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

Expert Rev Neurother. 2009 Mar;9(3):319-21. doi: 10.1586/14737175.9.3.319.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Antibodies / therapeutic use*
  • Drug Evaluation
  • Humans
  • Interleukin-12 / immunology*
  • Interleukin-23 / immunology*
  • Multiple Sclerosis / therapy*
  • Treatment Failure

Substances

  • Antibodies
  • Interleukin-23
  • Interleukin-12