TRITON BIOSCIENCES FLUDARA I.V. NDA SUBMITTED

TRITON BIOSCIENCES FLUDARA I.V. NDA SUBMITTED two days after the drug's Treatment IND/Group C protocol approval on Nov. 20 for selected patients with refractory chronic lymphocytic leukemia (CLL). In a Nov. 28 release, Triton said that the NDA submission for the company's first therapeutic product "focuses on the treatment of CLL patients who have failed to respond to conventional therapies." Triton pointed out that 90% of all CLL cases (27,000 in the U.S.) "eventually become refractory."

Under the Treatment IND/Group C protocol, Triton estimated that 4,000 to 5,000 people with refractory CLL would be eligible for treatment with Fludara (fludarabine phosphate). Patients will be administered the drug intravenously in outpatient settings.

The Alameda, California-based Shell Oil Co. subsidiary gained exclusive development and marketing rights for fludarabine from the National Cancer Institute in 1984 and has been supplying the drug for NCI studies. Triton said that it will continue to provide NCI with fludarabine free of charge for patients participating in the Group C protocol. The product is manufactured for Triton by Detroit-based Ash Stevens.

In a Phase II study conducted at the University of Texas M.D. Anderson Cancer Center, 39 (57%) of 68 patients showed some response to treatment with fludarabine -- 9 (13%) achieved complete remission and 30 (44%) achieved substantial regression of the disease. Fludarabine was given at two dose levels during the study, with 19 patients receiving 25 mg/m and 49 patients receiving 30 mg/m daily for five days given as a 30 minute infusion. The study was published in the July 1989 journal of Blood.

One of the most common adverse reactions with fludarabine treatment was significant myelosuppression,including thrombocytopenia and neutropenia, which occured in 30% to 50% of patients. Nausea and vomiting occurred in 5% of patients. "Nausea and hair loss frequently experienced by patients taking other chemotherapy agents are uncommon with fludarabine phosphate," according to a press release issued by NCI.

"Initially, fludarabine was considered a dead drug, because there were devastating central nervous sytem toxicities in early clinical trials," NCI Clinical Investigations Branch Director Bruce Chesen, MD, noted. "Toxicities resulting from initial high doses have not been observed since the total dose was spread out over five days," the NCI release states.

Phase III studies are underway to study fludarabine in combination with conventional chemotherapies such as chlorambucil (Burroughs-Wellcome's Leukeran) and prednisone, as well as new chemotherapies such as deoxy-coformycin (DCF).

NCI plans in the next few months to begin a Phase III trial comparing fludarabine and chlorambucil separately and in combination in untreated CLL patients. One study of 19 untreated CLL patients conducted at M.D. Anderson found that fludarabine treatment alone resulted in complete remission for 32% of patients and partial remission in 43%.

Triton also has a recombinant beta interferon (Betaseron) currently in Phase III for AIDS and multiple sclerosis. The company's nucleoside analog AzdU for AIDS, which the company is developing in conjunction with the National Institute for Allergy and Infective Diseases, has entered Phase I clinicals.