Trial Drug Looks Promising for Crohn's

WEDNESDAY, Nov. 10 (HealthDayNews) -- A genetically engineered antibody that blocks an immune system molecule has produced promising results in its first use against Crohn's disease, researchers report.
The antibody targets interleukin-12, whose proper purpose is defending against infection. In Crohn's disease, a flawed response to bacterial infection causes painful bowel inflammation; an as yet unidentified genetic factor makes the system go wrong, setting off a chain of molecular events that results in inflammation.
Although the study was designed only to test the safety of giving the anti-interleukin-12 treatment to human patients, "it was really gratifying to see that you could show a significant response" in the form of reduced symptoms, said study author Dr. Peter J. Mannon, head of the clinical inflammatory bowel diseases research unit at the National Institute of Allergy and Infectious Diseases. The report appears in the Nov. 11 issue of the New England Journal of Medicine.

Crohn's disease is one of two conditions that cause chronic inflammation of the intestinal tract and which together affect about 1 million Americans. The other is ulcerative colitis, which usually attacks the large intestine; Crohn's disease generally attacks the small intestine.
Research has indicated that the attack in both diseases is due to an improper response by immune system cells, which release excess amounts of cytokines, molecules that attack the intestinal cells and cause inflammation. One cytokine-blocking antibody, infliximab (brand name Remicade), which prevents production of a cytokine called tumor necrosis factor alpha, has been approved for treatment of Crohn's disease. It has been found to be only partially effective.
"We can think about inflammation as a chain reaction," Mannon said. Tumor necrosis factor alpha comes into action toward the end of the chain, he said, and "if we can intervene early in that process, we might have more benefit."

Interleukin-12 acts "higher in the inflammatory pathway," and blocking it can be more effective than blocking tumor necrosis factor, said Dr. Lloyd Mayer, chairman of the immunobiology center at Mount Sinai School of Medicine in New York, which participated in the trial.
The study included 79 patients with Crohn's disease. Some got seven weekly injections of 3 milligrams of the antibody per kilogram of body weight, some got injections of 1 milligram of the antibody per kilogram of body weight, and others got an inactive substance.

More than 70 percent of the patients who got the higher doses of the antibody experienced remissions, the researchers reported. Blood tests showed decreased production of interleukin-12 and other cytokines, such as tumor necrosis factor alpha, in those patients. There were no significant side effects.
The study is just a starting point, Mannon said, because the small number of participants makes it difficult to assess the lasting value of the treatment.

"There may be a powerful underlying effect," he said. "That needs to be tested in a larger study."
SOURCES: Peter J. Mannon, M.D., M.P.H., head, clinical inflammatory bowel diseases research unit, National Institute of Allergy and Infectious Diseases, Bethesda, Md.; Lloyd Mayer, M.D., chairman, immunobiology center, Mount Sinai School of Medicine, New York City; Nov. 11, 2004, New England Journal of Medicine