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In a phase 2 proof-of-concept trial, patients with celiac disease controlled on a gluten-free diet were assigned to one of three dose levels of ZED1227 (a selective transglutaminase 2 inhibitor) or placebo. Patients were challenged with 3 g of gluten daily for 6 weeks. Comparison of duodenal-biopsy samples between baseline and 6 weeks showed that ZED1227 attenuated gluten-induced mucosal damage.

Background Celiac disease (CeD) is an autoimmune disease triggered by dietary gluten in genetically predisposed individuals. Deamidation of gluten peptides by the CeD autoantigen and enzyme transglutaminase 2 (TG2) is central to the pathogenesis of CeD. Inhibition of TG2 with the specific inhibitor ZED1227 effectively prevents gluten-induced histological damage in CeD patients. Here we aimed to explore the systemic plasma lipidomic, proteomic and DNA methylomic changes in ZED1227-treated CeD patients undergoing a gluten challenge. Methods Individuals with CeD on a long-term gluten-free diet (GFD) underwent a 6-week gluten challenge combined with daily 100 mg ZED1227 drug (PGCd, n  = 28) or placebo (PGCp, n  = 19). Samples were collected at baseline (GFD) and post-gluten challenge (PGC). Mass spectrometry-based lipidomic and proteomics profiling were applied to plasma samples matched with duodenal histology. Whole blood samples (drug, n  = 20; placebo, n  = 16) were subjected to DNA methylation analysis. Comparative analyses were performed between the groups, with adjustment for BMI, age, sex, and country of origin. Results Significantly different gluten-induced plasma lipidomic changes were detected between GFD vs. PGCp and between GFD vs. PGCd, with 46 lipids differentially expressed in the placebo group and 6 in the drug group suggesting that the ZED1227 normalized gluten-induced lipidomic changes in plasma. Changes in medium-chain fatty acylcarnitines (CARs), particularly CAR 10:1 and CAR 9:0, were correlated with transient, non–clinically significant changes in renal biomarkers, with kidney function remaining within the normal range in the PGCp group. Glomerular filtration rate and plasma creatinine were restored with ZED1227. Integrated multi-omics analysis revealed a coordinated immune–epigenetic–lipid module centered on Ficolin-2, PUFA-enriched triglycerides, and a tightly co-regulated CpG cluster in the PER3 circadian regulator gene, highlighting selective immunometabolic coupling independent of clinical stratification. Drug treatment revealed consistent patterns suggesting normalization of the proteome and DNA methylome indicating that ZED1227 attenuated the systemic responses to gluten challenge. Conclusions These findings provide evidence that ZED1227 can significantly prevent the gluten-induced CeD-associated systemic changes in plasma/blood. Clinical trial EudraCT 2017-002241-30.

Mesalamine suppositories are first-line therapy in active ulcerative proctitis; the standard regime still recommends multiple doses per day. The primary objective of this study was to show the noninferiority of once-daily administration of a novel 1 g mesalamine suppository versus thrice-daily administration of the 0.5 g mesalamine suppository.MethodsThis was a single-blind (investigator-blinded), randomized, multicenter, comparative, Phase III clinical trial. Patients with mild to moderately active ulcerative proctitis inserted either one mesalamine 1 g suppository at bedtime or one mesalamine 0.5 g suppository thrice daily over a 6-week period. The primary endpoint was rate of remission (Disease Activity Index below 4).ResultsIn all, 354 patients were evaluable for safety and per-protocol analysis. The new regimen demonstrated noninferiority: The percentage of patients with remission was 87.9% for the once-daily 1 g mesalamine suppository and 90.7% for the thrice-daily 0.5 g mesalamine suppository. Each regimen resulted in prompt cessation of clinical symptoms (e.g., median time to ≤3 stools per day (all without blood): 5 days in the 1 g mesalamine once-daily and 7 days in the 0.5 g mesalamine thrice-daily group). Patients preferred applying suppositories once a day.ConclusionsIn active ulcerative proctitis the once-daily administration of a 1 g mesalamine suppository is as effective and safe, yet considerably more convenient, than the standard thrice-daily administration of a 0.5 g mesalamine suppository. (Inflamm Bowel Dis 2010)

Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2 / HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten. Viiri and colleagues show that an orally administered transglutaminase 2 inhibitor prevented gluten-induced intestinal damage and inflammation at the transcriptional level.

