By Karen Pihl-Carey

The FDA approved Centocor Inc.'s Remicade (infliximab) on Wednesday for use with methotrexate to treat rheumatoid arthritis (RA) in patients who do not respond to methotrexate alone.

The drug will now compete with Seattle-based Immunex Corp.'s Enbrel for the $600 million market, said Meg Malloy, a senior analyst with Hambrecht & Quist LLC in New York.

"It's clearly a positive for the company," she told BioWorld Today. "I think there's a great deal of enthusiasm for TNF-inhibitor therapy. I think Enbrel will be the market leader, but I think there is still a place for Remicade, and this market is definitely big enough for another player."

Malloy estimated Enbrel sales will be about $450 million, while Remicade's will be about $150 million. The market includes 400,000 patients with severe RA, she said.

"Our view is that the addition of another biologic is going to grow the market for biologics. That's been the trend of the pharmaceutical industry," said Mike King, a senior analyst with BancBoston Robertson Stephens Inc. in New York. "I would say that it won't stop investors from speculating whether it [Remicade] will cannibalize Enbrel. I don't think it will, but that doesn't mean people won't be talking about it."

King said his colleague, Jay Silverman, of BancBoston, who covers Centocor, was looking for Remicade sales for RA to be about $120 million for 2000 and about $182 million for 2001.

Centocor, of Malvern, Pa., which was acquired in July by Johnson & Johnson, of New Brunswick, N.J., in a $4.9 billion stock deal, will co-promote Remicade for RA in the U.S. with Ortho-McNeil Pharmaceuticals Inc., also a subsidiary of J&J. The average wholesale price will be $611.33 per vial, and the average patient will require two to three vials per infusion, and between six and eight infusions a year. Infused drugs, such as Remicade, are covered by Medicare, the company said, and as many as 50 percent of patients with RA receive Medicare benefits.

An application to market Remicade for RA in Europe was submitted in August to the European Agency for the Evaluation of Medicinal Products. Remicade was approved in August 1998 for use in patients with Crohn's disease. (See BioWorld Today, Aug. 25, 1998, p. 1.)

The monoclonal antibody works by reducing inflammation in patients with Crohn's disease and RA by blocking the activity of the tumor necrosis factor-alpha (TNF-a), a key inflammatory mediator, on the cell membrane and in the blood. Overproduction of TNF-a leads to inflammation in RA, Crohn's disease and other autoimmune disorders.

Remicade for RA is administered intravenously in 3 mg/kg doses two weeks after the first treatment, six weeks after the second treatment, then every eight weeks thereafter. Patients will receive about eight infusions in the first year of treatment and about six infusions in each subsequent year.

The FDA approval is based on findings from a double-blind, placebo-controlled, randomized trial called ATTRACT (anti-TNF trial in rheumatoid arthritis with concomitant therapy), which involved 428 patients at 34 sites. Patients enrolled in the trial had the disease for a median 8.4 years and found it particularly difficult to manage. All were receiving methotrexate therapy, with half having been on it for three or more years. The data were first presented in November 1998 at the American College of Rheumatology meeting in San Diego. (See BioWorld Today, Nov. 10, 1998, p. 1.)

Two weeks after therapy began, about 25 percent of Remicade and methotrexate-treated patients noticed an improvement in the number of tender joints, compared with 4 percent of patients receiving methotrexate alone. And 27 percent of the Remicade and methotrexate patients noticed improvement in the number of swollen joints, compared with 11 percent of those on only methotrexate.

At the trial's 30th week, half of all patients treated with Remicade and methotrexate, compared with 20 percent of patients treated with methotrexate alone, experienced a reduction in signs and symptoms.

Centocor markets Remicade in the U.S. for Crohn's disease, and Schering-Plough Corp., of Madison, N.J., has marketing rights in all other countries, except Japan and parts of the Far East, where it will be marketed by Tanabe Seiyaku Co. Ltd., of Osaka, Japan. Remicade has no competitor for its Crohn's disease market, although it will compete with Enbrel for the RA market.

"The primary difference is Enbrel is a soluble TNF receptor administered twice weekly in the home. It does not require methotrexate to be used with it," Malloy said. "Whereas Remicade is an antibody to TNF. It would be administered every eight weeks. You have to use methotrexate with Remicade treatment. The difference is with Remicade you need to go to the doctor or an infusion center. That's the down side, plus you have to do it every eight weeks."

Researchers also found Remicade is well tolerated, with the most common adverse events of upper respiratory tract infections, headache, nausea, sinusitis, rash and cough. The two groups tested displayed similar incidences of adverse events.

However, TNF-a mediates inflammation and cellular immune response, meaning patients who take Remicade may have an increased risk of infection. Serious infections have been reported in patients receiving TNF-blocking agents, the company said, stressing that Remicade should not be given to patients with a chronic and active infection.

Centocor released the approval after the market closed Wednesday.