FDA Expands Remicade Indication for Ulcerative Colitis

FDA Expands Remicade Indication for Ulcerative Colitis: Biologic Maintains Long-Term Clinical Remission and Mucosal Healing

Data Demonstrate Sustained Safety and Efficacy of Remicade

HORSHAM, Pa., October 19, 2006 -- Centocor, Inc. announced today that the U.S. Food and Drug Administration (FDA) has approved Remicade (infliximab) for maintaining clinical remission and mucosal healing in patients with moderately to severely active ulcerative colitis (UC), who have had an inadequate response to conventional therapy. The approval is based primarily on one-year data from the ACT 1 randomized, double-blind, multicenter, placebo-controlled clinical trial, which found that patients receiving Remicade were more than twice as likely to be in clinical remission at week 54 compared to placebo (35% vs. 17%, respectively). Furthermore, patients receiving Remicade were nearly three times as likely as patients in the placebo group to maintain clinical remission from their symptoms after one year (i.e., be in clinical remission at week 8, week 30, and week 54; 20 percent versus 7 percent, respectively). In addition, 45 percent of Remicade patients had mucosal healing at week 54 compared to 18 percent of patients in the placebo group.

"The data supporting this indication show that, in addition to helping ulcerative colitis patients achieve remission, Remicade is also effective in maintaining long-term remission and helping patients to discontinue use of corticosteroids," said Stephen B. Hanauer MD, Professor of Medicine at the University of Chicago Hospitals & Clinic and a study investigator of the ACT 1 and ACT 2 trials.

The efficacy of Remicade in the treatment of inflammatory bowel disease (IBD) is well established. Remicade was first approved in the United States for the treatment of Crohn’s disease (CD) in 1998 and later approved for the treatment of UC in September 2005. With this new expanded indication for maintenance therapy in UC, Remicade is now the only biologic indicated for inducing and maintaining clinical remission of both types of IBD.

An immune-mediated inflammatory disease (I.M.I.D.), UC affects more than 500,000 Americans and is characterized by inflammation and ulceration of the inner lining of the colon. UC symptoms can often include unwanted weight loss; severe, sometimes uncontrollable bloody diarrhea; fatigue and frequent abdominal pain. For some patients, symptoms may lead to surgical removal of the colon or to secondary complications such as colorectal cancer.

"This extended indication for Remicade is welcome news for UC patients who have failed other therapies," said Richard J. Geswell, President, Crohn’s & Colitis Foundation of America (CCFA). "For many of these patients, surgery had been the only option. With this new indication, patients for whom effective maintenance therapy is critical now have an additional therapeutic option that may reduce the need for surgical intervention."

Clinical Trial Information: ACT 1

The extended approval of Remicade for maintenance treatment of active, moderate-to-severe UC is based primarily on positive results seen in the ACT 1, randomized, double-blind, multicenter, placebo-controlled clinical trial.

In total, 364 patients with active UC who were unresponsive to at least one standard therapy (corticosteroids, immunosuppressants or 5-ASAs) were enrolled in the ACT 1 trial. Patients were randomized to receive placebo or Remicade 5 mg/kg or 10 mg/kg. Patients received the study agent at weeks 0, 2 and 6 and then every 8 weeks through week 46 and had their last evaluations at week 54.

In ACT 1, significantly higher proportions of patients receiving Remicade 5 mg/kg (69 percent) and 10 mg/kg (62 percent) achieved clinical response at week 8 versus placebo-treated patients (37 percent; P<0.001 for both). In addition, at week 30, 52 percent of patients in the 5 mg/kg and 51 percent of patients in the 10 mg/kg Remicade treatment group were in clinical response versus 30 percent of placebo-treated patients (P<0.001 and P<0.01, respectively). At week 8, 39 percent and 32 percent of patients treated with Remicade 5 mg/kg and 10 mg/kg, respectively, were in clinical remission compared with 15 percent of placebo-treated patients (P<0.001 and P<0.01, respectively). These differences in clinical remission rates persisted at week 30 (34 percent, 5 mg/kg; 37 percent, 10 mg/kg versus 16 percent, placebo; P<0.01 and P<0.001, respectively). Mucosal healing was achieved at week 8 in 62 percent and 59 percent of patients receiving Remicade 5 mg/kg and 10 mg/kg, respectively, versus 34 percent of placebo-treated patients (P<0.001 for both comparisons). This difference in mucosal healing was maintained at week 30 (50 percent, 5 mg/kg; 49 percent, 10 mg/kg versus 25 percent, placebo; P<0.001 for both). By week 30, the proportion of patients who were able to discontinue corticosteroids while being in clinical remission at week 30 was greater in both Remicade groups compared with the placebo group (24 percent, 5 mg/kg; 19 percent, 10 mg/kg; 10 percent, placebo; P=0.030 and P=0.125, respectively).

