REMICADE® Achieves Mucosal Healing, Remission in Ulcerative Colitis

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COPENHAGEN, Denmark -- A pooled analysis from two landmark clinical trials in patients with active ulcerative colitis (UC) shows a majority achieved mucosal healing soon after treatment with REMICADE® (infliximab), with positive results maintained over time. More than 60 percent of patients achieved mucosal healing after eight weeks of treatment, with approximately 50 percent maintaining results at 30 weeks. A significantly higher number of patients treated with REMICADE also experienced clinical remission after weeks 8 and 30 compared to patients not responding adequately despite treatment with standard therapy (azathioprine and/or steroids). In addition, two sub-analyses of the ACT I and II trials showed that patients treated with REMICADE experienced 50 percent fewer hospitalizations compared to the control group and reported significant improvements in quality of life. The findings were presented for the first time in Europe today at the 13th United European Gastroenterology Week (UEGW) meeting.

"Results achieved with REMICADE in patients with UC were significantly better than results in patients receiving conventional therapy. These findings should raise our treatment expectations because they show greater success in achieving the long-term goals of healing and remission," said Paul Rutgeerts, MD, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium, and lead investigator of the ACT I study and hospitalizations sub-study. "Further data from these trials demonstrate not only clinical benefit of REMICADE for these patients, but also fewer hospitalizations."

Currently, there are no biologic therapies approved to treat moderate to severe UC in the European Union (EU), a chronic disease with significant impact on quality of life which affects over 700,000 people in Europe. Alternative treatments are limited and, if conventional treatments do not control the symptoms of the disease, many patients may have to face surgical removal of the colon.

"The symptomatic flare-ups of ulcerative colitis can be very debilitating for patients, affecting their ability to enjoy a normal lifestyle," said Brian Feagan, MD, Robarts Research Institute, University of Western Ontario, London, Canada, and lead investigator of the quality of life sub-study. "The significant improvements in quality of life for patients treated with REMICADE in our study demonstrate the promise this therapy holds for these patients."

Additional results of an extension of the ACT I trial (which included patients who completed treatment through week 46 of that trial) were also presented at a symposium during UEGW. At 54 weeks, REMICADE use in patients with UC was associated with maintenance of clinical response, clinical remission and mucosal healing, in addition to remission off steroids.

Schering-Plough markets REMICADE in all countries outside of the United States, except in Japan and parts of the Far East, where Tanabe Seiyaku, Ltd. markets the product, and in China where Xian-Janssen markets REMICADE. Centocor, Inc., a wholly owned subsidiary of Johnson & Johnson, has exclusive marketing rights to the product in the United States.

About ACT I and ACT II
ACT I and ACT II are multicenter, Phase III, randomized, double-blind, placebo-controlled, clinical trials conducted to evaluate the safety and efficacy of REMICADE for the treatment of active UC. A total of 728 patients were enrolled in ACT I (n=364) and ACT II (n=364) with active UC who were unresponsive to at least one standard therapy. In both trials, patients were randomized to receive placebo or REMICADE 5 mg/kg or 10 mg/kg at weeks 0, 2, 6 and every 8 weeks through week 22; the ACT I study continued to follow patients through week 46.

Significantly higher proportions of patients receiving REMICADE 5 mg/kg (61.2 percent) and 10 mg/kg (60.3 percent) achieved mucosal healing (as defined as an endoscopy subscore of 0 or 1) at week 8 versus placebo-treated patients (32.4 percent, both p<0.001). At week 30, 48.3 percent and 52.9 percent of patients receiving REMICADE 5 and 10 mg/kg, respectively, achieved mucosal healing versus 27.5 percent of placebo-treated patients (both p<0.001).

