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Biopharmaceuticals FDA

 News Release - August 14, 2006

FDA Expands REMICADE(R) Psoriatic Arthritis Indication: Anti-TNF Shown to Inhibit Joint Damage and Improve Physical Function

Long-Term REMICADE Data Show Sustained Efficacy in Arthritic and Psoriatic Components of Complex Inflammatory Disease

HORSHAM, Pa., Aug. 14 (HSMN NewsFeed) -- Centocor, Inc. announced today that the U.S. Food and Drug Administration (FDA) has extended its approval for REMICADE® (infliximab) for inhibiting progression of structural damage and improving physical function in patients with psoriatic arthritis, in addition to reducing signs and symptoms of active arthritis. The approval is based on one-year data from the double-blind, placebo-controlled trial IMPACT 2 and two-year data from the double-blind, placebo-controlled trial IMPACT. Findings from IMPACT 2 showed that at week 24, REMICADE-treated patients had less structural damage as assessed radiographically compared with patients receiving placebo (mean change -0.70 vs. 0.82, P < 0.001), and REMICADE- treated patients were more than twice as likely to achieve a clinically meaningful improvement in physical function compared with patients receiving placebo (54 percent vs. 22 percent, respectively).

An immune-mediated inflammatory disease, psoriatic arthritis affects approximately one million men and women in the U.S.(i) and is often characterized by symptoms of joint inflammation and skin lesions. First approved in 1998 for Crohn's disease, REMICADE has been used to treat over 770,000 patients worldwide living with gastroenterologic, rheumatologic and dermatologic inflammatory diseases.

"The study findings supporting this approval show that treatment with infliximab can slow the progression in joint destruction often associated with this disease," said Arthur Kavanaugh, MD, Professor of Medicine at the University of California at San Diego and lead study investigator. "A significant proportion of infliximab-treated patients showed improvement in physical function in addition to improvement in both joint and skin symptoms, an important treatment outcome in a potentially debilitating inflammatory disease like psoriatic arthritis."

One-year radiographic analyses from IMPACT 2 showed that treatment with REMICADE resulted in significant inhibition of the progression of structural damage, compared with placebo (as measured by the change from baseline in van der Heijde-Sharp [vdH-S] score modified for psoriatic arthritis by adding measurement for distal interphalangeal joints of the hands). In this method, a higher change in score indicates greater progression of structural damage, while lower change in score indicates less progression of structural damage. At 24 weeks of treatment, REMICADE-treated patients experienced a mean change (+/- standard deviation) in vdH-S score of -0.70 (+/- 2.53) from baseline, compared with an average change of 0.82 (+/- 2.62) in the placebo group (P < 0.001). At week 54, patients who received a full 54-week regimen of REMICADE experienced a mean change of -0.94 (+/- 3.40) from baseline, compared with an average change of 0.53 (+/- 2.60) in patients who crossed over from placebo to REMICADE (P = 0.001) at week 16 or 24.

In terms of the skin component of the disease, 50 percent of REMICADE- treated patients in IMPACT 2 maintained at least 75 percent improvement from baseline, as assessed by Psoriasis Area Severity Index (PASI 75), in psoriasis at one year, and 64 percent of REMICADE-treated patients in IMPACT maintained PASI 75 through two years. Moreover, 42 percent of REMICADE-treated patients in IMPACT 2 achieved PASI 90, or near total skin clearance, at one year, and 48 percent in IMPACT achieved PASI 90 through two years.

REMICADE-treated patients demonstrated significant improvement in physical function as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI). The HAQ-DI assesses the difficulty a patient has accomplishing tasks in eight functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping and other activities of daily living). By week 14 of the IMPACT 2 trial, patients in the REMICADE group experienced a median improvement of 43 percent, compared with zero percent in the placebo group (P < 0.001), and results were maintained through one year. At week 54 of IMPACT 2, there was a median 50 percent improvement in HAQ-DI score from baseline in the group randomized to REMICADE, and a 46 percent improvement in placebo patients who switched to REMICADE. At week 16 of the IMPACT trial, REMICADE- treated patients demonstrated a median improvement in HAQ-DI score of 50 percent versus two percent in the placebo group (P < 0.01); these responses were generally sustained through two years.

In May 2005, REMICADE was approved in the United States for reducing signs and symptoms of active arthritis in patients with psoriatic arthritis. In September 2004, REMICADE received European Union (EU) approval, in combination with methotrexate, for the treatment of active and progressive psoriatic arthritis in patients who have responded inadequately to disease-modifying anti-rheumatic drugs (DMARDs). Additionally, in July 2006, the European Commission approved the use of REMICADE for the treatment of active and progressive psoriatic arthritis in patients who have responded inadequately to DMARDs to be used in combination with methotrexate or alone in patients who show intolerance to methotrexate or in whom methotrexate is contraindicated.