The enzyme transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis. Active TG2 is located mainly extracellularly in the lamina propria but also in the villous enterocytes of the duodenum. The TG2 inhibitor ZED1227 is a promising drug candidate for treating CeD and is designed to block the TG2-catalyzed deamidation and crosslinking of gliadin peptides. Our aim was to study the accumulation of ZED1227 after oral administration of the drug. We studied duodenal biopsies derived from a phase 2a clinical drug trial using an antibody that detects ZED1227 when bound to the catalytic center of TG2. Human epithelial organoids were studied in vitro for the effect of ZED1227 on the activity of TG2 using the 5-biotin-pentylamine assay. The ZED1227-TG2 complex was found mainly in the villous enterocytes in post-treatment biopsies. The signal of ZED1227-TG2 was strongest in the luminal epithelial brush border, while the intensity of the signal in the lamina propria was only ~20% of that in the villous enterocytes. No signal specific to ZED1227 could be detected in pretreatment biopsies or in biopsies from patients randomized to the placebo treatment arm. ZED1227-TG2 staining co-localized with total TG2 and native and deamidated gliadin peptides on the enterocyte luminal surface. Inhibition of TG2 activity by ZED1227 was demonstrated in epithelial organoids. Our findings suggest that active TG2 is present at the luminal side of the villous epithelium and that inhibition of TG2 activity by ZED1227 occurs already there before gliadin peptides enter the lamina propria.

Purpose The diagnosis microscopic colitis (MC) consisting of collagenous colitis (CC) and lymphocytic colitis (LC) relies on histological assessment of mucosal biopsies from the colon. The optimal biopsy strategy for reliable diagnosis of MC is controversial. The aim of this study was to evaluate the distribution of histopathological features of MC throughout the colon. Methods Mucosal biopsies from multiple colonic segments of patients with MC who participated in one of the three prospective European multicenter trials were analyzed. Histological slides were stained with hematoxylin-and-eosin, a connective tissue stain, and CD3 in selected cases. Results In total, 255 patients were included, 199 and 56 patients with CC and LC, respectively. Both groups exhibited a gradient with more pronounced inflammation in the lamina propria in the proximal colon compared with the distal colon. Similarly, the thickness of the subepithelial collagenous band in CC showed a gradient with higher values in the proximal colon. The mean number of intraepithelial lymphocytes was > 20 in all colonic segments in patients within both subgroups. Biopsies from 86 to 94% of individual segments were diagnostic, rectum excluded. Biopsies from non-diagnostic segments often showed features of another subgroup of MC. Conclusion Conclusively, although the severity of the histological changes in MC differed in the colonic mucosa, the minimum criteria required for the diagnosis were present in the random biopsies from the majority of segments. Thus, our findings show MC to be a pancolitis, rectum excluded, questioning previously proclaimed patchiness throughout the colon.

Background and aims Incomplete microscopic colitis (MCi) is a subtype of microscopic colitis (MC). Budesonide is recommended as a first‐line treatment for MC. However, randomised trials on efficacy of treatment in MCi are missing. We therefore performed a randomised, placebo‐controlled trial to evaluate budesonide as induction therapy for MCi. Methods Patients with active MCi were randomly assigned to either budesonide 9 mg once daily or placebo for 8 weeks in a double‐blind, double‐dummy design. The primary endpoint was clinical remission, defined as a mean of <3 stools/day and a mean of <1 watery stool/day in the 7 days before week 8. Results Due to insufficient patient recruitment, the trial was discontinued prematurely. The intention‐to‐treat analysis included 44 patients (21 budesonide and 23 placebo). The primary endpoint of clinical remission at week 8 was obtained by 71.4% on budesonide and 43.5% on placebo (p = 0.0582). All clinical secondary endpoints were in favour of budesonide. Budesonide decreased the number of soft or watery stools (16.3 vs. 7.7, p = 0.0186) and improved health‐related quality of life for all four dimensions of the short health scale. Adverse events with a suspected relation to study drug were reported in one patient in the budesonide group and two patients in the placebo group. Neither serious nor severe adverse events occurred during the double‐blind phase. Conclusions Budesonide decreased the frequency of soft or watery stools and improved the patients' quality of life significantly in MCi, but the primary endpoint was not met due to the low sample size (type 2 error). Budesonide was safe and well tolerated during the 8‐weeks treatment course.