BOSTON, MA — November 16, 1999 – Remicade™(infliximab), in combination with methotrexate, appeared to stop progression of rheumatoid arthritis (RA) in clinical trial patients, according to radiographic (x-ray) data presented here today at the annual meeting of the American College of Rheumatology. These findings from a controlled clinical trial are among the first to suggest that a drug can halt damage caused by rheumatoid arthritis, a chronic and debilitating disease that affects more than 2.5 million Americans.
“For decades, rheumatologists have searched for a medical therapy that can actually stop progression of rheumatoid arthritis. The data from this clinical trial could revolutionize the field of rheumatology,” said Dr. Peter Lipsky, (1), who was co-chairman of the Phase III Attract (Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy) trial while director of the Harold C. Simmons Arthritis Research Center at the University of Texas Southwestern Medical Center in Dallas. Dr. Lipsky presented the one-year x-ray findings from Attract at a symposium titled “Changing the Management of Rheumatoid Arthritis.”
In this study, prevention of structural damage was assessed using a modified Sharp score, which evaluates a combination of bone erosion and joint-space narrowing on a scale of 0-4 (higher score indicates more damage).
The data presented today found no median progression of joint damage from baseline (0.0 score) among all patients (n=285) treated with the combination of Remicade plus methotrexate compared to patients (n=63) treated with methotrexate alone (4.0 score). Year-one radiographic results found considerable progression of joint damage in patients receiving methotrexate alone. The methotrexate-only findings (control arm) represent a 7-to-8 percent deterioration in radiographic scores, which is comparable to that previously reported for patients with established rheumatoid arthritis treated with disease-modifying anti-rheumatic drug therapy, including methotrexate. Methotrexate is a standard treatment for rheumatoid arthritis.
Of those enrolled in the trial, 348 were included in the primary analysis. X-rays were taken of each patient at baseline, week 30 (30W) and week 54 (54W). Two experienced readers, who were blinded to patients and treatment arms, evaluated every x-ray. Each patient’s x-rays (baseline, 30W and 54W) were presented simultaneously and in random order and each reader individually calculated modified Sharp scores. The primary endpoint was the median change from baseline for each patient averaged between two readers.
X-ray data are from the one-year radiographic results of Attract , one of the largest studies ever conducted in patients with advanced rheumatoid arthritis. Attract is a double blind, placebo-controlled, randomized clinical trial of 428 patients at 34 clinical sites in North America and Europe. Four dosing regimens of Remicade plus methotrexate were compared to methotrexate alone (control).
The median duration of disease in trial patients was 8.4 years, and all patients were on methotrexate therapy with the majority for three or more years. More than one-third of all patients had previous joint surgery and approximately one half were classified as functional class three or four which indicates progressive and advanced disease. All patients were on stable doses of concomitant methotrexate, corticosteroids and nonsteroidal anti-inflammatory drugs.
“One of the most stunning aspects of this data is that patients treated with Remicade plus methotrexate achieved positive joint damage x-ray results regardless of whether they experienced relief from the signs and symptoms of the disease,” said Dr. Ravinder Maini, scientific director, Kennedy Institute of Rheumatology in London and co-chairman of Attract with Dr. Lipsky. “The Remicade data presented today suggest the need to establish new outcome measures for assessment of all therapies for rheumatoid arthritis.”
Based on Attract radiography data, Centocor, Inc. submitted in October a supplemental Biologics License Application (sBLA) to the Food and Drug Administration (FDA) seeking approval for the prevention of joint damage in patients with rheumatoid arthritis. If this submission is cleared for marketing, Remicade would be the first agent in a new class of drugs known as joint-damage arresting anti-rheumatic therapies (JDAART).
The most common adverse events in the Attract trial included upper respiratory tract infections, headache, nausea, sinusitis, rash and cough. There was no increased incidence of serious adverse events (11 percent with REMICADE and methotrexate vs. 16 percent with methotrexate alone) or serious infections (four percent with Remicade plus methotrexate vs. six percent with methotrexate alone). The incidence of infusion reactions was also low in REMICADE plus methotrexate patients (five percent) compared to those receiving methotrexate alone (two percent).
Tumor necrosis factor-alpha (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.
Approximately 2.5 million Americans — mostly women — suffer from rheumatoid arthritis, which is a chronic and often painful disease characterized by inflammation of the joints. Its initial symptoms include fatigue, joint pain and anemia. As the disease progresses, joints become swollen, inflamed and stiff. Rheumatoid arthritis usually begins with the hands, wrists, feet, knees and elbows, but often also attacks the shoulders, neck, hips and ankles. 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. This often occurs despite current therapy.
Many patients with rheumatoid arthritis will become physically disabled due to the joint erosion that occurs as the disease progresses. In fact, according to the American College of Rheumatology, 50 percent of patients with rheumatoid arthritis will be unable to work within 10 years of their initial diagnosis.
Remicade reduces inflammation in patients with Crohn’s disease and rheumatoid arthritis by binding to and neutralizing TNF-alpha on the cell membrane and in the blood. TNF-alpha is a key inflammatory mediator, or cytokine, in rheumatoid arthritis, Crohn’s disease and other autoimmune disorders. Overproduction of TNF-alpha leads to inflammation in these chronic conditions. A pioneer of TNF-alpha inhibitor technology, Centocor is among the world’s leading producers of monoclonal antibodies for therapeutic use.
On November 10, 1999, the FDA approved Remicade, in combination with methotrexate, for the reduction of signs and symptoms of rheumatoid arthritis in patients who have had an inadequate response to methotrexate. In the United States, Remicade is co-marketed by Centocor and Ortho-McNeil Pharmaceutical, Inc., both Johnson & Johnson subsidiaries, for rheumatoid arthritis. Remicade is also commercially available in the United States and Europe for use in patients with Crohn’s disease, a serious gastrointestinal disorder. Centocor, based in Malvern, Pa., manufactures Remicade.
Dr. Lipsky is scientific director of the Intramural Research Program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health in Bethesda, Md. The views expressed by Dr. Lipsky in this release do not necessarily represent those of the National Institutes of Health or the U. S. Department of Health and Human Services.
Source: Centocor and Ortho-McNeil Pharmaceutical, Inc.