cancer death in the United States for women aged 25 to 29, and it ranks second in incidence to breast cancer in women aged 30-34. Globally, 132,000 melanoma skin cancers will occur globally every year, according to the World Health Organization.