European Union CHMP Recommends Approval of First and Only Biologic Treatment for Pediatric Crohn's Disease: Remicade

First Positive Opinion Recommending Approval of Biologic Treatment for Severe, Active Crohn's Disease in Pediatric Patients

HORSHAM, Pa. and KENILWORTH, N.J., March 26, 2007 /PRNewswire-FirstCall/ -- Centocor, Inc. and Schering-Plough Corporation 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 REMICADE(R) (infliximab) for the treatment of severe, active Crohn's disease (CD) in pediatric patients aged 6 to 17 years, who have not responded to conventional therapy including a corticosteroid, an immunomodulator and primary nutrition therapy, or who are intolerant to, or have contraindications for, such therapies. REMICADE has been studied only in combination with conventional immunosuppressive therapy in Crohn's disease.

Upon receipt of the corresponding Commission Decision, REMICADE will be the first and only biologic therapy approved in the EU for the treatment of pediatric CD, a debilitating condition that causes inflammation of the gastrointestinal tract, typically resulting in symptoms such as diarrhea, fever, abdominal pain, weight loss and, in some sufferers, delayed development and stunted growth.

In May 2006, the United States Food and Drug Administration (FDA) approved REMICADE for pediatric patients with moderately to severely active CD who have had an inadequate response to conventional therapy -- establishing REMICADE as the only biologic therapy for this indication in the U.S. REMICADE was first approved in the U.S. for adult Crohn's disease in 1998 and later for adult ulcerative colitis in 2005.

The safety and efficacy of REMICADE have been well established in clinical trials over the past 14 years and through commercial experience with nearly 840,000 patients treated worldwide across all indications.

The label extension will permit physicians to administer a 5 mg/kg intravenous infusion of REMICADE over a 2-hour period followed by additional 5 mg/kg infusion doses at two and six weeks after the first infusion, then every eight weeks thereafter. Some patients may require a shorter dosing interval to maintain clinical benefit, while for others a longer dosing interval may be sufficient. Available data do not support further infliximab treatment in pediatric patients not responding within the first 10 weeks of treatment.

"The CHMP recommendation for infliximab is an important milestone in addressing an unmet need in treating pediatric patients with Crohn's disease," said Peter Milla, M.D., Professor of Paediatric Gastroenterology and Nutrition, Institute of Child Health and Great Ormond Street Hospital for Children, United Kingdom. "Children with Crohn's disease who do not respond sufficiently to standard treatments have a greatly reduced quality of life. For example, they run a greater risk of growth retardation and osteoporosis by adolescence and may undergo multiple surgical procedures involving the removal of sections of the small and large intestine."

"This positive opinion is significant for REMICADE as it will be the first biologic therapy available to children suffering with Crohn's disease in the EU," said Robert J. Spiegel, M.D., chief medical officer, Schering-Plough Research Institute. "One cannot stress enough the negative impact of the disease on these children, so there is a great medical need for new and effective treatments. This further validates the utility of REMICADE as an important treatment in inflammatory bowel disease, which currently is approved in Crohn's disease and ulcerative colitis in adults."

Clinical Trial Information: REACH

The positive opinion was based on data from the Phase 3 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. In the REACH trial, 112 patients (6 to 17 years of age; all required to be receiving 6-MP, AZA or MTX; 35% receiving corticosteroids) with moderate to severe, active Crohn's disease (median PCDAI of 40) and an inadequate response to conventional therapies were to receive 5 mg/kg infliximab at weeks 0, 2, and 6. Patients assessed by the investigator to be in clinical response at week 10 were randomized and received 5 mg/kg infliximab at either q8 weeks or q12 weeks as a maintenance treatment regimen. Patients who lost clinical response during maintenance treatment, could receive infliximab at a higher frequency or dose.

The proportion of subjects in clinical response at week 10 was 88.4% (99/112). The proportion of subjects achieving clinical remission at week 10 was 58.9% (66/112). At week 30, the proportion of subjects in clinical remission was higher in the q8 week (59.6%, 31/52) than the q12 week maintenance treatment group (35.3%, 18/51; p=0.013). At week 54, the proportion of subjects in clinical remission was 55.8% (29/52) and 23.5% (12/51) in the q8 week and q12 week maintenance groups, respectively (p<0.001).