About IMPACT/IMPACT 2

The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT) was a Phase 2b randomized, double-blind, placebo-controlled study that involved 104 patients with active psoriatic arthritis (defined as affecting at least five joints) who failed at least one DMARD. Patients received either REMICADE (5 mg/kg) or placebo, administered at weeks 0, 2, 6 and 14. The REMICADE group continued on maintenance treatments every eight weeks through week 94. Beginning at week 16, patients randomized to the placebo group received an induction regimen of REMICADE followed by maintenance treatment every eight weeks through week 94. Hands and feet radiographs were taken at screening and at weeks 50 and 98. Physical function was measured at multiple visits including screening and at weeks 16, 22, 50 and 94.

REMICADE was generally well tolerated in this study, with one REMICADE and one placebo patient experiencing serious adverse events (AEs) in the placebo- controlled portion of the study through week 16. Fourteen patients out of 104 experienced serious AEs from week 16 through 50 in placebo/REMICADE crossover and REMICADE groups together. In the second year of IMPACT, seven patients out of 78 treated with REMICADE were reported with serious AEs. No deaths, cases of tuberculosis or other opportunistic infections were reported and serious infections were uncommon. There were no serious infusion reactions. One patient had a serious AE relating to malignancy: a ductal adenocarcinoma of the pancreas three months after week 98. See "Important Safety Information" below.

The Induction and Maintenance of Psoriatic Arthritis Clinical Trial 2 (IMPACT 2) was a Phase 3, randomized, double-blind, placebo-controlled study of 200 patients with active psoriatic arthritis (defined as affecting at least five joints). The study evaluated the safety and efficacy of REMICADE in patients who had an inadequate response to DMARDs or nonsteroidal anti- inflammatory drugs (NSAIDs). Patients received REMICADE (5 mg/kg) at weeks 0, 2, 6 and every 8 weeks until week 46 or placebo at weeks 0, 2, 6, 14 and 22. Placebo patients with less than 10 percent improvement in both swollen and tender joints at week 16 entered early escape and received REMICADE at weeks 16, 18 and 22 (n=47). At week 24, placebo patients who did not qualify for early escape received REMICADE at weeks 24, 26, 30, 38 and 46. Patients randomized to REMICADE who had less than 20 percent improvement in combined swollen and tender joint count at week 38 received REMICADE 10 mg/kg at weeks 38 and 46 (n=15). Patients were allowed concomitant methotrexate use at a stable dose. Hand and foot radiographs were taken at weeks 0, 24 and 54. Physical function was measured at multiple visits including weeks 0, 14, 24 and 54.

Through 54 weeks, 12 percent of patients in combined REMICADE treatment groups experienced serious AEs (during average follow-up of 42.8 weeks) as compared to 6 percent of placebo patients (average follow-up 20.2 weeks). No deaths, cases of tuberculosis or other opportunistic infections or serious infusion reactions were reported; serious infections were uncommon. Two patients reported an AE of malignancy: one case of basal cell carcinoma in the placebo group and one case of stage I Hodgkin lymphoma in the REMICADE group. The only laboratory abnormalities that occurred more frequently with REMICADE compared with placebo were asymptomatic liver enzyme test elevations. See "Important Safety Information" below.

About Psoriatic Arthritis

Psoriatic arthritis is a chronic inflammatory arthropathy manifesting with joint pain and swelling that can lead to joint destruction and debilitation. It is frequently associated with inflamed, scaly, red patches of skin psoriasis. Symptoms may include stiffness and tenderness of the joints and surrounding tissue, reduced range of motion, nail changes and redness and pain of the eye (uveitis). Joints of the hands, wrists, knees, ankles, feet, lower back and neck are commonly affected. Psoriasis affects an estimated two to three percent of the world's population, and approximately one out of three patients affected by psoriasis may develop psoriatic arthritis. Both men and women are equally affected by psoriatic arthritis, most commonly between the ages of 30 and 50, in the peak of their productive years.

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), 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.

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), 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

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.

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. 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). 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.

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.

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 http://www.remicade.com.

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 and pediatric Crohn's disease.

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.

(i) National Institute of Arthritis and Musculoskeletal and Skin Disorders. Questions and Answers About Psoriasis. U.S. Department of Health and Human Services, National Institutes of Health; 2003. NIH Publication No. 03-5040.


Source: Centocor

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