By week 54 of ACT 1, 45 percent of patients receiving 5 mg/kg and 44 percent of patients receiving 10 mg/kg Remicade achieved clinical response versus 20 percent for placebo (P<0.001 for both comparisons). A sustained response from week 8 through week 54 was seen in 39 percent of the 5 mg/kg and 37 percent of 10 mg/kg Remicade patients versus 14 percent for placebo (P<0.001 for both comparisons). In addition, by week 54, 35 percent of patients receiving 5 mg/kg and 34 percent receiving 10 mg/kg Remicade were in clinical remission versus 17 percent for placebo (P<0.01 for both comparisons). Sustained remission from week 8 through week 54 was seen in 20 percent of patients receiving 5 mg/kg and 10 mg/kg Remicade treatments versus a 7 percent sustained remission rate for placebo (P<0.01 for both comparisons). Forty-five percent of patients in the 5 mg/kg and 47 percent of patients in the 10 mg/kg Remicade treatment group had mucosal healing at week 54 of the ACT 1 trial versus 18 percent for placebo (P<0.001 for both comparisons), and 21 percent of patients receiving Remicade were able to discontinue corticosteroid use while being in clinical remission at week 54 versus 9 percent for placebo.

The serious adverse events reported in the trial were similar to those reported in previous Remicade clinical trials. (See Important Safety Information below).

About Remicade

Remicade is the global market leader among anti-tumor necrosis factor alpha (TNF-alpha) therapies and has demonstrated broad clinical utility in Crohn’s disease (CD), rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), plaque psoriasis, ulcerative colitis (UC), and pediatric Crohn’s disease (PCD). The safety and efficacy of Remicade have been well established in clinical trials over the past 14 years and with more than 770,000 patients treated worldwide through commercial experience.

In the U.S., 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 RA. Remicade is the only biologic indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active CD who have had an inadequate response to conventional therapy. Remicade is also indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in patients with fistulizing CD. In December 2004, Remicade was approved for reducing signs and symptoms in patients with active AS. In May 2005, Remicade was approved for reducing signs and symptoms of active arthritis in patients with PsA. Additionally, in September 2005, Remicade was approved for reducing signs and symptoms, achieving clinical remission and mucosal healing, and eliminating corticosteroid use in patients with moderately to severely active UC who have had an inadequate response to conventional therapy. This approval makes Remicade the first and only biologic approved for the treatment of moderate to severe UC. In addition, on May 19, 2006, Remicade was approved for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. This approval establishes Remicade as the first and only biologic therapy approved for the treatment of PCD. In August 2006, Remicade received the expanded indication for inhibiting the progression of structural damage and improving physical function in patients with psoriatic arthritis. Further, in September 2006, FDA approved Remicade for the treatment of adult patients with chronic severe plaque psoriasis.

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 by caregivers in the clinic or office setting. In RA (3 mg/kg), CD (5 mg/kg), PsA (5 mg/kg), psoriasis (5 mg/kg), UC (5 mg/kg), and PCD (5 mg/kg) Remicade is a two-hour infusion administered every 8 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 (5 mg/kg), Remicade is a two-hour infusion administered every 6 weeks, following a standard induction regimen that requires treatment at weeks 0, 2, and 6.

Important Safety Information

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 TB 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, flu or warm, red or painful skin while taking Remicade, tell your doctor right away. Also, tell your doctor if you are scheduled to receive a vaccine or if you have lived in a region where histoplasmosis or coccidioidomycosis is common.

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, psoriatic arthritis, or plaque psoriasis 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. Children and young adults who have been treated for Crohn’s disease with Remicade have developed a rare type of lymphoma that often results in death. These patients also were receiving drugs known as azathioprine or 6- mercaptopurine. 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 or if you have a lung disease called chronic obstructive pulmonary disease (COPD).

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, swelling of your ankles or feet, or sudden weight gain).

Reactivation of hepatitis B virus has been reported in patients who are carriers of this virus and are taking TNF blockers, such as Remicade. Some of these cases have been fatal. Tell your doctor if you know or think you may be a carrier of hepatitis B virus or if you experience signs of hepatitis B infection, such as feeling unwell, poor appetite, tiredness, fever, skin rash, and/or joint pain.

There have been rare cases of serious liver injury in people taking Remicade, some fatal. Tell your doctor if you have liver problems and 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, visual disturbances, or seizures while taking Remicade.

Allergic reactions, some severe, have been reported during or after infusions with Remicade. Signs of an allergic reaction include hives, difficulty breathing, chest pain, high or low blood pressure, swelling of face and hands, and fever or chills. Tell your doctor if you have experienced a severe allergic reaction. The most common side effects of Remicade are: respiratory infections (such as sinus infections and sore throat), headache, rash, coughing, and stomach pain.

Please read the Medication Guide for Remicade and discuss it with your doctor.

Source: Centocor

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