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| |  FDA Committee Recommends Enbrel (etanercept) for Early Rheumatoid Arthritis GAITHERSBURG, MD -- April 12, 2000 -- The U.S. Food and Drug Administration's Arthritis Advisory Committee today unanimously recommended approval of Enbrel (R) (etanercept) for use to delay radiographic progression of joint damage in patients with early rheumatoid arthritis (RA), and voted in favor of approval of Enbrel for use to improve signs and symptoms of patients with early stage disease. The panel's recommendations today were based on data presented by officials of Immunex the bulk of which were the radiographic and clinical results of a phase III randomized, double-blind, multi-center trial that included 632 adults who had RA for less than three years and had never been treated previously with methotrexate. The 632 participants in the Enbrel "ERA" study were randomized to receive either 25 mg or 10 mg of Enbrel, or up to 20 mg of methotrexate per week for 12 months. To ensure blinding of study treatments, patients received both injections and pills: Enbrel by injections twice weekly plus placebo pills weekly or methotrexate pills weekly plus placebo injections twice weekly. Patients enrolled in this study had RA for a relatively short time (mean of 1 year), and had very active disease (mean tender and swollen joint counts of 30 and 24, respectively, and reported a mean duration of four hours of morning stiffness). All patients had risk factors for rapidly progressive, erosive RA including the presence of rheumatoid factor and or erosions on baseline x-rays of the hands, wrists and feet.
The ability of Enbrel and methotrexate to delay joint damage characteristic of RA was assessed using radiographic (x-ray) criteria, measured by the modified total Sharp scoring method, a validated method used in clinical trials to quantify progression or lack thereof, of joint destruction. Radiographs of the hands/wrists and feet of each patient were obtained at baseline and at six and 12 months. Digitized images of each radiograph were scored by two of six physicians (five radiologists and one rheumatologist) who were trained in the modified total Sharp scoring method. The assessors were blinded to study treatment and the chronological order of the images. The modified total Sharp scoring method required seventeen joints of each hand/wrist and six joints of each forefoot to be scored for erosions on a scale from zero (no damage) to five. Sixteen joints of each hand/wrist and five joints of each forefoot were also scored for joint space narrowing on a scale of zero (no damage) to four. The erosion score and the narrowing score were added to determine the total Sharp Score (TSS). The co-primary endpoint of the study was the effect on markers of activity of RA as measured by the ACR-N AUC, which uses the American College of Rheumatology standard composite scoring method including: assessment of 71 joints for tenderness and 68 joints for swelling; a physician's and patient's global assessment of disease; a patient's assessment of pain, using a visual analog scale; a patient's assessment of disability (Health Assessment Questionnaire); and blood serum levels of ESR and CRP. Each patient is assigned an actual percent improvement from baseline on these criteria on each visit (the ACR-N). The ACR-N AUC represents the average amount of improvement over all of the visits for each patient. The mean ACR-N AUC for the patients in each group is used to compare the groups. The FDA approved Enbrel on November 2, 1998 to treat moderately to severely active rheumatoid arthritis in patients who have an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs). The FDA included children and teen-agers (age four to 17 years) in the Enbrel label when it granted the drug a new indication on May 28, 1999 for the treatment of moderately to severely active polyarticular-course juvenile rheumatoid arthritis patients who have had an inadequate response to one or more DMARDs. In postmarketing use, serious infections and sepsis, including fatalities, have been reported. Many of these events occurred in patients predisposed to infections, such as those with advanced or poorly controlled diabetes. Discontinue Enbrel in patients with serious infections or sepsis. Do not start Enbrel in the presence of sepsis, infection (including chronic or localized), or allergy to Enbrel or its components. Use caution in patients predisposed to infection. The most frequent adverse events in adult clinical trials in rheumatoid arthritis (n=349) were injection site reactions (isr) 37 percent, infections (35 percent) and headache (17 percent ). Malignancies were rare (+> 1 percent). Only the rate of isr was higher than placebo. In a JRA study (n=69), infections (62 percent), headache (19 percent), abdominal pain (19 percent), vomiting (13 percent) and nausea (9 percent) occurred more frequently than in adults. The types of infections reported in JRA patients were generally mild and consistent with those commonly seen in outpatient pediatric populations. Serious adverse reactions reported rarely were varicella (3 percent), gastroenteritis (3 percent), depression/personality disorder (1 percent), cutaneous ulcer (1 percent), and esophagitis/gastritis (1 percent). The first in a new class of rheumatoid arthritis (RA) drugs known as biologic response modifiers, Enbrel is an entirely new approach to the management of rheumatoid arthritis. Enbrel acts by binding tumor necrosis factor (TNF). TNF is one of the dominant cytokines or proteins that play an important role in the cascade of reactions that cause the inflammatory process of RA. Enbrel competitively inhibits the binding of TNF molecules to the TNF (TNFR) sites. The binding of Enbrel to TNF renders the bound TNF biologically inactive, resulting in significant reduction in inflammatory activity. Immunex Corporation and Wyeth-Ayerst Laboratories, division of American Home Products Corporation market Enbrel in North America. Other Wyeth-Ayerst affiliates will market Enbrel outside of North America. Immunex is a biopharmaceutical company dedicated to developing immune system science to protect human health. The company's products offer hope to patients with cancer, inflammatory and infectious diseases. American Home Products Corporation's Wyeth-Ayerst division is a major research-oriented pharmaceutical company with leading products in the areas of women's health care, cardiovascular disease therapies, central nervous system drugs, anti-inflammatory agents, vaccines and generic pharmaceuticals. American Home Products owns a majority interest in Immunex. AHP is one of the world's largest research-based pharmaceutical and health care products companies. It is a leader in the discovery, development, manufacturing and marketing of prescription drugs and over-the-counter medications. It is also a leader in vaccines, biotechnology, agricultural products and animal health care. Related Links: Enbrel (etanercept), Immunex Corporation, Wyeth-Ayerst Laboratories and American Home Products Corporation.
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