Washington Editor

SILVER SPRING, Md. - The risk of lymphoma in the rheumatoid arthritis population doesn't appear to increase among patients taking a TNF blocker, members of an FDA advisory panel said on Tuesday.

As part of a periodic safety update on that class of blocking agents, the Arthritis Advisory Committee heard follow-up data presentations from Amgen Inc., for Enbrel; Centocor Inc., for Remicade; and Abbott Laboratories, for Humira.

"The lymphoma pattern is similar to what you would see in RA [rheumatoid arthritis] patients, but I think some of what we are seeing in RA may be a result of other agents like methotrexate," said Elaine Jaffe, a consultant to the panel and physician representing the National Institutes of Health in Bethesda, Md.

While Li Liang, an FDA reviewer, said incidents of lymphoma have appeared among users of each of the drugs, it is difficult to draw a conclusion because accurate data are not available. Each of the three companies is following between 1,000 and 2,000 RA patients for updated information on malignancies.

But Janet Elashoff, panel member and director of the division of biostatics at Cedars-Sinai Medical Center in Los Angeles, said 1,000- to 2,000-patient registries seem small considering the size of the clinical trials. For example, the clinical database through 2002 for Enbrel included 3,389 patients.

Lymphoma is associated with both RA and Crohn's disease. Centocor, a Johnson & Johnson company based in Malvern, Pa., said Remicade (infliximab) is the only TNF (tumor necrosis factor) antagonist approved for Crohn's. However, Humira, approved for RA in December 2002, is being studied in Crohn's.

"The risk of lymphoma increases with advancement of disease and in Remicade studies, most incidents occurred in high-risk patients," Jerome Boscia, vice president for clinical research at Centocor, told the committee. "The rate of lymphoma may not be greater in RA populations treated with Remicade than in non-treated populations. We feel current evidence is inclusive to reach a conclusion that use of Remicade is associated with lymphoma."

For example, in a 555-patient Remicade clinical program, four RA patients developed lymphoma and two Crohn's patients developed it. However, according to the FDA, Centocor has recently completed the one-year treatment phase of a 1,050-patient trial and no incidents of lymphoma have been observed (the trial remains blinded).

Meanwhile, Amgen, of Thousand Oaks, Calif., in prepared remarks said the reporting rates of lymphoma from Enbrel post-marketing safety surveillance and the standardized incident ratio observed in Enbrel clinical trials are consistent with the background rates expected in RA patients. Amgen acquired Enbrel (etanercept) via its merger with Seattle-based Immunex Corp. last July. Enbrel, a fully human anti-TNF receptor launched in 1998 for RA, was developed by Immunex and partner Wyeth Pharmaceuticals, of Madison, N.J. The Wyeth partnership survived the Amgen merger. (See BioWorld Today, July 17, 2002, and Dec. 18, 2001.)

The committee was scheduled to discuss congestive heart failure (CHF) associated with the products, but as discussed by Amgen and Centocor representatives, many patients with pre-existing conditions were not included in the clinical trials.

FDA investigator Jeffrey Siegel said the Enbrel trials showed "concerning" trends in CHF. Both Enbrel and Remicade carry CHF cautions and warnings, respectively, and while such data are not available for Humira (adalimumab), several panel members said it is likely that it, too, will need to carry a warning or caution.

Still, others say the three drugs are substantially different molecules and should not be lumped together as one in producing a risk to CHF patients.

Humira, a human monoclonal antibody to TNF developed through phage display technology containing solely human sequences, has a half-life of approximately two weeks and is effective when given alone or in combination with methotrexate or other disease-modifying anti-rheumatic drugs (DMARDs).

In remarks before the committee, Steven Fischkoff, a presenter for Abbott Laboratories, of Abbott Park, Ill., said that while TNF antagonists have been associated with a risk of tuberculosis and lymphoma, the risk doesn't appear to be higher than that which is consistent with RA patients. Nevertheless, he said the Humira packaging warns patients and physicians of the risk.

Abbott continues conducting 1,700-patient, five-year safety trials. While approved in RA, Abbott is studying Humira for juvenile RA, Crohn's, psoriasis and arthritic psoriasis. Enbrel, a protein comprised of the extracellular domains of two human TNF receptors attached to a portion of a human IgG immunoglobulin, is approved for reducing signs and symptoms of moderately to severely active RA as a monotherapy or in combination with methotrexate in patients who had an inadequate response to one or more DMARDs. Also, it's approved for polyarticular-course juvenile RA; inhibition of structural damage in patients with moderately to severely active RA including those who have not previously failed DMARD; and reduction in signs and symptoms in psoriatic arthritis either as monotherapy or in combination with methotrexate.

Remicade, a monoclonal antibody that binds with high affinity and specificity to human TNF-alpha and neutralizes its biologic activity, is approved for Crohn's; the inhibition of structural damage to RA; and the improvement in physical function in RA. The FDA currently is reviewing Centocor's supplemental biologics license application for maintenance therapy in patients with fistulizing Crohn's. Remicade also is being studied in psoriasis, ulcerative colitis and spondyloarthropathies (such as ankylosing spondylitis).