NEW YORK (Reuters Health) - Results of an early phase II study show that a monoclonal antibody targeting interleukin-12 (IL-12) p40 protein is safe and may induce clinical responses and remissions in patients with active Crohn’s disease.
“IL-12 is a key cytokine that initiates Th1-mediated inflammatory responses,” the Anti-IL-12 Crohn’s Disease Study Group notes in its report, published in the November 11th issue of The New England Journal of Medicine. IL-12 antibody treatment has also been shown effective in animal models of Crohn’s disease.
Led by Dr. Peter J. Mannon at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, the group enrolled 79 patients with scores on the Crohn’s Disease Activity Index (CDAI) of 220 to 450 out of a possible 600 (with higher scores indicating more severe disease). Remission was defined as a CDAI score of 150 points or less, while clinical response was defined as a decrease of at least 100 points.
In one cohort, 16 patients were randomly assigned to 1 mg/kg anti-IL-12, 16 were assigned to 3 mg/kg and 8 to placebo, with subcutaneous injections administered weekly for 7 weeks. At the time of the final injections, the 3 mg/kg group exhibited a significantly higher response rate than the placebo group, 75% versus 25% (p = 0.03). The 1 mg/kg had a response rate of 27%, not significantly different from placebo.
At the end of 18 weeks, response rates were 69% in the 3 mg group, 20% in the 1 mg group and 25% in the placebo group, although differences were no longer significant.
In a separate cohort a single subcutaneous dose of anti-IL-12, with 15 patients assigned to 1 mg/kg, 16 assigned to 3 mg/kg and 8 assigned to placebo, led to nonsignificant increases in remissions and response rates after 1 month.
These findings show that “clinical responses and remissions could be rapid in onset and durable,” Dr. Mannon’s team writes.
The most frequent adverse events were local reactions at the injection site, which were more frequent in the active treatment groups and which responded to symptomatic therapy. Otherwise, adverse events did not differ significantly between groups, and there were no serious infections.
Clinical improvement was accompanied by decreases in the secretion of IL-12, interferon-gamma and tumor necrosis factor alpha by mononuclear cells of the colonic lamina propria, the authors note.
“The development of anticytokine therapies as part of the physician’s armamentarium is an important staging post on the road to a cure for Crohn’s disease,” Dr. Fabio Cominelli, at the University of Virginia, Charlottesville, writes in a related editorial.
He points out that the long-term safety of such drugs remains unproven. Moreover, Crohn’s disease may exist in multiple phases, such that effective treatment for this inflammatory bowel disease may “involve the blockade of multiple cytokines in order to intervene in several pathways,” he proposes.
Source: N Engl J Med 2004;351:2045-2048,2069-2079. [ Google search on this article ]
MeSH Headings:Clinical Trials: Environment and Public Health: Epidemiologic Methods: Evaluation Studies: Health: Health Occupations: Health Services Administration: Medicine: Investigative Techniques: Population Characteristics: Preventive Medicine: Public Health: Quality of Health Care: Specialties, Medical: Epidemiologic Study Characteristics: Clinical Trials, Phase II: Health Care Quality, Access, and Evaluation: Health Care Evaluation Mechanisms: Analytical, Diagnostic and Therapeutic Techniques and Equipment: Biological Sciences: Health CareCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
