Why did IL-12/IL-23 antibody therapy fail in multiple sclerosis?

Abstract

Evaluation of: Segal BM, Constantinescu CS, Raychaudhuri A et al. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing–remitting multiple sclerosis: a Phase II, double-blind, placebo-controlled, randomized, dose-ranging study. Lancet Neurol. 7, 796–804 (2008).

IL-12 and IL-23 are two cytokines that appear to play a key role in the pathogenesis of multiple sclerosis. Blocking these cytokines via a neutralizing antibody caused dramatic improvements in animal models of the disease, and Phase I trials found the antibody to be safe in humans. The paper under review is a Phase II clinical trial of ustekinumab, an anti-IL-12/23p40 antibody for treatment of multiple sclerosis. Investigators found no clinical or radiologic improvement in any treatment group compared with placebo controls. We consider the known mechanisms of action for IL-12/23 in multiple sclerosis and suggest that ustekinumab’s lack of efficacy was partially due to the study’s inclusion of patients with advanced disease. Studies of the antibody in a more limited subset of patients (those with very early disease) might show a treatment effect.

Keywords::

• IL-12
• IL-23
• multiple sclerosis

Financial & competing interests disclosure

Michael Racke has received grant support from the NIH and the National Multiple Sclerosis Society. He has served as a consultant for Peptimmune, Inc, Teva Neuroscience and Bristol Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.