TAK-227 / Zedira, Dr Falk, Takeda - LARVOL DELTA

Viral infection as a catalyst for type 1 diabetes: transglutaminase-2 inhibition delays coxsackievirus B3 accelerated disease by limiting stress induced neo-antigens and T cell reprogramming (EASD 2026) - "CVB-induced ER stress-induced Ca2+-Flux activates tTG2, promoting neo-antigen formation and pathogenic T-cell metabolic reprogramming while altering immune regulation. Pharmacologic tTG2 inhibition dampens autoreactive responses, preserves regulatory T-cell frequencies, improves metabolic control, and delays disease progression, supporting repurposing of the FDA-approved inhibitor ZED1227 for at-risk or newly diagnosed individuals."

Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus • CD4 • CD8 • CHGA • FOXP3 • IFNG • SLC2A1 • SLC3A2 • SLC7A5 • TFRC • TGM2

CEC-013/CEL: A study to discover if ZED1227 can improve continued celiac disease symptoms despite a gluten-free diet (clinicaltrialsregister.eu) - P1/2 | N=436 | Recruiting | Sponsor: Dr. Falk Pharma GmbH | Active, not recruiting ➔ Recruiting

Enrollment open • Celiac Disease • Immunology

CEC-013/CEL: Evaluating the Efficacy and Tolerability of ZED1227 in Subjects With Non-responsive Celiac Disease (clinicaltrials.gov) - P2 | N=356 | Recruiting | Sponsor: Dr. Falk Pharma GmbH | Active, not recruiting ➔ Recruiting

Enrollment open • Celiac Disease • Immunology

CEC-013/CEL: Evaluating the Efficacy and Tolerability of ZED1227 in Subjects With Non-responsive Celiac Disease (clinicaltrials.gov) - P2 | N=356 | Active, not recruiting | Sponsor: Dr. Falk Pharma GmbH

New P2 trial • Celiac Disease • Immunology

CLINICAL, HISTOLOGIC AND SAFETY OUTCOMES OF ZED1227 TREATMENT IN SYMPTOMATIC CELIAC DISEASE PATIENTS: RESULTS FROM THE PHASE 2B CEC-004/CEL RANDOMIZED CLINICAL TRIAL (UEGW 2025) - "The CEC-004/CEL study did not meet its primary endpoint of combined improvement in histology and symptoms. However, changes in the VH:CrD ratio achieved with 50 mg ZED1227 QD were statistically superior to placebo, consistent with the results of the prior CEC-003/CEL study. Significant within-group improvement from baseline to week 12 in both histologic and symptom outcomes within the placebo group underscored the challenges of clinical trials without deliberate gluten exposure in patients with the heterogeneous symptom and histology typical of partially treated CeD."

Clinical • P2b data • Celiac Disease • Immunology • TGM2

REGULATORY IMMUNE CELLS MODULATE THE INTESTINAL IMMUNE RESPONSE TO GLUTEN CHALLENGE IN CELIAC DISEASE – EFFECT OF THE TG2 INHIBITOR ZED1227: RESULTS FROM THE CEC-3 CLINICAL TRIAL (UEGW 2025) - "Our data derived from superbly analyzed pre- and post challenge duodenal biopsies demonstrate an active anti-inflammatory immune modulation, largely Treg cell mediated, in CeD in patients prior to and during gluten challenge. Zed1227 treatment potently activates this regulatory response. The balance of several beneficial vs detrimental predisposing Treg-related genes may play a causative role in the variable sensitivity of CeD patients to gluten exposure."

