Review article: therapeutic targets for the pharmacologic management of coeliac disease—the future beyond a gluten‐free diet

Summary Background Coeliac disease (CeD) is an immune‐mediated small bowel enteropathy resulting from dietary gluten exposure. Presently, the only effective treatment is adoption of a gluten‐free diet (GFD), although strict adherence is challenging to maintain, and inadvertent gluten exposures are inevitable for most patients. Hence, there is substantial interest in drug development in CeD and multiple novel therapies are under investigation. Aims To review existing and upcoming clinical trial programmes for pharmacologic agents for CeD. Methods A narrative review was performed, informed by a search of MEDLINE, Embase, the Cochrane CENTRAL Library and clinicaltrials.gov. Results We summarise the pathophysiology of CeD and the specific steps that are potentially amenable to pharmacologic treatment. We evaluate the evidence supporting existing and future drug targets, including trials of peptidases, gluten sequestrants, tight junction regulators, anti‐transglutaminase 2 therapies, immune tolerizing agents, advanced biologics and small molecules, and microbiome‐targeted strategies. We highlight unique considerations for conducting CeD trials, including identifying appropriate study populations, assessing results in the context of a gluten challenge, and interpreting CeD‐specific clinical and histologic outcomes. Understanding these factors is crucial for accurately appraising the evidence. Finally, we outline what the future of CeD therapy may hold with the introduction of pharmacotherapies. Conclusions There is a need for pharmacologic options for CeD, either used adjunctively with a GFD for accidental or intentional gluten exposures or for refractory disease. Multiple promising agents are in development, and these trials are likely to lead to approvals for the first generation of pharmacologic agents for CeD within the next 5 years. Novel therapies are being developed for the treatment of coeliac disease. Unique considerations apply to the design and interpretation of clinical trials for this indication, and the role of pharmacotherapy in long‐term coeliac disease management is reviewed.