Additionally, at week 8, a significantly higher proportion of patients receiving REMICADE 5 mg/kg (25.2 percent) and 10 mg/kg (24.4 percent) had no evidence of active colitis versus placebo-treated patients (8.2 percent, p<0.001). At week 30, 27.7 percent and 30.6 percent of REMICADE 5 and 10 mg/kg treated patients, respectively, were free of active colitis versus 9.4 percent of placebo-treated patients (both p<0.001). At week 8, 36.4 percent and 29.8 percent of REMICADE 5 and 10 mg/kg treated patients, respectively, were in clinical remission versus 10.2 percent of placebo-treated patients (both p<0.001). The proportion of patients in clinical remission was similar at week 30: 29.8 percent and 36.4 percent of patients receiving REMICADE 5 mg/kg and 10 mg/kg, respectively, versus 13.1 percent of placebo-treated patients (both p<0.001).

At week 30, the proportion of REMICADE-treated patients who were in clinical remission was four-fold greater for patients with mucosal healing at week 8 (48.3 percent) than for patients without mucosal healing at week 8 (9.5 percent).

For both trials, REMICADE 5 mg/kg and 10 mg/kg dosages were well tolerated with a safety profile similar to that described in the label.

Hospitalizations
UC-related hospitalization data were collected and presented through week 30 and compared for both treatment groups. The mean number of hospitalizations was 50.0 percent lower in the combined REMICADE group than in the placebo group (9 vs. 18 per 100 patients, p<0.01). The percentage of patients hospitalized was lower in the combined REMICADE group versus the placebo group (9.1 percent vs. 13.9 percent, p<0.05). The time to first hospitalization was longer in the combined REMICADE group than in the placebo group (p<0.01). No notable differences were observed between the 5 mg/kg and 10 mg/kg groups or between the two trials, although ACT II showed a slightly greater REMICADE benefit.

Quality of Life
Health-related quality of life (HRQL) was assessed using the disease-specific inflammatory bowel disease questionnaire (IBDQ) and generic Short Form 36 questionnaire (SF-36) through week 30. Baseline scores for each questionnaire were similar among treatment groups. At both week 8 and week 30, the combined REMICADE group had significantly greater improvements (p<0.001) from baseline scores. There were no notable differences between the two trials or the two REMICADE groups.

54-Week Extension
REMICADE provided maintenance of mucosal healing in a greater proportion of subjects than placebo (p<0.001), and sustained response was attained in 37.9 percent of the REMICADE-treated subjects compared with 14 percent of placebo-treated (p<0.001). Further, sustained remission was attained in 20.2 percent of the REMICADE-treated subjects compared with 6.6 percent of placebo-treated (p<0.001). A greater proportion of REMICADE-treated subjects were in clinical remission and not receiving corticosteroids at week 54 (21.0 percent) compared with the placebo treatment group (8.9 percent; p=0.022).

About UC
UC is a chronic inflammatory bowel disease affecting more than 700,000 people in the European Union. It is marked by the inflammation and ulceration of the colon mucosa, or innermost lining, which causes bloody stools, severe diarrhea and frequent abdominal pain. Tiny open sores, or ulcers, form on the surface of the lining, where they bleed and produce pus and mucus. Because the inflammation makes the colon empty frequently, symptoms typically include diarrhea (sometimes bloody) and severe abdominal pain, often leading to unwanted weight loss, blood loss and a host of secondary complications. When conventional treatments do not control the symptoms of the disease, it is estimated that as many as 30 percent of UC patients will undergo a colectomy, which is a surgical removal of the colon.

About REMICADE
REMICADE is a monoclonal antibody that specifically targets TNF-alpha, which has been shown to play a role in Crohn's disease (CD), rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA) and psoriasis. REMICADE is the global market leader among anti-tumor necrosis factor alpha (TNF-alpha) therapies and the only agent approved for the treatment of both RA and Crohn's disease in North America, the EU and Japan.

In the European Union (EU), REMICADE is indicated for the treatment of severe, active CD in patients who have not responded despite a full and adequate course of therapy with a corticosteroid and an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies. REMICADE also is indicated for the treatment of fistulizing, active CD in patients who have not responded despite a full and adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy).

For RA patients in the EU, REMICADE, in combination with methotrexate, is indicated for the reduction of signs and symptoms as well as the improvement in physical function in patients with active disease when the response to disease-modifying drugs, including methotrexate, has been inadequate, and in patients with severe, active and progressive disease not previously treated with methotrexate or other DMARDs. In these patient populations, a reduction in the rate of the progression of joint damage, as measured by X-ray, has been demonstrated.

