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Trial Results Demonstrate Safety, Efficacy of Adalimumab To Induce Remission in Crohn's Disease

NEW ORLEANS, May 18 /PRNewswire-FirstCall/ -- New data presented this week at the Digestive Disease Week (DDW) annual meeting demonstrate that patients with moderate to severely active Crohn's disease treated with HUMIRA® (adalimumab) achieved remission and clinical response in two separate clinical trials. In one of the trials, a Phase III pivotal study designed to evaluate the efficacy and tolerability of HUMIRA to induce remission in patients with active Crohn's disease, treatment with HUMIRA induced a statistically significant increase in remission at four weeks compared to placebo.

HUMIRA is the first TNF antagonist since infliximab to achieve its primary endpoint of induction of clinical remission in moderate to severely active Crohn's disease in a placebo-controlled trial.

In a second, open-label, investigator-initiated study of Crohn's patients who had lost response to or became intolerant to infliximab, 59 percent of patients with moderate to severely active disease achieved clinical response at 12 weeks. HUMIRA was generally well tolerated, even in patients with previous reactions to infliximab.

"The results of these studies reinforce our confidence in our Crohn's development program for HUMIRA and our vision of HUMIRA as a pipeline in a drug," said Jim Lefkowith, M.D., divisional vice president, Development, Abbott Immunology.

Crohn's disease is a serious chronic and inflammatory disease of the gastrointestinal (GI) tract that affects approximately 500,000 Americans and is typically diagnosed before age 30. Common symptoms of the disease include diarrhea, cramping, abdominal pain, weight loss, fever, and in some cases rectal bleeding. Currently, there is no cure for Crohn's disease.

The CLASSIC Study

Results from the CLASSIC (CLinical assessment of Adalimumab Safety and efficacy Studied as an Induction therapy in Crohn's) trial will be presented Wednesday at DDW during the late-breaking clinical trial session. CLASSIC was a randomized, double-blind, placebo controlled study of 299 patients with moderate to severely active Crohn's disease (as measured by mean Crohn's Disease Activity Index, or CDAI, of 220-450) that compared three dosing regimens of HUMIRA against placebo. CDAI is a weighted composite score of eight clinical factors, including daily number of liquid or very soft stools, severity of abdominal pain, level of general well-being, presence of extraintestinal manifestations or abdominal mass, use of anti-diarrheal agents, hematocrit and decrease in standard body weight.

In the CLASSIC trial, one group of patients received placebo (n=74), and three other groups received one of the following HUMIRA dose regimens: 40 mg of HUMIRA at baseline, then 20 mg at week two (40/20 mg; n=74); 80 mg of HUMIRA at baseline, then 40 mg at week two (80/40 mg; n=75); or 160 mg of HUMIRA at baseline, then 80 mg at week two (160/80 mg; n=76).

The primary endpoint of the study was the induction of clinical remission (defined as a CDAI score of

At week four, 30 percent of the patients receiving HUMIRA (160/80 mg and 80/40 mg dose groups) were in clinical remission compared to 12 percent treated with placebo (p=0.004). Among the distinct dose groups, 36 percent of the patients in the 160/80 mg HUMIRA dose group (p=0.001) and 24 percent of the patients in the 80/40mg dose group (p=0.06) achieved clinical remission versus only 12 percent of patients on placebo. Fifty percent of the patients on the 160/80 mg dose of HUMIRA experienced a response to treatment versus 25 percent on placebo as defined by a decrease in CDAI of greater than or equal to 100 points (p=0.002) -- which many physicians believe to be a more stringent, clinically meaningful measure of response. Additionally, 60 percent of the patients in the 160/80 mg HUMIRA group experienced a decrease in CDAI score greater than or equal to 70 points, as did 59 percent of the patients receiving the 80/40 mg dose of HUMIRA, versus 37 percent of placebo patients (p

"The main goals for treatment of Crohn's are to induce remission, maintain that remission and improve quality of life for patients," said Stephen Hanauer, M.D., professor of medicine and clinical pharmacology, and director, Section of Gastroenterology and Nutrition, at the University of Chicago Hospitals. "These data are highly encouraging as we look to the potential of HUMIRA in treating this serious disease."

The rates of adverse events in the trial were generally low and comparable between HUMIRA and placebo. The most common adverse events were injection site reactions, most of which were mild.

