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FDA Approves Infliximab for Long-term Use in Crohn’s Disease Patients

MALVERN, PA -- (INTERNET WIRE) -- 04/03/2003 -- The U.S. Food and Drug Administration (FDA) granted marketing approval for REMICADE® (infliximab) for reducing the number of draining enterocutaneous and rectovaginal fistulas and for maintaining fistula closure in patients with fistulizing Crohn’s disease (CD). The new maintenance indication requires treatment every eight weeks, following an induction regimen in which patients receive doses at weeks 0, 2, and 6. Up to 30 percent of the estimated half-million Americans with CD have fistulas associated with their disease -- openings that extend through the bowel wall into nearby organs or through the surface of the skin. REMICADE is the worldwide market share leader among tumor necrosis factor alpha (TNF-alpha) therapies and is the only biologic drug indicated for the treatment of both CD and rheumatoid arthritis (RA).

“This indication further solidifies the important role REMICADE plays in the treatment of Crohn’s disease, particularly among those struggling with fistulas,” said Jerome A. Boscia, M.D., Vice President, Clinical Research & Development. “For many patients, REMICADE can reduce the number of fistulas, while potentially reducing the need for hospitalizations, and therefore, fills a significant unmet medical need. Centocor is delighted that the FDA’s Center for Biologics Evaluation and Research was able to review and approve this important treatment option within the six-month priority review cycle.”

In June 2002, the FDA approved REMICADE for use in inducing and maintaining clinical remission in patients with moderate-to-severe Crohn’s disease using maintenance dosing every eight weeks.

REMICADE is a monoclonal antibody that specifically targets and irreversibly binds to TNF-alpha on the cell membrane and in the blood. Overproduction of TNF-alpha is believed to play a role in CD and RA, in addition to a wide range of Immune-Mediated Inflammatory Disorders (I.M.I.D.) in which REMICADE is currently being studied.

ACCENT II Trial
The approval was based on a priority review of 54-week data from the ACCENT II trial, the largest clinical trial in fistulizing CD, which was conducted at 45 sites in North America, Europe and Israel. The FDA grants priority review status to products that are considered to be a potential significant therapeutic advance over existing therapies. The objective of the study was to evaluate the safety and efficacy of REMICADE in maintaining fistula closure when administered every eight weeks.

Study Design
Two hundred and ninety-six patients with draining enterocutaneous fistula(s), and in some cases rectovaginal fistulas, were enrolled in the trial and received 5mg/kg REMICADE at weeks 0, 2 and 6. Patients in fistula response at both weeks 10 and 14 were randomized to receive a maintenance dose of either placebo or 5 mg/kg REMICADE at week 14 and then every eight weeks through week 46. The primary endpoint was time from randomization to loss of fistula response. Concurrent use of stable doses of immunosuppressive and antibiotic therapy was permitted.

Of 273 patients randomized at week 14, 87 percent had perianal fistulas, 14 percent had abdominal fistulas and eight percent had rectovaginal fistulas.

At week 14, 65 percent (177/273) of patients were in fistula response. Patients randomized to REMICADE maintenance had a significantly longer time to loss of fistula response compared to the placebo maintenance group (greater than 40 weeks vs. 14 weeks, p=0.001). At week 54, 38 percent of REMICADE-treated patients had no draining fistulas compared with 22 percent of placebo-treated patients (p=0.02). Patients who had not achieved a response by week 14 were unlikely to respond to additional doses of REMICADE.

The ACCENT II study also evaluated the impact of REMICADE maintenance therapy on the number of hospitalizations per patient. Compared to placebo maintenance, patients on REMICADE maintenance had a trend toward fewer hospitalizations per patient.

The most common adverse events reported among all randomized patients were upper respiratory tract infection, abdominal pain and headache. Worsening of Crohn’s disease was the most commonly reported serious adverse event, occurring at an incidence of 9.7 percent in the placebo group and 2.9 percent in the REMICADE group.

“The approval of REMICADE for use in long-term therapy in fistulizing Crohn’s disease provides a new option for thousands of patients,” said Russell Cohen, M.D., Assistant Professor of Medicine, Co-director, Clinical Inflammatory Bowel Disease, The University of Chicago Medical Center. “This approval is good news for patients and the physicians who treat them.”

About Crohn’s Disease
CD is a chronic inflammatory bowel disorder that commonly affects the lower part of the small intestine and the large intestine and typically begins in late childhood or early adulthood. The disease causes inflammation of the gastrointestinal tract, usually resulting in symptoms such as diarrhea, fever, abdominal pain and weight loss. REMICADE is currently used to induce and maintain long-term remission-level control of the debilitating symptoms of CD. Patients interested in learning more about the new CD indication may contact a special toll-free hotline (1-866-870-1783) or visit www.remicade.com or contact the Crohn’s and Colitis Foundation of America at www.ccfa.org.

About REMICADE
REMICADE, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate.

REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. It is also indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in patients with fistulizing Crohn’s disease.

Important Information
Many people with heart failure should not take REMICADE; so, prior to treatment, patients should discuss any heart condition with their doctor. Patients should tell their doctor right away if they develop new or worsening symptoms of heart failure (such as shortness of breath or swelling of their feet).

There are reports of serious infections, including tuberculosis (TB) and sepsis. Some of these infections have been fatal. Patients should tell their doctor if they have had recent or past exposure to people with TB. Their doctor will evaluate them for TB and perform a skin test. If a patient has latent (inactive) TB, his or her doctor should begin TB treatment before starting REMICADE. If a patient is prone to or has a history of infections, currently has one, or develops one while taking REMICADE, he or she should tell his or her doctor right away. Patients should also tell their doctor if they have lived in a region where histoplasmosis or coccidioidomycosis is common, or if they have or have had a disease that affects the nervous system, or if they experience any numbness, tingling, or visual disturbances.

There are also reports of serious infusion reactions with hives, difficulty breathing, and low blood pressure. In clinical studies, some people experienced the following common side effects: upper respiratory infections, headache, nausea, cough, sinusitis or mild reactions to the infusion such as rash or itchy skin. Please read important information about REMICADE, including full prescribing information, at www.remicade.com.

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