Healthcare Industry News: Methotrexate
News Release - January 30, 2006
European Union CHMP Recommends Approval of REMICADE(R) for Treatment of Moderately to Severely Active Ulcerative ColitisFirst Positive Opinion of Its Kind Recommending Approval of Biologic for Treatment of Moderately to Severely Active Ulcerative Colitis
HORSHAM, Pa. and KENILWORTH, N.J., Jan. 30 (HSMN NewsFeed) -- Centocor, Inc. and Schering-Plough Corporation (NYSE: SGP ) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) issued a positive opinion recommending the approval of an expanded indication for REMICADE®(infliximab). The expanded indication would include treatment of moderately to severely active ulcerative colitis (UC) in patients who have had an inadequate response to conventional therapy, including corticosteroids and 6-MP or AZA, or who are intolerant to or have medical contraindications for such therapies. Currently, there are no biologic therapies approved to treat moderately to severely active UC in the European Union (EU), hence patients have limited treatment options.
"The CHMP's positive opinion represents a milestone in the treatment of ulcerative colitis where an unmet need in effective therapy currently exists," said Robert J. Spiegel, M.D., chief medical officer and senior vice president of medical affairs, Schering-Plough Research Institute. "In the pivotal clinical studies, patients receiving REMICADE achieved high rates of clinical response and clinical remission as well as mucosal healing and reduced rates of hospitalization. These are excellent results for this patient population that had failed available therapeutic options."
The CHMP recommendation is an important step towards a European Commission approval. A Commission approval of the application will result in Marketing Authorization with unified labeling that will be valid in all EU-member states, including the current 25 member states as well as Iceland and Norway.
The positive opinion for REMICADE for UC is based on data from the ACT 1 and ACT 2 clinical trials. ACT 1 and ACT 2 were multicenter, Phase 3, randomized, double-blind, placebo-controlled, clinical trials conducted to evaluate the safety and efficacy of REMICADE for the treatment of adult patients with moderately to severely active UC who experienced an inadequate response to conventional therapy. A total of 728 patients with active UC who were unresponsive to at least one standard therapy, including corticosteroids, other immunosuppressants, or 5-ASAs, were enrolled in ACT 1 (n=364) and ACT 2 (n=364). Patients in ACT 1 and ACT 2 had endoscopic evidence of moderately to severely active UC (total Mayo score of 6 to 12) and an endoscopy sub-score greater than or equal to 2. ACT 1 patients received treatment with placebo or REMICADE 5 mg/kg or REMICADE 10 mg/kg at weeks 0, 2 and 6 and then every eight weeks through week 46 and had their last evaluation at week 54. ACT 2 patients received treatment with placebo or REMICADE 5 mg/kg or REMICADE 10 mg/kg at weeks 0, 2, and 6 and then every eight weeks through week 22 and had their last evaluation at week 30. In these studies, the primary assessments of efficacy were based on clinical response, defined as a decrease from baseline in the Mayo score by greater than or equal to 30 percent and greater than or equal to 3 points, accompanied by a decrease in the rectal bleeding subscore of greater than or equal to 1 or a rectal bleeding subscore of 0 or 1, and clinical remission, defined as a Mayo score less than or equal to 2 points, with no individual subscore > 1. Based on this definition, patients in clinical remission will have a rectal bleeding subscore of 0 or 1.
In ACT 1, at week eight, 69 percent of patients in the REMICADE 5 mg/kg group and 62 percent of patients in the REMICADE 10 mg/kg group were in clinical response, compared with 37 percent of patients in the placebo group (P < 0.001 for both comparisons). In ACT 2, at week eight, 65 percent of patients in the REMICADE 5 mg/kg group and 69 percent of patients in the REMICADE 10 mg/kg group were in clinical response compared with 29 percent of patients in the placebo group (P < 0.001 for both comparisons).
The proportions of patients who achieved clinical response or clinical remission at weeks eight and 30 in ACT 1 and ACT 2 and at week 54 in ACT 1 were significantly greater among the REMICADE 5 mg/kg and 10 mg/kg treated patients than placebo-treated patients (P < 0.01 for all comparisons with placebo). The rates of clinical response were similar between the corticosteroid-refractory and corticosteroid-responsive subgroups. For both studies, the proportions of patients with sustained clinical response or sustained clinical remission were significantly higher in each REMICADE group than in the placebo group (P <0.01 for all comparisons with placebo). Additionally, the proportion of REMICADE 5 mg/kg and 10 mg/kg treated patients who achieved mucosal healing at weeks eight and 30 (in ACT 1 and ACT 2) and at week 54 (in ACT 1) was significantly greater than that for the placebo-treated patients (P <0.01 for all comparisons with placebo).
