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| |  Vesanoid Cleared for Marketing by FDA NUTLEY, N.J., Nov. 28, 1995 - As a result of more than 30 years of research, Roche Laboratories announced today that the U.S. Food and Drug Administration (FDA) has cleared for marketing in the U.S., a breakthrough treatment for a rare, deadly form of leukemia known as acute promyelocytic leukemia (APL). Vesanoid(R) (tretinoin, all-trans retinoic acid) (ATRA) is the first retinoid or vitamin A derivative to receive a cancer treatment indication in the U.S. Vesanoid is indicated for induction of remission of acute promyelocytic leukemia (APL) in patients who are refractory to or are contraindicated for anthracycline chemotherapy, or who have relapsed from anthracycline chemotherapy. "The sizable number of patients in relapse who responded to this drug in clinical trials is impressive and encouraging," said David Parkinson, M.D., Chief of NCI's Investigational Drug Branch. "The implications of Vesanoid's clearance by FDA is significant because it signals an important advance in oncology as it validates the use of a differentiation agent in cancer therapy." Vesanoid is distinct based on its unique mechanism of action which causes leukemic cells to "differentiate" to mature cells and be eliminated. Once the leukemic cells are differentiated and eliminated by Vesanoid, the body can produce healthy, maturing cells. APL is consistently associated with a chromosomal abnormality characterized by the translocation between chromosomes 15 and 17. This translocation is specific to APL and is the definitive marker for the disease. Side Effects/Adverse Reactions Patients should be observed for Retinoic Acid-APL (RA-APL) Syndrome which is characterized by fever, dyspnea, weight gain, radiographic pulmonary infiltrates and pleural or pericardial effusions. About 25% of patients treated with Vesanoid in clinical trials experienced RA-APL syndrome. Some deaths have occurred as a result of progressive hypoxemia. Although the management of RA-APL syndrome has not been defined rigorously, high-dose steroids given at the first suspicion of the RA-APL syndrome appear to reduce morbidity and mortality. APL patients who present with leukocytosis at diagnosis have an increased risk of life-threatening complications and concomitant treatment with full-dose anthracycline-based chemotherapy may be recommended. There is a high risk that a severely deformed infant will result if Vesanoid is administered during pregnancy. If, nonetheless, it is determined that Vesanoid represents the best available treatment for a pregnant woman or a woman of child bearing potential, it must be assured that the patient has received full information and warnings of the risk to a fetus. Virtually all patients on retinoid therapy experience side effects ranging in severity from cardiac arrhythmia to headache, fever, nausea, vomiting, rash, skin/mucous membrane dryness and bone pain. These side effects must be weighed against the life-threatening consequences of APL. Vesanoid is contraindicated in patients with a known hypersensitivity to retinoids. Vesanoid should not be given to patients who are sensitive to parabens, which are used as preservatives in the gelatin capsule. About APL APL is a catastrophic disease associated with life-threatening diathesis and is a distinct subset of acute myeloblastic leukemia (AML). Annually, about 800 new cases of APL are diagnosed in the U.S., and about 2,000 new cases are diagnosed worldwide. A small group of patients are contraindicated for traditional anthracycline-based chemotherapy because of concomitant medical diagnoses, mainly cardiac. In addition, a high proportion of patients (39 percent to 82 percent) will relapse from chemotherapy induced remission. Vesanoid has been studied in several open-label trials with these patients. Study data shows that the number of patients that experience a complete response is high (60 percent to 76 percent), resulting in dramatically longer survival when combined with additional chemotherapy. According to Raymond Warrell, M.D., Memorial Sloan-Kettering Cancer Center, "In clinical trials where all-trans retinoic acid was used, we saw a very substantial improvement in overall survival of APL patients, a striking decrease in morbidity and manageable toxicities." "For a company that has invested many resources and years in retinoid research, Roche is pleased to be the first to successfully introduce a differentiation-inducing drug on the market," said Robert Armstrong, M.D., Vice President of Medical Affairs for Roche. "Roche's commitment to oncology remains strong, as evidenced by the delivery of this novel class of therapeutics," Dr. Armstrong added. "More importantly, Vesanoid provides a new alternative therapy for patients with APL who are refractory to or have relapsed from chemotherapy." NDA Specifics Roche filed a New Drug Application for Vesanoid with the FDA in July 1994. Data for the NDA came from three open label clinical studies and the NCI's compassionate distribution program. A total of 369 APL patients were treated in these programs between 1990 and 1994. The U.S. clinical study was conducted by Dr. Warrell at Memorial Sloan-Kettering Cancer Center. Two additional studies were conducted at the Hopital Saint-Louis, Paris, France, and at Service des Maladies du Sang, Lille, France. The approval of Vesanoid represents the fourth novel therapeutic class of drugs Roche has developed in oncology. Roche pioneered the commercial development of the first cytokine, interferon alfa-2a in 1986 and the first cytotoxic chemotherapy agent, fluorouracil (5-FU) in 1962 as well as the antineoplastic, procarbazine, in 1965. As the first company to extensively explore retinoids, Roche has acquired a strong expertise in the chemical synthesis and biological function of this therapeutic class. Vesanoid is administered orally in 10 mg gelatin capsules at 45 mg/m2 daily until complete remission is achieved, for a maximum of 90 days. Chemically, Vesanoid is all-trans retinoic acid and is related to retinol (Vitamin A). See package insert for complete prescribing information. About Roche Laboratories Roche Laboratories is the pharmaceutical sales and marketing division of Hoffmann-La Roche Inc. and has a strong history in the area of oncology. One of the world's leading research-intensive health care companies, Roche has discovered, developed and introduced numerous important prescription pharmaceuticals. The company is also a major provider of diagnostic products and services, as well as vitamins, premixes and other products for human and animal nutrition and health. CONTACT: Alfred Wasilewski of Hoffmann-La Roche, 201-562-2231, or home, 201-762-7545, or e-mail, Alfred.Wasilewski@roche.com/
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