The filing is based primarily on Phase 3 study results showing the unprecedented efficacy of REMICADE in the treatment of children with moderately to severely active Crohn's disease. In the REACH (a Randomized, Multicenter, Open-label Study to Evaluate the Safety and Efficacy of Anti-TNF Monoclonal Antibody REMICADE in Pediatric Subjects with Moderate to Severe Crohn's Disease) trial, nearly 90 percent (88.4 percent) of pediatric patients with moderately to severely active Crohn's disease who had an inadequate response to conventional therapy achieved clinical response at week 10 when treated with REMICADE. Nearly two-thirds (63.5 percent) of the patients who were randomized to treatment with REMICADE every 8 weeks were in clinical response at one year. Additionally, more than half of the patients treated with REMICADE every 8 weeks were in clinical remission at the end of one year.
"We are extremely pleased by the results of the REACH trial and by the FDA's decision to accept the application with a Priority Review," said Jerome A. Boscia, MD, Senior Vice President, Clinical Research and Development, Centocor, Inc. "REMICADE, if approved for the treatment of pediatric Crohn's disease, would represent a major advancement for children with this serious condition. We look forward to working closely with the FDA as it reviews these data for approval."
Priority Review is granted by the FDA to products that are considered to be a potential therapeutic advance over current therapies. Acceptance of the sBLA filing does not mean that a license has been issued for this indication nor does it represent any evaluation of the adequacy of the data submitted in the sBLA. REMICADE was FDA-approved in 1998 as the first biologic treatment for adults with moderate to severe Crohn's disease. In September 2005, REMICADE also became the first approved biologic treatment for moderate to severe ulcerative colitis (UC), making it the only biologic indicated for the treatment of both types of inflammatory bowel disease (IBD) in adults.
REACH was a randomized, multicenter, open-label study designed to evaluate the safety and efficacy of REMICADE in pediatric patients with moderate to severe Crohn's disease. Patients (n=112) aged 6 to 17 years with moderately to severely active Crohn's disease, despite treatment with an immunomodulator +/- corticosteroids, received REMICADE 5 mg/kg at weeks 0, 2 and 6. One hundred three patients were randomized at week 10 to receive REMICADE every 8 weeks (n=52) or every 12 weeks (n=51) through week 46. Ninety-nine of the 112 patients were in clinical response at week 10. Patients who lost response in the maintenance phase were eligible for a higher or more frequent dose of REMICADE. Baseline demographic and disease characteristics were similar between groups. The median patient age was 13 years.
Data from the REACH trial showed that 88 percent of patients treated with REMICADE 5 mg/kg at 0, 2 and 6 weeks achieved the primary end point of the trial, clinical response at week 10, which was defined as a decrease from baseline of at least 15 points in the Pediatric Crohn's Disease Activity Index (PCDAI), and a PCDAI less than or equal to 30. Significantly more patients randomized to the REMICADE maintenance regimen of one infusion every 8 weeks demonstrated clinical response and clinical remission at week 54 than those receiving REMICADE maintenance every 12 weeks, a comparison made to better understand the pediatric dosing regimen. Sixty-three percent of patients (33 of 52) receiving REMICADE every 8 weeks maintained clinical response after one year of treatment compared with 33 percent of patients (17 of 51) receiving maintenance therapy every 12 weeks (P = 0.002). At 54 weeks, 56 percent of patients (29 of 52) receiving REMICADE maintenance every 8 weeks were in clinical remission as assessed by a PCDAI score of less than or equal to 10, compared with 24 percent (12 of 51) in the every 12-week maintenance group (P < 0.001).
Additionally, some patients in the trial were able to reduce their corticosteroid dose. At baseline, the median average daily corticosteroid dose of randomized patients who were receiving corticosteroids was 0.4 mg/kg/day. By their first maintenance visit (week 14 for the every 8 week group and week 18 for the every 12 week group), at least half of the patients had discontinued corticosteroids, an important step for many with Crohn's who experience side effects as a result of corticosteroid use. The median changes from baseline in average daily corticosteroid dose at weeks 10, 30 and 54 were -0.2, -0.3 and -0.3 mg/kg/day, respectively. The change from baseline in average daily corticosteroid dose was significant (P < 0.001 for all comparisons).
In the REACH trial, patients were closely monitored, and the proportion of patients who experienced adverse events (AEs), serious adverse events (SAEs), serious infections, infusion reactions and immune responses were similar between the 8-week and 12-week REMICADE maintenance groups. Through the entire clinical trial, the most common SAEs were related to Crohn's disease. Infections were reported more frequently for subjects who received infusions every 8 weeks as opposed to every 12 weeks (73.6 percent and 38.0 percent, respectively), while serious infections were reported for 3 patients in the every 8 week and 4 patients in the every 12 week maintenance treatment group. As reported by investigators, infections were primarily upper respiratory infections, such as the common cold and bronchitis. Three patients developed antibodies to infliximab, and nine patients in each maintenance group experienced an infusion reaction; there were no serious infusion reactions. No deaths, malignancies, reactivation of latent tuberculosis, neurological disorders or autoimmune disorders were noted. Overall, the AEs were consistent with those seen in previous trials in adult patients. Please see Important Safety Information below. REMICADE has not been studied in patients with pediatric Crohn's disease six years of age or younger.
About Pediatric Crohn's Disease
Crohn's disease is a chronic illness that causes inflammation of the gastrointestinal tract, typically resulting in symptoms such as diarrhea, fever, abdominal pain and weight loss. Children with Crohn's disease may also experience delayed development and stunted growth. Although it can involve any area of the gastrointestinal tract from the mouth to the anus, it most commonly affects the small intestine and/or colon.
REMICADE is the global market leader among anti-tumor necrosis factor alpha (TNF-alpha) therapies and has demonstrated broad clinical utility in rheumatoid arthritis (RA), Crohn's disease (CD), psoriatic arthritis (PsA), ulcerative colitis (UC), and ankylosing spondylitis (AS). The safety and efficacy of REMICADE have been well established in clinical trials over the past 13 years and through commercial experience with more than 700,000 patients treated worldwide.
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 the treatment of 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.
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), and UC (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
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.
Patients with a specific type of lung disease called COPD (Chronic Obstructive Pulmonary Disease) may be at increased risk for cancer with REMICADE treatment. If you have COPD, you should discuss with your doctor whether REMICADE is appropriate for you.
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 full U.S. prescribing information, at www.remicade.com.
Centocor is harnessing the power of world-leading research and biomanufacturing to deliver innovative biomedicines that transform patients' lives. Centocor has already brought innovation to the treatment of Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and ulcerative colitis.
The world leader in monoclonal antibody production and technology, Centocor has brought critical biologic therapies to patients suffering from debilitating immune disorders. Centocor, Inc. is a wholly owned subsidiary of Johnson & Johnson.