Clinical • Immune cell • Celiac Disease • Immune Modulation • Immunology • Inflammation • Psychiatry • Targeted Protein Degradation • ACAT1 • BAG1 • CD96 • CLDN5 • MERTK • SMAD7 • SOCS2 • SQSTM1 • TAP1 • TGFB1 • TGM2

Is There a Future Without Gluten Restrictions for Celiac Patients? Update on Current Treatments. (PubMed, Nutrients) - "These include gluten-degrading enzymes (e.g., AN-PEP, Latiglutenase, Zamaglutenase), gluten-sequestering agents (e.g., AGY-010, BL-7010), modulators of intestinal permeability (e.g., Larazotide acetate, IMU-856), immune-modulating agents (e.g., ZED1227, AMG 714, EQ102), and strategies for immune tolerization (e.g., TAK-101, KAN-101, Nexvax2). Continued research is essential to validate efficacy, optimize dosing, and ensure safety in broader patient populations. Here, we provide a comprehensive overview of the therapeutic landscape for CeD, analyze the main strengths and limitations of each treatment and highlight promising directions for future management of CeD, altogether evidencing the urgent need to develop effective alternatives for these patients."

Journal • Review • Allergy • Celiac Disease • Immunology

New Therapeutic Challenges in Pediatric Gastroenterology: A Narrative Review. (PubMed, Healthcare (Basel)) - "For CeD, therapies like gluten-degrading enzymes (latiglutenase, Kuma030) and zonulin inhibitors (larazotide acetate) show promise, though clinical outcomes are inconsistent...Transglutaminase 2 inhibitors like ZED-1227 could help prevent gluten-induced damage. Monoclonal antibodies targeting immune pathways, such as AMG 714 and larazotide acetate, require further validation in pediatric populations. In EoE, biologics like dupilumab, cendakimab, dectrekumab (IL-13 inhibitors), and mepolizumab, reslizumab, and benralizumab (IL-5/IL-5R inhibitors) show varying efficacy, while thymic stromal lymphopoietin (TSLP) inhibitors like tezepelumab are also being investigated...For IBD, biologics like vedolizumab, ustekinumab, and risankizumab, as well as small molecules like tofacitinib, etrasimod, and upadacitinib, are emerging treatments...Personalized therapy, integrating precision medicine, therapeutic drug monitoring, and lifestyle changes, is increasingly guiding pediatric..."

Journal • Review • Autoimmune Hepatitis • Celiac Disease • Eosinophilic Esophagitis • Gastroenterology • Gastrointestinal Disorder • Hepatitis B • Hepatology • Immunology • Inflammation • Inflammatory Bowel Disease • Pediatrics • Transplantation • IL13 • IL5 • TGM2 • TSLP

KI67+ INTRAEPITHELIAL LYMPHOCYTES IMPROVE PREDICTION OF THERAPEUTIC RESPONSE TO THE TRANSGLUTAMINASE INHIBITOR ZED1227 IN A CELIAC DISEASE PHASE II GLUTEN CHALLENGE TRIAL (CEC-3/CEL) (DDW 2025) - No abstract available

P2 data • Celiac Disease • Immunology

IMPACT OF TRANSGLUTAMINASE 2 INHIBITOR ZED1227 ON SYSTEMIC LIPIDOMIC RESPONSES IN CELIAC DISEASE: A GLUTEN CHALLENGE STUDY (UEGW 2024) - "This study highlights the potential of lipidomic analysis as a tool for early detection of systemic responses to gluten in CeD. The differential lipidomic profiles between the drug and placebo groups suggest that ZED1227 attenuates gluten-induced lipidomic alterations."

Celiac Disease • Immunology • PGCP • TGM2

TG2 INHIBITOR (ZED1227) SHOWS DOSE-DEPENDENT PROTECTION FROM GLUTEN-INDUCED INTESTINAL DAMAGE IN CELIAC DISEASE: TRANSCRIPTOMIC ANALYSIS FROM A PHASE 2A STUDY (UEGW 2024) - P2 | "ZED1227 effectively prevents gluten-induced mucosal damage in patients with CeD and beneficially modulates gene expression associated with mucosal integrity and the immune response, particularly of the IFN-γ pathway that is central to CD4 T cell mediated CeD pathogenesis. These data corroborate and further elucidate key pathways of intestinal damage in CeD and may suggest new biomarkers of mucosal injury."

Omic analysis • P2a data • Celiac Disease • Immunology • CD4 • IFNG • TGM2

Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease. (PubMed, Nat Immunol) - "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...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."

