S2260 Efficacy and Safety of LatiglutinaseIn Celiac Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Introduction: Celiac disease is a chronic immune disorder triggered by dietary gluten, leading to mucosal inflammation in genetically predisposed individuals. Despite adherence to a gluten-free diet (GFD), many patients experience persistent symptoms and mucosal damage, prompting the exploration of non-dietary therapeutic approaches like latiglutenase. Latiglutenase is an enzyme therapy designed to degrade gluten proteins into non-immunogenic fragments, potentially reducing gut mucosa inflammation. This meta-analysis aimed to evaluate the efficacy and safety of latiglutenase in treating celiac disease. Methods: A systematic review of major databases, including Cochrane, SCOPUS, PubMed, Web of Science, and EMBASE till April 2024 was conducted, adhering to PRISMA guidelines. Randomized controlled trials (RCTs) comparing latiglutenase to placebo in celiac disease patients were included. Risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) were calculated using the DerSimonian–Laird method. Primary outcomes were the villus height to crypt depth ratio and intraepithelial lymphocyte densities; secondary outcomes included adverse events (AEs). Results: Three RCTs involving 253 patients were analyzed (Table 1). No significant difference was observed between latiglutenase and placebo in the villus height to crypt depth ratio (MD: 0.05, 95% CI [-0.41, 0.51], P = 0.82) (Figure 1A) or intraepithelial lymphocyte densities (MD: -11.82, 95% CI [-28.41, 4.78], P = 0.16) (Figure 1B). Additionally, there were no significant differences in overall AEs (RR: 0.99, 95% CI [0.81, 1.21], P = 0.90), medication-related AEs (RR: 1.33, 95% CI [0.71, 2.49], P = 0.37), or gastrointestinal-related AEs (RR: 1.05, 95% CI [0.82, 1.34], P = 0.70) (Figure 1C). Specific symptoms like diarrhea, nausea, headache, fatigue/tiredness, and abdominal distension did not differ between groups. Stratified by severity, both latiglutenase and placebo displayed comparable outcomes for mild, moderate, and severe AEs. Conclusion: While no significant differences were found in symptomatic, histological, and serological parameters between latiglutenase and placebo groups, previous trials indicated symptom improvements. This suggests that histological and serological parameters may require more time to normalize compared to symptomatic improvements. Longer-term RCTs are essential to comprehensively evaluate latiglutenase's effects on symptomatic, histological, and serological outcomes, along with its long-term safety profile.Figure 1.: Forest plot for A) Change in ratio of villus height to crypt ratio B) Change in densities of intraepithelial lymphocytes C) Any adverse events. Table 1. - Characteristics of participants in includedrandomized control trials Study ID Study Design Countries/center Total Participants Primary Outcome Inclusion Criteria Patients included in analysis Mean Age (SD) Latiglutinase group Placebo Latiglutinase group Placebo 1 Murray 2022 Phase 2, Randomized, double-blind, single-centre, placebo-controlled, USA/One center 50 Change in the ratio of villus height to crypt depth Adult patients (18–80 years), biopsy-confirmed CeD; to be following a GFD for longer than 1 year; and to have histologically well controlled disease, as evidenced by a measured ratio of villus height (Vh) to crypt depth (Cd) of 2.0 26 24 42.7 (10.88) 45.0 (13.88) 2 Murray 2017 Phase 2, randomized, double-blinded, Multicenter, placebo-controlled, USA, Canada, Finland, Norway, Ireland, and the UK 494 change in the villous height: crypt depth ratio Adult outpatients (age, 18–80 y) were required to have physician-diagnosed celiac disease, following a GFD for 1 year or more, and self-report at least 1 gastrointestinal symptom as moderate or severe during the 28 days before screening. 37 125 48.5 (12.90) 50.6 (13.59) 3 Lähdeaho 2014 Phase 2, Randomized, Multicenter, placebo-controlled, parallel-group study Finland/ 3 centers 41 The ratio of villus height to crypt depth and densities of intraepithelial lymphocytes Celiac disease diagnosis established by duodenal mucosal biopsy, attempted adherence to a GFD for 1 year or more, and being in clinical remission (ie, TG2-IgA negative and reporting minimal to no gluten-associated symptoms). 20 21 51.5 (10) 47.5 (13)

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