Current and emerging therapies for coeliac disease

Abstract

Coeliac disease is a common enteropathy that occurs in genetically susceptible individuals in response to the ingestion of gluten proteins present in wheat, rye and barley. Currently, the only available treatment for the condition is a strict, life-long gluten-free diet that, despite being safe and often effective, is associated with several challenges. Due to the high cost, particularly restrictive nature and perception of decreased quality of life associated with the diet, some patients are continuously exposed to gluten, which prevents an adequate disease control. Moreover, a subgroup of patients does not respond to the diet adequately, and healing of the small-bowel mucosa can be incomplete. Thus, there is a need for alternative treatment forms. The increasingly understood pathogenetic process of coeliac disease has enabled the identification of various targets for future therapies. Multiple investigational therapies ranging from tolerogenic to immunological approaches are in the pipeline, and several drug candidates have entered phase II/III clinical trials. This Review gives a broad overview of the different investigative treatment modalities for coeliac disease and summarizes the latest advances in this field.

Key points

  • At present, a gluten-free diet is the only effective treatment for coeliac disease but is associated with several possible challenges, including a high economic and societal burden, inferior quality of life and sometimes inadequate response.

  • An increased understanding of the pathogenetic process in coeliac disease has revealed various therapeutic targets for future drugs that could complement or replace a gluten-free diet.

  • Novel therapeutic strategies include approaches to detoxify gluten already in the gastrointestinal tract by sequestrants or peptidases.

  • Other investigational approaches comprise blocking intestinal epithelial permeability or the enzymatic activity of transglutaminase 2.

  • Restoring immune tolerance to gluten or targeting the gluten-induced immune activation has also been investigated as possible therapeutic options.

  • The most advanced drug candidates have now entered phase III clinical trials.

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Fig. 1: The pathogenesis of coeliac disease and investigational approaches that have been tested as future treatments.
Fig. 2: Proposed mechanisms for gluten tolerization strategies.

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Acknowledgements

The authors thank the Academy of Finland and the Sigrid Juselius Foundation (K.L.), Emil Aaltonen foundation and the Finnish-Norwegian Medical Foundation (L.K.), the National Health and Medical Research Council of Australia (NHMRC, Investigator Grant APP1176553), and the Mathison Centenary Fellowship, University of Melbourne (J.T.-D.). A.C. holds a Paul Douglas chair in intestinal research.

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Correspondence to Katri Lindfors.

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L.K. reports personal fees for lectures from the Finnish Coeliac Society outside the submitted work and participation in the AMG 714 trial. D.A.L. is the Medical Director for Takeda Pharmaceuticals. J.T.-D. is an inventor of patents pertaining to the use of gluten-derived T cell epitopes for use in coeliac disease therapeutics and was an investigator in the Nexvax2 phase II trial. The other authors declare no competing interests.

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Nature Reviews Gastroenterology & Hepatology thanks P. Green, G. Makharia and D.S. Sanders for their contribution to the peer review of this work.

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Kivelä, L., Caminero, A., Leffler, D.A. et al. Current and emerging therapies for coeliac disease. Nat Rev Gastroenterol Hepatol (2020). https://doi.org/10.1038/s41575-020-00378-1

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