Crohn’s Disease Drug Called Promising

Researchers at Cedars-Sinai Medical Center have developed what may be the first effective drug to treat Crohn’s disease, a disabling bowel disorder that affects as many as 500,000 Americans.

In clinical trials conducted at 18 medical centers in the United States and Europe, a single infusion of the medication produced a “dramatic reduction” in symptoms in 65% of the patients treated, Dr. Stephan R. Targan of Cedars will report today at a meeting of the Federated Societies of Gastroenterology and Hepatology in San Francisco.

Most of those patients were still showing a marked reduction in symptoms at the end of the study three months later, Targan said, and none showed any adverse effects from the treatment.

If the findings are replicated, “this could be a dramatic and novel product that could help a lot of other people,” said Jim Romano, director of research and education programs for the Crohn’s and Colitis Foundation of America.

No other drug significantly reduces symptoms in Crohn’s, he said, and the fact that the new drug does so “is very important.”

Crohn’s disease is a painful, incurable condition that inflames the small and large intestines, causing diarrhea, abdominal cramps, fever, weight loss and numerous complications, such as bowel obstructions. “It’s like a severe, permanent case of Montezuma’s revenge,” Targan said.

Most victims are teenagers or young children when they are first diagnosed, and they face a lifetime of problems. Those with the most severe forms of the disease are unable to work or participate in any normal activities.

The only current treatment is steroids, but they are only modestly effective and they often cause severe side effects that prevent further use. Surgery to remove the most severely affected parts of the bowel is usually attempted as a last resort, but it is not a cure and symptoms inevitably return.

Researchers do not know what causes Crohn’s, although it is clear that some people have a genetic predisposition. The immediate symptoms result when the immune system attacks the cells lining the intestines.

“It’s the same response that occurs in an infection,” Targan said, “but it never stops.”

Close examination of the affected cells shows that they contain large quantities of several cytokines, proteins produced by the immune system. Researchers have speculated that attacking these cytokines before they reach the intestine might reduce symptoms.

Targan and his colleagues used monoclonal antibodies against a cytokine called tumor necrosis factor, or TNF, which has been implicated in cancer and a variety of other diseases. The monoclonal antibodies, which are produced by biotechnology processes, bind specifically to TNF, removing it from the bloodstream.

The study involved 108 patients. A quarter of them received a placebo, while the rest got different doses of an antibody called anti-TNF. About 65% of the patients who received anti-TNF showed a dramatic reduction in symptoms, while the rest showed no reduction, Targan said. That finding suggests that there may be several subtypes of Crohn’s that are caused by different cytokines, he said.

Among those who received the placebo, only 17% showed a reduction in symptoms.

The question that must now be answered is whether subsequent treatments will provide similar results, Targan said. The antibodies used in the treatment were originally produced in mice. Studies employing mouse antibodies to treat other diseases have shown that the human body builds up a resistance to them so that they lose their effectiveness, often after only one treatment.

The anti-TNF, however, has been “humanized” by a process in which many segments of the mouse protein are replaced by similar protein segments of human origin. Such humanized monoclonal antibodies often do not provoke an immune response in the recipient, and Targan hopes that that will be the case here.

He notes that some patients in an earlier study received multiple infusions of the anti-TNF “and there have been no problems.”

The researchers are now planning a much larger clinical trial that will be necessary before the Food and Drug Administration will approve the medication. If those are successful, he predicts that the drug could be commercially available in a couple of years.

The research team is also studying the distribution of cytokines in the patients who did not respond to the anti-TNF. His hope, Targan said, is that they will be able to treat those non-responders with antibodies directed at other cytokines.