Seventeen in Crohn's disease: less prime than we thought?
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
- Correspondence to Arthur Kaser, Division of Gastroenterology & Hepatology, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Level 5, Box 157, Cambridge CB2 0QQ, UK; ak729{at}cam.ac.uk
Over the past decade, population genetic studies and animal models have pointed us to the importance of multiple components of the interleukin (IL)-23 receptor signalling pathway in inflammatory bowel disease (IBD). This receptor is expressed on, and is critical for, the function of the T-helper 17 subset of T cells (Th17), upon which an almost doctrinal focus has been placed, along with, by extension, the prototypic Th17 cytokine, IL-17A, as the pathogenic molecule. However, biology appears to be more complex, as Hueber et al report the surprising failure of the IL17A antibody, secukinumab, in Crohn's disease (CD).1 In their multicentre phase IIa study, 59 patients with established moderate to severe CD were randomised to treatment with secukinumab versus placebo. At a scheduled interim analysis of the data from the first 41 patients, prespecified futility criteria were met, and the trial was therefore prematurely terminated.
A number of aspects of the study design merit further comment. The authors chose an unconventional Bayesian approach to study analysis, reporting as their primary end point the probability of the study drug achieving a reduction in the CD activity index (CDAI) from baseline of ≥50 points compared with placebo. Initial study recruitment was poor, which necessitated a number of amendments to the study protocol, and randomisation caused some imbalances in prior medical and surgical treatment. In an …