Furthermore, 61 percent of the patients in ACT 1 and 51 percent of the patients in ACT 2 were receiving corticosteroids at baseline. The baseline median daily corticosteroid dose was 20 mg per day in both studies. Of the patients who were receiving corticosteroids at baseline, the proportion of patients who were in clinical remission and had discontinued corticosteroids at week 30 was significantly greater in the 5 mg/kg REMICADE group (24 percent for ACT 1 and 18 percent for ACT 2) versus the placebo group (10 percent and 3 percent, respectively) (P = 0.030 for ACT 1 and P = 0.010 for ACT 2). Additionally, at week 54 in ACT 1, 26 percent of patients receiving REMICADE 5 mg/kg were in clinical remission and had discontinued corticosteroids versus 9 percent of patients receiving placebo (P = 0.006). This outcome is important for patients with UC who may experience considerable morbidity as a result of corticosteroids.
"These results highlight the promising benefits of REMICADE for the treatment of UC," said William J. Sandborn, MD, professor of medicine, Mayo Clinic College of Medicine, head of the Inflammatory Bowel Disease (IBD) Interest Group, director of the IBD Clinical Research Unit at Mayo Medical Center, and lead study investigator on one of the two Phase III clinical trials. "These data demonstrate that many patients treated with REMICADE experienced not only a reduction in symptoms but had remission of their colitis and mucosal healing, findings that support a new therapeutic approach and standard of care for physicians and their UC patients."
The serious adverse events reported in these trials were similar to those reported in previous REMICADE clinical trials. See Important Safety Information below.
UC is a chronic inflammatory bowel disease affecting more than 700,000 people in the EU. 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 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. It is estimated that as many as 30 percent of UC patients will undergo a colectomy, which is a surgical removal of the colon.
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), psoriasis and ulcerative colitis (UC). 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 CD in North America, the EU and Japan. The safety and efficacy of REMICADE have been well established in clinical trials over the past 13 years and through commercial experience with nearly 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. On May 13, 2005, REMICADE was approved for reducing signs and symptoms of active arthritis in patients with PsA. Additionally, on September 15, 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 the 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 the treatment of AS in patients who have severe axial symptoms, elevated serological markers of inflammatory activity and who have responded inadequately to conventional therapy. REMICADE, in combination with Methotrexate, is also approved for the treatment of active and progressive PsA in patients who have responded inadequately to disease modifying anti-rheumatic drugs. Additionally, in September 2005, REMICADE was approved in the EU 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 PUVA (psoralen plus ultraviolet A light).
REMICADE is the only anti-TNF biologic therapy available as an IV form. 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) 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 to 8 weeks, following a standard induction regimen that requires treatment at weeks 0, 2 and 6.
Centocor discovered REMICADE and has exclusive marketing rights to the product in the United States. 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.
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.
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 US prescribing information, at http://www.remicade.com. For complete EU prescribing information, please visit http://www.emea.eu.int.
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.
(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from Johnson & Johnson's expectations and projections. Risks and uncertainties include general industry conditions and competition; economic conditions, such as interest rate and currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; domestic and foreign health care reforms and governmental laws and regulations; and trends toward health care cost containment. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99(b) of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 2, 2005. Copies of this Form 10-K are available online at http://www.sec.gov or on request from Johnson & Johnson. Johnson & Johnson assumes no obligation to update any forward-looking statements as a result of new information or future events or developments.)
Schering-Plough is a global science-based health care company with leading prescription, consumer and animal health products. Through internal research and collaborations with partners, Schering-Plough discovers, develops, manufactures and markets advanced drug therapies to meet important medical needs. Schering-Plough's vision is to earn the trust of the physicians, patients and customers served by its more than 30,000 people around the world. The company is based in Kenilworth, N.J., and its Web site is http://www.schering-plough.com.
SCHERING-PLOUGH DISCLOSURE NOTICE: The information in this press release contains certain "forward-looking" statements within the meaning of the Securities Reform Act of 1995, including statements related to REMICADE and the potential market for REMICADE. Forward-looking statements relate to expectations or forecasts of future events. Schering-Plough does not assume the obligation to update any forward-looking statement. Many factors could cause actual results to differ materially from Schering-Plough's forward- looking statements, including market forces, economic factors, product availability, current and future branded, generic or over-the-counter competition and the regulatory process, among other uncertainties. For further details and a discussion of risks and uncertainties that may affect forward- looking statements, see the company's Securities and Exchange Commission filings, including the company's third quarter 2005 10-Q.
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