By Lisa Seachrist
GAITHERSBURG, Md. - Centocor Inc. came to the FDA advisory panel looking for the "Holy Grail" of indications in rheumatoid arthritis - a label saying the drug prevents the structural damage associated with the disease.
The company came away, instead, with a unanimous endorsement for the drug as a means to significantly reduce the radiographically measured structural damage.
The Arthritis Advisory Committee voted 8-0 in recommending the agency approve Centocor's request for an expanded indication. However, the panel failed to endorse the drug's ability to prevent structural damage to joints, and recommended the drug's indication be expanded to say only that it delays the progression of structural damage.
"It's clear we will get a label that says [Remicade] has a significant effect on the course of this disease," said Harlan Weisman, senior vice president of research and development for Centocor, of Malvern, Pa., now a wholly owned subsidiary of Johnson & Johnson. "The exact wording is up to the agency, but I am very comfortable and confident that we will be able to present the data that we presented today in our package insert."
Expanding the RA indication will be particularly important for Centocor, since Seattle-based Immunex Corp.'s Enbrel has been granted an indication in delaying the progression of joint damage, as has Aventis Pharmaceutical's Arava. No therapy has been granted an indication saying the drug prevents joint destruction.
Remicade (infliximab) is a monoclonal antibody that blocks the activity of 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 rheumatoid arthritis (RA), Crohn's disease and other autoimmune diseases. Remicade in combination with methotrexate received approval as a therapy for the signs and symptoms of RA last November. (See BioWorld Today, Nov. 11, 1999, p. 1.)
In RA, specifically, TNF-a plays a key role in the destruction of joints characteristic of RA - joint space narrowing and bone erosion as seen on X-rays. Centocor tested the drug for its ability to prevent the structural damage in the joints as a result of TNF-a by treating patients for more than a year and examining X-rays of the hands/wrists and feet taken at baseline, after 30 weeks of treatment and 54 weeks of treatment.
Centocor presented data on 428 patients who received Remicade in a Phase III double-blind study testing two doses of Remicade plus methotrexate in two different dose schedules against methotrexate plus placebo. Patients on the treatment received infusions of either 3 milligrams per kilogram or 10 milligrams per kilogram of Remicade. The timing of the infusions came every four or eight weeks.
Blinded readers examined the X-rays of the patients over time and determined the extent of structural damage in the hands and feet. In addition, the company took measures of the severity of signs and symptoms, and functioning.
The company presented data showing no change in the number of bone erosions and joint space narrowing in the hands/wrists and feet of patients treated with Remicade and methotrexate. Those in the placebo and methotrexate group, on the other hand, experienced significant damage over the 54-week period.
In addition, the company reported the drug improved symptoms of RA as well as improved patients' abilities to walk, dress themselves and conduct other basic activities.
"I'm sure all of us our impressed with the robustness of the data we've seen," said committee chair Lee Simon, associate professor of medicine at Harvard Medical School. "The question is, Do we believe the data are strong enough to say infliximab prevents structural damage?"
The panel had significant questions about whether the results - no matter how compelling - from a single-year trial could adequately support a prevention indication. Part of the problem comes from the fact that X-rays offer an imperfect means of measuring joint damage. The other part of the problem is some of the data showed treatment with Remicade actually improved the level of bone erosions and joint space narrowing, calling some to question whether radiographic techniques were up to the task of supporting a claim for prevention. A finding of erosions and joint space narrowing is usually considered permanent damage.
"The data is very good," Simon said. "The technology is just not up to the task. As a result we just don't know if we can use the word 'prevention.'"
The quality and robustness of the data may have confounded the committee a little.
"What has happened is nobody expected to have to deal with this issue this soon," Weisman said. "These results are of such a different magnitude than what's been seen before, that they almost didn't know what to do with them. Nobody questioned the data. They are unequivocal, profound and compelling."
Centocor will be presenting two-year results from this trial at the November meeting of the American College of Rheumatology. In addition, the company intends to initiate monotherapy trials of Remicade in patients with early RA later this year.