title: Not all monoclonals are created equal - lessons from failed drug trials in Crohn's disease.
abstract: 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 IFNγ 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 endpoints 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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, United Kingdom. Electronic address: ak729@cam.ac.uk.
authors.forename: Arthur
authors.initials: A
authors.lastname: Kaser
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003424:Crohn Disease / Q000628:therapy*; D016207:Cytokines / Q000037:antagonists & inhibitors*; D006801:Humans; D017211:Treatment Failure
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines
keywords: Clinical trials; Crohn's disease