Open-Label Study Information

In a separate open-label trial, researchers evaluated the efficacy and safety of HUMIRA in Crohn's patients who had lost response to or became intolerant to infliximab. This 12-week, uncontrolled trial included 24 of these difficult-to-treat patients. Nine patients were treated at the Mayo Clinic and 15 were treated at the University of Chicago with a baseline dose of 80 mg of HUMIRA at week 0. Starting at week two, patients received 40 mg HUMIRA every other week. At week four, patients were assessed for remission and response, at which point dosing could be adjusted to weekly administration of 40 mg HUMIRA as needed.

At week 12, of 17 patients with baseline CDAI scores of greater than or equal to 220, 29 percent achieved clinical remission, as measured by a CDAI score of

A fistula is a tunnel connecting one loop of intestine to another, or that connects the intestine to the bladder, vagina or skin. When a fistula develops, patients may notice drainage of mucus, pus or stool from this opening. Fistulas result from inflammation and subsequent damage to the intestine, and are a common complication in Crohn's patients.

HUMIRA was generally well tolerated in patients, including 14 who previously experienced treatment-limiting acute hypersensitivity reactions to infliximab and six who previously experienced delayed hypersensitivity reactions with infliximab.

"The results of this trial are encouraging for these difficult-to-treat patients with Crohn's disease who have lost their response to, or cannot tolerate infliximab," said William J. Sandborn, M.D., Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Medical School. "Moreover, because HUMIRA is subcutaneously injected, it not only can offer convenience for patients but also may avoid the potential infusion reactions associated with other biologics currently used to treat Crohn's."

Important Safety Information

Cases of tuberculosis (TB), frequently disseminated or extra pulmonary at clinical presentation, have been observed in patients receiving HUMIRA. Serious infections and sepsis, including fatalities, have been reported with the use of TNF-blocking agents, including HUMIRA. Many of these infections occurred in patients on concomitant immunosuppressive therapy that in addition to their underlying disease could predispose them to infections. Other invasive opportunistic fungal infections also have been observed in patients treated with TNF-blocking agents, including HUMIRA.

TNF-blocking agents, including HUMIRA, have been associated in rare cases with exacerbation of demyelinating disease. Lymphoma has been observed in patients treated with TNF-blocking agents. The most frequent adverse events seen in the placebo-controlled clinical trials in rheumatoid arthritis (HUMIRA vs. placebo) were injection site reactions (20 percent vs. 14 percent), upper respiratory infection (17 percent vs. 13 percent), injection site pain (12 percent vs. 12 percent), headache (12 percent vs. 8 percent), rash (12 percent vs. 6 percent) and sinusitis (11 percent vs. 9 percent). Discontinuations due to adverse events were 7 percent for HUMIRA and 4 percent for placebo. As with any treatment program, the benefits and risks of HUMIRA should be carefully considered before initiating therapy.

About HUMIRA

On Dec. 31, 2002, HUMIRA became the first fully human monoclonal antibody approved by the U.S. Food and Drug Administration (FDA) for reducing the signs and symptoms and inhibiting the progression of structural damage in adults with moderately to severely active rheumatoid arthritis (RA) who have had insufficient response to one or more disease modifying antirheumatic drugs (DMARDs). HUMIRA can be used alone or in combination with methotrexate or other DMARDs. The efficacy and safety of HUMIRA have been studied in 23 clinical trials and in more than 2,300 patients, making it the most-studied TNF antagonist for RA at the time of regulatory submission.

HUMIRA offers convenient every-other-week dosing by subcutaneous injection (shot beneath the skin) via a specially designed pre-filled syringe.

HUMIRA is the first fully human monoclonal antibody approved in Europe for RA, and the first tumor necrosis factor alpha (TNF-a) antagonist approved with an indication for use with methotrexate or as monotherapy. Last month, the European Medicines Evaluation Agency (EMEA) granted a positive opinion for a HUMIRA label extension for reducing the rate of progression of joint damage as measured by X-ray and improving physical function in adults with RA. To date, HUMIRA has been approved in 41 countries, launched in 26 (including the United States) and prescribed to more than 40,000 patients suffering from rheumatoid arthritis.

Clinical trials are also currently underway evaluating the potential of HUMIRA in other autoimmune diseases.

HUMIRA was discovered through a broad scientific collaboration between Abbott and Cambridge Antibody Technology (CAT). As part of the collaboration, Abbott had the right to select several target antigens for which a joint Abbott/CAT research team would discover human antibody therapeutics. HUMIRA was isolated and optimized by Abbott and CAT as part of this collaboration. Abbott owns exclusive worldwide rights to HUMIRA, including responsibility for clinical development, manufacturing, sales and marketing. Abbott will book all revenues for HUMIRA, and CAT will receive a royalty fee based on HUMIRA sales.

Source: Abbott Laboratories

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