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| |  European Committee Recommends Use Of Remicade (Infliximab) With Methotrexate For Rheumatoid Arthritis KENILWORTH, NJ and MALVERN, PA -- October 10, 2000 -- The Committee for Proprietary Medicinal Products (CPMP) of the European Agency for the Evaluation of Medicinal Products (EMEA) has issued a positive opinion recommending approval of Remicade® (infliximab) with methotrexate for the improvement in physical function of patients with rheumatoid arthritis and a reduction in the rate of the progression of joint damage when the response to disease-modifying drugs, including methotrexate, has been inadequate. The CPMP opinion serves as the basis for a European Commission approval, which is typically issued in approximately three months. Commission approval of the centralized Type II variation for Remicade will result in one single Marketing Authorization with unified labeling that will be valid in all 15 EU-Member States. Remicade is currently marketed in the EU for rheumatoid arthritis, following the European Commission granting in June 2000 centralized marketing authorization to Remicade with methotrexate for the reduction of the signs and symptoms of rheumatoid arthritis in patients with active disease when the response to disease-modifying drugs, including methotrexate, has been inadequate. Remicade is also marketed in the EU for the treatment of Crohn's disease, a serious gastrointestinal disorder. Centocor, Inc. has exclusive marketing rights to Remicade in the United States. Schering-Plough Corporation has rights to market the product in all other countries throughout the world, except in Japan and parts of the Far East where the product will be marketed by Tanabe Seiyaku, Ltd. The centralized Type II variation application for Remicade for the improvement of physical function and the reduction in the rate of the progression of joint damage in rheumatoid arthritis patients is based on 102 week radiographic (x-ray) data from ATTRACT (Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy), a double-blind, placebo-controlled, randomized clinical trial involving 428 patients at 34 clinical sites. Structural joint damage (erosions and joint space narrowing) in both hands and feet was measured by the change from baseline in the total van der Heijde- modified Sharp score (0-440). The Health Assessment Questionnaire (HAQ; scale 0-3) was used to measure patients' average change from baseline scores over time in physical function. Based on x-ray data from the ATTRACT trial, a reduction in the rate of the progression of structural joint damage was observed in all infliximab groups at 54 weeks. The effects observed at 54 weeks were maintained through 102 weeks. ATTRACT, one of the largest clinical studies ever conducted in patients with advanced rheumatoid arthritis, studied the safety and efficacy of Remicade at 30, 54 and 102 weeks. All treated patients had active disease despite methotrexate treatment. At week 54, a higher percentage of patients in all infliximab treated groups had a significant reduction in signs and symptoms compared with methotrexate alone. This response was seen as early as two weeks and was maintained through 102 weeks of treatment. The CPMP recommendation is for the lowest dose studied in ATTRACT - 3 mg/kg at zero, two and six weeks, then every eight weeks thereafter. Patients enrolled in the ATTRACT trial were characterized as having disease that was particularly difficult to manage. The median duration of disease in trial patients was 8.4 years, and all patients were receiving methotrexate therapy. Half of the trial patients had been on methotrexate for three or more years. More than one-third of all patients had previous joint surgery, and half were classified as functional class 3 or 4, which indicates progressive and advanced disease. The one-year results from ATTRACT indicate that Remicade was generally well tolerated. The most common adverse events in the ATTRACT trial included upper respiratory tract infections, headache, nausea, sinusitis, diarrhea, cough and rash. There was no increased incidence of serious adverse events (17 percent with Remicade and methotrexate versus 21 percent with methotrexate alone) or serious infections (6 percent with Remicade plus methotrexate versus 8 percent with methotrexate alone). The incidence of infusion reactions in patients receiving Remicade plus methotrexate (4 percent) was comparable to that in patients receiving methotrexate alone (2 percent). It is estimated that 2.5 million people -- mostly women -- in Europe are affected by rheumatoid arthritis, which is a chronic and often painful disease characterized by inflammation of the joints. Its initial symptoms include fatigue, fever and anemia. As the disease progresses, joints become swollen, inflamed, painful and stiff. Rheumatoid arthritis usually begins with the hands, wrists, feet, knees and elbows, but often also attacks the shoulders, neck, hips and back. When inflammation persists or does not respond well to treatment, destruction of nearby cartilage, bone, tendons and ligaments can occur and lead to permanent disability. In the United States, Remicade was approved by the Food and Drug Administration (FDA) in November 1999 for use in combination with methotrexate for the treatment of rheumatoid arthritis patients who have had an inadequate response to methotrexate. In July 2000, the FDA Arthritis Advisory Committee recommended approval of Remicade in combination with methotrexate for reduction of joint damage in patients with rheumatoid arthritis. Remicade is also marketed in the United States for the short-term treatment of active and fistulizing Crohn's disease. Remicade is the first of a new class of agents for the treatment of rheumatoid arthritis that neutralizes a key inflammatory mediator called TNF- alpha. Overproduction of TNF-alpha leads to inflammation in chronic autoimmune conditions such as rheumatoid arthritis and Crohn's disease. It is believed that Remicade reduces inflammation in patients with rheumatoid arthritis by binding to and neutralizing TNF-alpha on the cell membrane and in the blood. TNF-alpha mediates inflammation and cellular immune response including response to infection. Serious infections, including sepsis and fatal infections, have been reported in patients receiving TNF-blocking agents. Many of the serious infections in patients treated with Remicade have occurred in patients on concomitant immunosuppressive therapy that, in addition to their Crohn's disease or rheumatoid arthritis, could predispose them to infections. Patients treated with Remicade may have an increased risk of infection. Caution should be exercised when considering the use of Remicade in patients with chronic infection or a history of recurrent infection. Remicade should not be given to patients with a clinically important, active infection. Patients who develop a new infection while undergoing treatment with Remicade should be monitored closely. If a patient develops a serious infection or sepsis, Remicade therapy should be discontinued. Related link: Remicade.
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