A New Target for Crohn's Disease Therapy: Interleukin-12

A new study found that an experimental drug that targets an immune system protein known as interleukin-12 (IL-12) has been shown to be helpful in a small group of Crohn's patients. The study was published on November 10 in the New England Journal of Medicine, a prominent medical journal.

Researchers have longed believed that IL-12 has played a role in Crohn's disease. IL-12 is known as an inflammatory cytokine - a protein that helps cause and continue the inflammation in Crohn's disease.

About the Study

This small, placebo-controlled study of 79 patients with moderately active Crohn's disease was primarily designed to demonstrate the safety of a new antibody to IL-12 (ABT 874). Placebo-controlled trials compare the active drug to an inactive substance. Patients were randomly chosen to receive the antibody to IL-12 by one of two treatment schedules. Patients either received IL-12 as a series of weekly injections under the skin over seven weeks or with a four-week interval between the first and second injection followed by five subsequent injections every week. The rates of side effects among patients who received anti-IL-12 were similar to those who received placebo, except for a higher rate of local, injection site reactions among patients who got anti-IL-12. The investigators found that 75 percent of patients who received uninterrupted injections at the higher dose of 3 milligrams of ABT 874 per kilogram of the patient's weight every week for seven consecutive weeks had significantly reduced symptoms compared to those who received placebo. About 38 percent were in remission at the end of the seven injection continuous treatment regimen compared to none in the placebo group. The response and remission rates among patients who received the interrupted anti-IL-12 injection regimen were not a high as for the uninterrupted regimen and the differences were not significant compared to the placebo group.

Study Significance

Dr. William Sandborn, one of the investigators in the study, said, "For the first time, study results have shown that IL-12 may be involved in Crohn's disease. This represents a new pathway to explore to manage this condition."

ABT 874 is an experimental drug that appears to bind to IL-12 and shuts it down. Although the cause of Crohn's disease is not known, the current theory states that the disease is triggered when the immune system overreacts to harmless bacteria normally present in the gut. IL-12 is one of the messengers the immune system uses to signal the attack on the bacteria. By shutting it down, the immune system does not get the message to attack and no inflammation occurs. The study investigators also noted that decreased secretions of interferon-gamma and tumor necrosis factor alpha, two other inflammatory cytokines, as well as IL-12 in the patients who clinically responded to anti-interleukin-12 therapy.

"A lot of work has to be done, but it's very exciting," said Dr. Richard MacDermott, a former chairman of the CCFA's National Scientific Advisory Board and the current director of the inflammatory bowel disease center at Albany Medical College.

Dr. Fabio Cominelli of the University of Virginia Health Sciences Center and the current chairman of CCFA's Research Initiatives Committee said, "Important questions remain regarding the safety of long-term treatment. Despite these limitations, the development of anticytokine therapies is an important staging post on the road to a cure for Crohn's disease."

ABT-874 is made by Abbott. There are currently no ongoing trials with ABT-874. Although the preliminary data is encouraging and introduces the idea of subcutaneous injection therapy for patients with Crohn's disease, ABT-874 is still in the early stages of development. CCFA will continue to bring you updates on the progress of this therapy and any forthcoming clinical trials.


Reference:

Anti–Interleukin-12 Antibody for Active Crohn's Disease
Peter J. Mannon, M.D., M.P.H., Ivan J. Fuss, M.D., Lloyd Mayer, M.D., Charles O. Elson, M.D., William J. Sandborn, M.D., Daniel Present, M.D., Ben Dolin, M.D., Nancy Goodman, R.N., B.S.N., Catherine Groden, R.N., M.S., Ronald L. Hornung, Ph.D., Martha Quezado, M.D., Markus F. Neurath, M.D., Jochen Salfeld, Ph.D., Geertruida M. Veldman, Ph.D., Ullrich Schwertschlag, M.D., Ph.D., and Warren Strober, M.D., for the Anti–IL-12 Crohn's Disease Study Group

N Engl J Med. 2004;351:2069, 2045-2048.

Article posted:  11/15/04