Crohn's Disease Treatment Shows Promise in Clinical Trial

In a small, initial clinical trial led by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, doctors found that up to 75 percent of people with Crohn's disease responded to an experimental new treatment, and up to 50 percent had long-term remission of symptoms. They report these findings in the Nov. 11 issue of The New England Journal of Medicine.

Crohn's, which affects an estimated 500,000 Americans, is an autoimmune disease that attacks the bowels, causing abdominal pain, cramping, diarrhea and rectal bleeding. In severe cases, damaged bowel sections must be surgically removed.

The new treatment is an antibody designed to disable interleukin-12 (IL-12), an immune system protein involved in inflammation. People with Crohn's produce excess IL-12. Previous studies by NIAID researcher Warren Strober, M.D., linked IL-12 to the cascade of immune system events that leads to the debilitating symptoms of Crohn's disease.

"NIAID researchers have taken advantage of a potential target for preventing, early in the disease process, the devastating inflammation that excess IL-12 seems to trigger. Existing treatments, which often fail, attempt to interrupt inflammation far later in the process," says Anthony S. Fauci, M.D., director of NIAID. "This is the first test of this potential new treatment in people with Crohn's disease, and we are encouraged by the results."

The clinical trial was conducted at 15 centers in the United States, Germany and the Netherlands. Peter Mannon, M.D., and Ivan Fuss, M.D., of NIAID led the study, which enrolled 79 men and women with Crohn's disease. Most study volunteers were randomly assigned to groups where they were injected with either low- or high-dose antibody treatments on one of two possible dosing schedules. The remaining sixteen volunteers received placebo injections.

The treatment consisted of a human antibody genetically modified to attach to and disable IL-12. High IL-12 levels in people with Crohn's disease activate T cells, which in turn produce a variety of proteins-interferon, tumor necrosis factor, IL-6 and IL-18-that cause damage in Crohn's disease.

After seven injections given weekly, 75 percent of 16 people receiving the higher dose of anti-IL-12 antibody responded to the treatment. At the end of the 24-week trial, six of those volunteers' symptoms were in remission.

Other volunteers received seven injections, with four weeks between the first and second injection, followed by six weekly injections. In this group, 56 percent (9 of 16 people) receiving the higher dose had responded to the treatment at week nine. At the end of the 18-week follow-up phase, half of these responders had remission of their symptoms.

The researchers also measured levels of the other immune system proteins-interferon, tumor necrosis factor, IL-10, IL-6 and IL-18-that are produced by the activated T cells in eight volunteers who received treatment at the National Institutes of Health Clinical Center. The researchers measured the proteins before and after treatment and found that many of the inflammatory proteins had dropped dramatically by the end of treatment. The decline in these proteins suggests that blocking IL-12 worked as the doctors hoped it would, by slowing or halting the Crohn's disease process.

"Data from this early study show us that the treatment was safe and also provide evidence that the antibody treatment may be effective against inflammation in Crohn's disease. The next step is to test the treatment in a larger group of volunteers and seek the most effective dose and treatment schedule," says Dr. Mannon.

Abbott Laboratories produced the anti-IL-12 antibody. Another pharmaceutical company, Wyeth, and the National Cancer Institute, also part of NIH, contributed to study costs.

NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.