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Executive Summary

LEDERLE LABS' ANTICANCER AGENT ISOVORIN APPROVAL RECOMMENDED by FDA's Oncologic Drugs Advisory Committee at its July 1 meeting. The committee voted 6-2 in favor of approving the new version of Lederle's folic acid antagonist, despite concerns about the small number of patients in the clinical trial. Isovorin (l-leucovorin) is indicated as an antidote for rescue after high-dose methotrexate therapy in osteosarcoma, to counteract effects of impaired methotrexate elimination, and in inadvertent methotrexate overdose. The product, for which an NDA was filed in December 1990, is made in injectable and oral formulations; the committee recommended that both be approved. Isovorin is a new, single-isomer version of Lederle's original methotrexate rescue therapy, Leucovorin Calcium. Information was presented from a clinical study of Isovorin in 16 patients with osteosarcoma compared with historical controls of 28 patients treated with the original leucovorin. The rareness of osteosarcoma made it difficult to construct a larger trial, Lederle told the committee. The company also presented results from extensive bioequivalence and pharmacokinetic studies in 116 healthy volunteers. The studies found that the remodeled Isovorin leucovorin, which includes only the biologically active I-isomer, provided the same efficacy and no more toxicity than the older, diasteroisomer version ("dl"-leucovorin), at half the dosage. L-leucovorin is purer than dl-leucovorin in that it lacks the inactive d-isomer and provides less inert matter for the renal system to process, Lederle Scientific and Medical Services Director Jerry Johnson told the committee. The new version represents a possible treatment advantage for renally-impaired chemotherapy patients, he said. The firm indicated that Isovorin will be priced comparably to Leucovorin Calcium. Lederle VP-Oncology Group Mike Marquard said that although the company is "in the process of determining our pricing, I think we can say at this point that it will essentially be equivalent to the current product." Marquard was responding to a concern raised by committee members Harold Harvey, PhD, Hershey, Pennsylvania University Hospital, and Nancy Kemeny, MD, Sloan- Kettering Cancer Center, who cited the high medical costs already faced by osteosarcoma patients. Lederle also has an NDA pending for Isovorin for combination use with 5-FU chemotherapy for treatment of metastatic colon cancer. Isovorin's approval for either the osteosarcoma or the colorectal cancer indication would give Lederle an exclusive version of a compound that has multiple generic competitors. Companies that currently market leucovorin products include Burroughs Wellcome (Wellcovorin), Barr, Elkins-Sinn, Quad, Par and Cetus-BenVenue.

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