Abbott's investigational anti-interleukin-12 fully human monoclonal antibody in Crohn's disease study

Results of a Phase II study of Abbott's ABT-874, a fully human anti-interleukin-12 (IL-12) monoclonal antibody, will appear tomorrow in the New England Journal of Medicine citing treatment with ABT-874 shows differences in response and remission in patients with active Crohn's disease compared to placebo, in one arm of the study.

ABT-874 is an investigational agent designed to target and neutralize IL-12, a known mediator of inflammation in Crohn's disease, multiple sclerosis and other autoimmune disorders. IL-12 mediators are an emerging and important new area of research in the treatment of autoimmune diseases.

"The New England Journal of Medicine report on the study of Crohn's disease patients with active symptoms addresses onset and the sustainability of clinical responses," said William J. Sandborn, M.D., Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Medical School. "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 serious condition."

Crohn's disease is a serious chronic and inflammatory disease of the gastrointestinal (GI) tract that affects approximately 500,000 Americans and is typically diagnosed before age 30. Common symptoms of the disease include diarrhea, cramping, abdominal pain, weight loss, fever and in some cases rectal bleeding. Currently, there is no cure for Crohn's disease.

Seventy-nine patients with active Crohn's disease were enrolled in a randomized, double-blind trial of ABT-874 to evaluate safety and efficacy. Participants had active Crohn's disease as indicated by a Crohn's Disease Activity Index (CDAI) score between 220 and 450, measured within two weeks of beginning treatment. Results were measured using the CDAI, which is a weighted composite score of eight clinical factors, including daily number of liquid or very loose stools, severity of abdominal pain or cramping, level of general well-being, presence of extraintestinal manifestations or abdominal mass, use of anti-diarrheal agents, hematocrit and decrease in ideal body weight. Remission was defined as a CDAI less than or equal to 150 points and clinical response as a decrease in the CDAI score of at least 100 points.

Patients were randomly assigned to receive seven weekly subcutaneous injections of ABT-874 (1 mg/kg or 3 mg/kg or placebo) either with a four-week interval between the first and second injection (Cohort 1) or with no interruption (Cohort 2). All patients were followed for 18 weeks after the final injection of study drug. Safety was the primary endpoint, and clinical response (reduction in CDAI of greater than or equal to 100 points) and remission (CDAI <150) were secondary endpoints.

The most frequently reported adverse event was local injection site reaction, noted more commonly in patients receiving ABT-874 (77 percent in Cohort 1 to 88 percent in Cohort 2) compared to patients receiving placebo (25 percent). Seven serious adverse events occurred in patients receiving ABT- 874, although none were attributed to ABT-874. The other seven occurred in patients who received anti-interleukin-12: two had adverse events two to three months after the last dose of drug (one had diarrhea and dehydration and one had migraine and bone pain); one was hospitalized for partial obstruction of the small bowel, which did not recur despite continued administration of drug; two had adverse events related to preexisting neoplastic conditions (skin cancer and dysplastic tubular adenoma); one had substance abuse requiring an evaluation in the emergency room; and one patient's wife became pregnant during the study (a concern because of unknown teratogenic effects).

Two serious adverse events occurred in patients receiving placebo. Four patients discontinued the study due to adverse events: two who received ABT- 874 (one experienced frequent migraine headaches, and one was diagnosed with a small bowel dysplastic adenoma after four injections had been received), and two from the placebo group (one was diagnosed with a peritoneal abscess, and one experienced an increase in Crohn's disease symptoms).

Patients in Cohort 2 (n=39) who received 3 mg/kg of ABT-874 achieved higher response rates compared to patients who received placebo (75 percent vs. 25 percent, p = 0.03) by the end of treatment. Patients treated with 3 mg/kg of ABT-874 showed clinical response after three weekly injections and the response was sustained for at least 18 weeks after treatment. Response rates at week 18 and remission rates, at both end of treatment and 18 weeks, were not statistically significant. Similarly, response and remission rates for patients receiving ABT-874 in Cohort 1 (n=40) were not significantly different from the placebo group.

"This news is promising for people with Crohn's disease. While the data are preliminary, they suggest that targeting IL-12 with a specific antibody may induce a clinical response or remission in patients who have active symptoms," said Elliot Chartash, M.D., global project head, Immunology Development, Abbott.

Autoimmune diseases are a group of illnesses in which the body attacks itself. Researchers have identified more than 80 different autoimmune disorders ranging in severity from mild to disabling, depending on which system of the body is under attack and to what degree. Worldwide, an autoimmune disease affects an estimated one in 31 people and while the exact cause is unknown, researchers have identified a number of possible causes and influences.

ABT-874 is an investigational agent designed to target and neutralize interleukin-12 (IL-12), a protein that regulates inflammatory response. IL-12 is associated with a number of chronic inflammatory autoimmune disorders, including Crohn's disease. ABT-874 is currently in phase II studies for multiple sclerosis (MS).