Thirty-two evaluable pediatric patients (9 in the q8 week and 23 in the q12 week maintenance group) lost response and then received infliximab at a greater dose or frequency. Twenty-four of these thirty-two patients (75.0%) regained clinical response.

Of the 22 subjects that had fistulas at baseline, 63.6% (14/22), 59.1% (13/22) and 68.2% (15/22) were in complete fistula response at week 10, 30 and 54, respectively, in the combined q8 week and q12 weeks maintenance groups.

In addition, statistically and clinically significant improvements in quality of life and height, as well as a significant reduction in corticosteroid use, were observed.

The following adverse events were reported more commonly in pediatric Crohn's disease patients in the REACH trial (see section 5.1) than in adult Crohn's disease patients: anaemia (10.7%), blood in stool (9.7%), leukopenia (8.7%), flushing (8.7%), viral infection (7.8%), neutropenia (6.8%), bone fracture (6.8%), bacterial infection (5.8%), and respiratory tract allergic reaction (5.8%). Other special considerations are discussed below.

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.

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), ulcerative colitis (UC) and psoriasis (PsO). 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.

REMICADE was approved in the EU in 1999 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/or 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 is also approved for the treatment of active and progressive PsA in adults when the response to previous disease-modifying anti-rheumatic drugs therapy has been inadequate. REMICADE should be administered in combination with MTX or alone in patients who show intolerance to MTX or for whom MTX is contraindicated. REMICADE is also 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, MTX or PUVA (psoralen plus ultraviolet A light).

In February 2006, REMICADE was approved in the EU for the treatment of moderately-to-severely active 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. This approval made REMICADE the first and only biologic therapy approved to treat moderate-to-severe UC in the EU.

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. In carefully selected patients with RA who have tolerated three initial two-hour infusions of REMICADE, consideration may be given to administering subsequent infusions over a period of not less than one hour. Shortened infusions at doses greater than 6 mg/kg have not been studied.

Furthermore, if an RA patient has an inadequate response or loses response after initial treatment with REMICADE, consideration may be given to increase the dose step-wise by approximately 1.5 mg/kg, up to a maximum of 7.5 mg/kg every 8 weeks. Alternatively, administration of 3 mg/kg as often as every 4 weeks may be considered. If adequate response is achieved, patients should be continued on the selected dose or dose frequency. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within the first 12 weeks of treatment or after the dose has been adjusted.

REMICADE treatment is to be initiated and supervised by qualified physicians experienced in the diagnosis and treatment of rheumatoid arthritis, inflammatory bowel diseases, ankylosing spondylitis, psoriatic arthritis or psoriasis. REMICADE infusions should be administered by qualified healthcare professionals trained to detect any infusion related issues. Patients treated with REMICADE should be given a package leaflet and a special alert card.

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

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, 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. Rarely, children and young adults who have been treated for Crohn's disease with REMICADE in combination with azathioprine or 6-mercaptopurine have developed a rare type of lymphoma, hepatosplenic T cell lymphoma (HSTL), that often results in death. 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 you 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.

For complete EU prescribing information, please visit http://www.emea.eu.int.

About Centocor

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, ulcerative colitis, pediatric Crohn's disease and psoriasis.

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 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 31, 2006. Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov or on request from Johnson & Johnson. Johnson & Johnson does not undertake to update any forward-looking statements as a result of new information or future events or developments.

About Schering-Plough

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 approximately 33,500 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 Private Securities Litigation Reform Act of 1995, including statements related to the approval of REMICADE for CD in the EU 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, patent and other intellectual property protection, current and future branded, generic or over-the-counter competition, the regulatory process, and any developments following regulatory approval, among other uncertainties. For further details and a discussion of risks and uncertainties that may impact forward-looking statements, see Schering-Plough's Securities and Exchange Commission filings, including Part I, Item 1A, "Risk Factors" in the company's 2006 10-K.

CONTACT: Melissa Katz of Centocor, +1-215-325-6875, cell: +1-215-514-0957; or Catherine Cantone, +1-908-298-3944, cell: +1-908-327-3013, orInvestor Contact: Alex Kelly, +1-908-298-7436, both of Schering-Plough

Web site: http://www.schering-plough.com/http://www.emea.eu.int/

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Posted: March 2007


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