In the EU, REMICADE is also indicated for treatment of AS in patients who have severe axial symptoms, elevated serological markers of inflammatory activity and who have responded inadequately to conventional therapy.

In the EU, REMICADE, in combination with methotrexate, is approved for the treatment of active and progressive psoriatic arthritis (PsA) in patients who have responded inadequately to disease modifying anti-rheumatic drugs. In addition, in the EU, REMICADE is approved for the treatment of moderate to severe plaque psoriasis in adults who failed to respond to, or have a contraindication to, or are intolerant of other systemic therapy including cyclosporine, methotrexate or psoralen plus ultraviolet A light (PUVA).

REMICADE is unique among available anti-TNF biologic therapies. Unlike self-administered therapies that require patients to inject themselves frequently, REMICADE is the only anti-TNF biologic administered directly under supervision and monitoring of specialized physicians. In RA, CD, psoriatic arthritis and psoriasis patients, REMICADE is a two-hour infusion administered every eight weeks, following a standard induction regimen that requires treatment at weeks 0, 2 and 6. As a result, REMICADE patients may require as few as six treatments each year. In AS, REMICADE is a two-hour infusion (5 mg/kg) administered every six weeks, following a standard induction regimen that requires treatment at weeks 0, 2 and 6. The safety and efficacy of REMICADE have been well established in clinical trials conducted over the past 12 years and through commercial experience with more than half a million patients treated worldwide.

Important Information About REMICADE
Many people with heart failure should not take REMICADE; so prior to treatment you should discuss any heart condition with your doctor. Tell your doctor right away if you develop new or worsening symptoms of heart failure (such as shortness of breath or swelling of your ankles or feet). There are reports of serious infections, including tuberculosis (TB), sepsis and pneumonia. Some of these infections have been fatal. Tell your doctor if you have had recent or past exposure to people with TB. Your doctor will evaluate you for TB and perform a skin test. If you have latent (inactive) TB, your doctor should begin TB treatment before you start REMICADE. REMICADE can lower your ability to fight infections, so if you are prone to or have a history of infections, or develop any signs of an infection such as fever, fatigue, cough, or the flu while taking REMICADE, tell your doctor right away. Also tell your doctor if you have lived in a region where histoplasmosis or coccidioidomycosis is common.

There have been rare cases of serious liver injury in people taking REMICADE, some fatal. Contact your doctor immediately if you develop symptoms such as jaundice (yellow skin and eyes), dark brown urine, right-sided abdominal pain, fever, or severe fatigue.

Blood disorders have been reported, some fatal. Tell your doctor if you develop possible signs of blood disorders such as persistent fever, bruising, bleeding, or paleness while taking REMICADE. Nervous system disorders have also been reported. Tell your doctor if you have or have had a disease that affects the nervous system, or if you experience any numbness, weakness, tingling, or visual disturbances while taking REMICADE.

Reports of a type of blood cancer called lymphoma in patients on REMICADE or other TNF blockers are rare but occur more often than expected for people in general. People who have been treated for rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, or psoriatic arthritis for a long time, particularly those with highly active disease, may be more prone to develop lymphoma. Cancers, other than lymphoma, have also been reported. If you take REMICADE or other TNF blockers, your risk for developing lymphoma or other cancers may increase. You should also tell your doctor if you have had or develop lymphoma or other cancers while you are taking REMICADE.

Serious infusion reactions have been reported with REMICADE, including hives, difficulty breathing, and low blood pressure. Reactions have occurred during or after infusions. In clinical studies, some people experienced the following common side effects: respiratory infections (that may include sinus infections and sore throat), coughing, and stomach pain or mild reactions to infusion such as rash or itchy skin.

Please read important information about REMICADE, including EU prescribing information, at www.emea.eu.int.

About Schering-Plough
Schering-Plough is a global science-based healthcare company with leading prescription, consumer and animal health products.

Source: Schering-Plough

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