Mtx Remicade

 

European Committee Recommends Use Of Remicade (Infliximab) With Methotrexate
For Rheumatoid Arthritis



KENILWORTH, NJ and MALVERN, PA -- October 10, 2000 -- The Committee for
Proprietary Medicinal Products (CPMP) of the European Agency for the
Evaluation of Medicinal Products (EMEA) has issued a positive opinion
recommending approval of Remicade« (infliximab) with methotrexate for the
improvement in physical function of patients with rheumatoid arthritis and a
reduction in the rate of the progression of joint damage when the response
to disease-modifying drugs, including methotrexate, has been inadequate.

The CPMP opinion serves as the basis for a European Commission approval,
which is typically issued in approximately three months. Commission approval
of the centralized Type II variation for Remicade will result in one single
Marketing Authorization with unified labeling that will be valid in all 15
EU-Member States.

Remicade is currently marketed in the EU for rheumatoid arthritis, following
the European Commission granting in June 2000 centralized marketing
authorization to Remicade with methotrexate for the reduction of the signs
and symptoms of rheumatoid arthritis in patients with active disease when
the response to disease-modifying drugs, including methotrexate, has been
inadequate. Remicade is also marketed in the EU for the treatment of Crohn's
disease, a serious gastrointestinal disorder.

Centocor, Inc. has exclusive marketing rights to Remicade in the United
States. Schering-Plough Corporation has rights to market the product in all
other countries throughout the world, except in Japan and parts of the Far
East where the product will be marketed by Tanabe Seiyaku, Ltd.

The centralized Type II variation application for Remicade for the
improvement of physical function and the reduction in the rate of the
progression of joint damage in rheumatoid arthritis patients is based on 102
week radiographic (x-ray) data from ATTRACT (Anti-TNF Trial in Rheumatoid
Arthritis with Concomitant Therapy), a double-blind, placebo-controlled,
randomized clinical trial involving 428 patients at 34 clinical sites.

Structural joint damage (erosions and joint space narrowing) in both hands
and feet was measured by the change from baseline in the total van der
Heijde- modified Sharp score (0-440). The Health Assessment Questionnaire
(HAQ; scale 0-3) was used to measure patients' average change from baseline
scores over time in physical function.

Based on x-ray data from the ATTRACT trial, a reduction in the rate of the
progression of structural joint damage was observed in all infliximab groups
at 54 weeks. The effects observed at 54 weeks were maintained through 102
weeks.

ATTRACT, one of the largest clinical studies ever conducted in patients with
advanced rheumatoid arthritis, studied the safety and efficacy of Remicade
at 30, 54 and 102 weeks. All treated patients had active disease despite
methotrexate treatment. At week 54, a higher percentage of patients in all
infliximab treated groups had a significant reduction in signs and symptoms
compared with methotrexate alone. This response was seen as early as two
weeks and was maintained through 102 weeks of treatment.

The CPMP recommendation is for the lowest dose studied in ATTRACT - 3 mg/kg
at zero, two and six weeks, then every eight weeks thereafter.

Patients enrolled in the ATTRACT trial were characterized as having disease
that was particularly difficult to manage. The median duration of disease in
trial patients was 8.4 years, and all patients were receiving methotrexate
therapy.

Half of the trial patients had been on methotrexate for three or more years.
More than one-third of all patients had previous joint surgery, and half
were classified as functional class 3 or 4, which indicates progressive and
advanced disease.

The one-year results from ATTRACT indicate that Remicade was generally well
tolerated. The most common adverse events in the ATTRACT trial included
upper respiratory tract infections, headache, nausea, sinusitis, diarrhea,
cough and rash.

There was no increased incidence of serious adverse events (17 percent with
Remicade and methotrexate versus 21 percent with methotrexate alone) or
serious infections (6 percent with Remicade plus methotrexate versus 8
percent with methotrexate alone). The incidence of infusion reactions in
patients receiving Remicade plus methotrexate (4 percent) was comparable to
that in patients receiving methotrexate alone (2 percent).

It is estimated that 2.5 million people -- mostly women -- in Europe are
affected by rheumatoid arthritis, which is a chronic and often painful
disease characterized by inflammation of the joints. Its initial symptoms
include fatigue, fever and anemia.

As the disease progresses, joints become swollen, inflamed, painful and
stiff. Rheumatoid arthritis usually begins with the hands, wrists, feet,
knees and elbows, but often also attacks the shoulders, neck, hips and back.
When inflammation persists or does not respond well to treatment,
destruction of nearby cartilage, bone, tendons and ligaments can occur and
lead to permanent disability.

In the United States, Remicade was approved by the Food and Drug
Administration (FDA) in November 1999 for use in combination with
methotrexate for the treatment of rheumatoid arthritis patients who have had
an inadequate response to methotrexate. In July 2000, the FDA Arthritis
Advisory Committee recommended approval of Remicade in combination with
methotrexate for reduction of joint damage in patients with rheumatoid
arthritis. Remicade is also marketed in the United States for the short-term
treatment of active and fistulizing Crohn's disease.

Remicade is the first of a new class of agents for the treatment of
rheumatoid arthritis that neutralizes a key inflammatory mediator called
TNF- alpha. Overproduction of TNF-alpha leads to inflammation in chronic
autoimmune conditions such as rheumatoid arthritis and Crohn's disease. It
is believed that Remicade reduces inflammation in patients with rheumatoid
arthritis by binding to and neutralizing TNF-alpha on the cell membrane and
in the blood.

TNF-alpha mediates inflammation and cellular immune response including
response to infection. Serious infections, including sepsis and fatal
infections, have been reported in patients receiving TNF-blocking agents.
Many of the serious infections in patients treated with Remicade have
occurred in patients on concomitant immunosuppressive therapy that, in
addition to their Crohn's disease or rheumatoid arthritis, could predispose
them to infections. Patients treated with Remicade may have an increased
risk of infection. Caution should be exercised when considering the use of
Remicade in patients with chronic infection or a history of recurrent
infection. Remicade should not be given to patients with a clinically
important, active infection.

Patients who develop a new infection while undergoing treatment with
Remicade should be monitored closely. If a patient develops a serious
infection or sepsis, Remicade therapy should be discontinued.

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