Coeliac disease - Emerging treatments

Endopeptidases

Latiglutenase (formerly ALV003) may digest gluten within the intestinal lumen resulting in non-antigenic peptides. One study failed to demonstrate overall histological or symptom improvement in non-responsive coeliac disease.[154] A post-hoc subgroup analysis suggested symptom improvement among patients with coeliac disease with positive tissue transglutaminase (tTG) despite a gluten-free diet.[155] A more recent study has shown that it prevented the development of histological damages and symptoms in individuals with well-controlled coeliac disease undergoing a 6-week gluten challenge.[156] Another endopeptidase, TAK-062, has been shown to rapidly and effectively degrade gluten in healthy controls in a phase 1 trial.[157] Further studies in people with coeliac disease are required.

Tissue transglutaminase (tTG) inhibitors

tTG inhibitors may prevent the deamidation and resultant potentiation of gliadin peptides.[31] One phase 2A efficacy/tolerability study of the tTG inhibitor ZED1227 showed that patients receiving ZED1227 had less gluten-induced duodenal mucosal injury after a gluten challenge, compared with patients receiving placebo.[158] One phase 2 study is currently ongoing in Europe, enrolling individuals with symptoms despite the gluten-free diet.

Immunomodulation

Immunomodulation may restore gluten tolerance.[159] TAK-101 is a nanoparticle-based therapeutic being studied for the treatment of coeliac disease. It is designed to reverse gluten sensitivity and stimulate immune tolerance by delivering encapsulated gliadin to tolerogenic immune cells. In a phase 2A trial, TAK-101 was shown to be effective in preventing immune activation and histological deterioration among individuals with well-controlled coeliac disease undergoing a 14-day gluten challenge.[160] KAN-101 is an investigational drug that adds a glycosylation signature to the deamidated peptides reaching the T-reg in the liver. In a recent phase 1 trial, it was shown to reduce immune activation assessed by interleukin-2 and interferon gamma production, as well as the absence of increase in gut homing cytotoxic CD8 T cells in patients undergoing a gluten challenge. These results are preliminary, and a phase 2A study is still ongoing.[161]

Interleukin-15 antagonists

Interleukin-15 has been shown to be a key component for intra-epithelial lymphocyte survival and mucosal damage. Agents that act to block this cytokine are under development for non-responsive and refractory coeliac disease. One phase 2A trial of an interleukin-15 inhibitor, AMG 714, in patients with refractory coeliac disease reported no change in the proportion of aberrant intra-epithelial lymphocytes in the treatment group compared with the placebo group. The patients in the treatment group reported a reduction in diarrhoea symptoms.[162] Anti-IL15 efficacy was also examined among individuals with well controlled coeliac disease undergoing a gluten challenge. There was no significant difference between AMG 714 and placebo in preventing histological deterioration.[163] This agent is now being studied among individuals with persistent symptoms despite a gluten-free diet. It has also shown some promising results in the management of refractory coeliac disease type 2.

Probiotics

Early evidence suggests that some strains of probiotics may act on gluten immunogenicity, assist with intestinal healing, and improve patients' symptoms.[164][165] One meta-analysis showed symptomatic improvement, mostly when gastrointestinal (GI) symptoms were assessed by the GI Symptoms Rating Scale.[166] Caution is advised because some probiotics may be contaminated with gluten and there is currently insufficient evidence to recommend for or against the use of probiotics in coeliac disease.[73]

Modified wheat gluten

Various methods are being examined to alter the gluten immunogenic peptides present in wheat flour, thus decreasing their immunogenicity, either by microwaves, gamma irradiation, hydrolysation with lactobacilli and fungal proteases, or gene sequencing alterations.[167][168][169] Treatment of wheat flour with microbial transglutaminases is another option being explored.[170]

Tight junction regulators

Larazotide may strengthen the tight junctions and prevent gluten from infiltrating the mucosa.[171] Symptomatic improvement among individuals experiencing continued symptoms, despite gluten-free diet adherence, has been noted.[140][171] A phase 3 trial comparing larazotide with placebo for symptom relief in patients with coeliac disease who have persistent symptoms despite a gluten free diet was halted in 2022 for lack of symptoms improvement on an interim analysis.[172]