Journal • Celiac Disease • Immunology • Inflammation • IFNG • TGM2

Results from a phase 2a randomized trial with the transglutaminase 2 inhibitor ZED1227 in patients with MASLD (EASL-ILC 2024) - "ZED1227 was well tolerated and showed a positive trend for reducing profibrogenic PRO-C3 in phenotypic MASLD that however, did not reach statistical significance. In the subgroup of pts with higher PRO-C3 at baseline, the ZED1227 effect was more pronounced and dose dependent."

Clinical • P2a data • Cardiovascular • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Type 2 Diabetes Mellitus • TGM2

NormaliZED: Different Doses of ZED1227 vs. Placebo in NAFLD (clinicaltrials.gov) - P2 | N=186 | Completed | Sponsor: Dr. Falk Pharma GmbH | Recruiting ➔ Completed

Trial completion • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Celiac disease: Hope for new treatments beyond a gluten-free diet. (PubMed, Clin Nutr) - "Despite significant efforts, no treatment has yet completed a phase III clinical trial. Future studies will likely focus on the use of supplemental drugs in conjunction to a GFD, with ALV003 and ZED-1227 currently being the most promising therapeutic options."

Journal • Review • Celiac Disease • Immunology • Inflammation

A Study of TAK-227 in Healthy Adults (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Takeda | Active, not recruiting ➔ Completed

Trial completion

The Oral Transglutaminase 2 Inhibitor ZED1227 Accumulates in the Villous Enterocytes in Celiac Disease Patients during Gluten Challenge and Drug Treatment. (PubMed, Int J Mol Sci) - "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."

Journal • Celiac Disease • Immunology • TGM2

A Study of TAK-227 in Healthy Adults (clinicaltrials.gov) - P1 | N=24 | Active, not recruiting | Sponsor: Takeda | Recruiting ➔ Active, not recruiting

Enrollment closed

A Study of TAK-227 in Healthy Adults (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Takeda | Not yet recruiting ➔ Recruiting

Enrollment open

"Any news on Zed1227?" (,@Hamifon)

A Study of TAK-227 in Healthy Adults (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Takeda

New P1 trial

"Takeda, Zedira and Dr Falk Pharma ink pact to develop Celiac Disease therapy @TakedaPharma #Takeda #Zedira #DrFalkPharma #ZED1227 #celiacdisease #takedanews https://t.co/kTAYjkQObt" (,@medicaldialogs)

Celiac Disease • Immunology

THE ORAL TISSUE TRANSGLUTAMINASE INHIBITOR ZED1227 PREVENTS GLUTEN-INDUCED ENTEROPATHY IN A HUMANIZED MOUSE MODEL OF CELIAC DISEASE (UEGW 2022) - "1.Oral ZED1227 effectively blocked TG2 activity in vivo and attenuated CeD in our transgenic NOD-DQ8 mouse model.2.The NOD-DQ8 model predicted therapeutic efficacy of ZED1227 that was later demonstrated in a phase 2a clinical trial of 160 CeD patients in remission who were challenged with gluten (Schuppan et al, NEJM 2021)."

Preclinical • Celiac Disease • Immunology • Inflammation • Inflammatory Bowel Disease • CD68 • CD8 • PTPRC

NormaliZED: Different Doses of ZED1227 vs. Placebo in NAFLD (clinicaltrials.gov) - P2 | N=160 | Recruiting | Sponsor: Dr. Falk Pharma GmbH | Not yet recruiting ➔ Recruiting | Trial completion date: Jun 2022 ➔ Jun 2023 | Trial primary completion date: Jun 2022 ➔ Jun 2023

Enrollment open • Trial completion date • Trial primary completion date • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease

Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease. (PubMed, Cells) - "Here, we describe the specific features and profiling data of the drug candidate ZED1227. Further, we give an outlook on TG2 inhibition as a therapeutic approach in indications beyond celiac disease."

Journal • Celiac Disease • Immunology