NEW YORK (Reuters Health) - An experimental drug, comprised of cytotoxic T-lymphocyte-associated antigen 4 fused to IgG1 (CTLA4Ig, Bristol-Myers Squibb), seems to be an effective and safe new treatment for rheumatoid arthritis that does not respond to other disease-modifying antirheumatic drugs (DMARDs), investigators report in The New England Journal of Medicine for November 13th.
CTLA4Ig binds to CD80 and CD86 on antigen-presenting cells and prevents binding of CD28 on T cells. As a result, T cell, B cell and macrophage activation is prevented, Dr. Joel M. Kremer and colleagues explain. Thus, CTLA4Ig acts earlier in the inflammatory cascade than do other biologic agents that target cytokines produced by macrophages.
In a phase II trial, Dr. Kremer, with the Center for Rheumatology in Albany, New York, and colleagues tested the new drug in patients with rheumatoid arthritis that had inadequately responded to treatment with methotrexate and other DMARDs.
Three hundred thirty-nine patients were randomized to intravenous CTLA4Ig 2mg/kg, 10mg/kg or placebo on days 1, 15 and 30 and monthly thereafter, while being maintained on methotrexate.
ACR20 responses at 6 months were significantly more frequent in the 10 mg/kg CTLA4Ig group than in the control group (60% versus 35.3%, p < 0.001). Both active treatment arms had significantly more ACR50 responders and ACR70 responders than did placebo.
Health-related quality of life responses for physical and social function, pain, and emotional health were significantly greater and “clinically meaningful” in the 10mg/kg group compared with the placebo group.
There were no serious adverse events attributed to the study drug, although one patient in the 2 mg/kg arm required hospitalization for cellulitis. Overall, fewer patients in the 10 mg/kg group discontinued treatment because of adverse events, and there were no clinically significant antibody responses to CTLA4Ig.
“The science of [this intervention] is really pristine,” Dr. Kremer told Reuters Health. “There’s enormous interest now in T cell signaling and second messenger generation. To selectively block T cell activation in this manner is enormously appealing, because it’s not toxic to cells.”
“Based on the mechanism of action, I think it would be interesting to test CTLA4Ig for several other autoimmune diseases,” he added. His team is now enrolling patients for a phase III trial of the agent.
Source: N Engl J Med 2003;349:1907-1915. [ Google search on this article ]
MeSH Headings:Cytotoxicity, Immunologic: Macrophage Activation: T-Lymphocytes, Cytotoxic: Drugs, Investigational: CD8-Positive T-LymphocytesCopyright © 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.
