Journal
BEST PRACTICE & RESEARCH CLINICAL GASTROENTEROLOGY
Volume 28, Issue 3, Pages 437-449Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.bpg.2014.04.005
Keywords
Crohn's disease; Clinical trials
Categories
Funding
- European Research Council under the European Community's Seventh Framework Programme/ERC [260961]
- National Institute for Health Research, Cambridge Biomedical Research Centre
- Addenbrooke's Charitable Trust, Cambridge University Hospitals
- Evelyn Trust
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The recent success of the anti-integrin antibody Vedolizumab can barely conceal the fact that the biologics armamentarium in Crohn's disease has barely evolved beyond TNF blockers so far. This contrasts with other immune-related diseases considered mechanistically and genetically closely related, such as psoriasis and rheumatoid arthritis, where approved biologics target a variety of independent biological mechanisms. Several pharmacological assets that entered clinical development have proven ineffective, or less effective than originally anticipated. While blockade of IL-17A and its receptor via Secukinumab and Brodalumab, respectively, worsened Crohn's disease, the beneficial effect of IL-12/23 p40 blockade via Ustekinumab appeared confined to a subpopulation of Crohn's disease patients who have previously failed on TNF blockers. Clinical development of the IFN gamma blocker Fontolizumab was stopped despite demonstrating some clinical benefit, while the T cell co-stimulation blocker Abatacept did not exhibit any hint towards efficacy in Crohn's disease. Here I review results from these individual development programmes, and also reflect on the lack of efficacy of the TNF blocker Etanercept. I will discuss aspects of individual trials that might have confounded their interpretation and highlight the evolution in primary and secondary end-points that have contributed to increasing robustness of results obtained in recent years. Finally, I suggest that mechanistic studies in murine genetic models combined with exploratory immunological studies incorporated in early drug development may represent the key for identifying the next generation of successful pharmacological targets in Crohn's disease. (C) 2014 Elsevier Ltd. All rights reserved.
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