一项随机对照试验：转谷氨酰胺酶 2 抑制剂治疗乳糜泻。

A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease.

机构信息

From the Institute of Translational Immunology and Celiac Center, Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz (D.S., T.F.-S.), the Department of Internal and Integrative Medicine, Sozialstiftung Bamberg, Bamberg (J.L.), the Department of Integrative Medicine, University of Duisburg-Essen, Duisburg-Essen (J.L.), the Division of Gastroenterology, Hepatology, and Infectious Diseases, Department of Internal Medicine I, University Hospital Tübingen, Tübingen (S.F.), the Department of Gastroenterology, Infectious Diseases, and Rheumatology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Berlin (M. Schumann), the Department of Medicine II, University Hospital, Ludwig Maximilians University, Munich (H.P.T.), the Department of Medicine 1, Hector Center for Nutrition, Exercise, and Sports, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen (Y.Z.), the Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg (A.W.L.), the Department of Internal Medicine IV, University Hospital, Friedrich-Schiller University Jena, Jena (A.S.), and Dr. Falk Pharma, Freiburg (R.M., R.G.) - all in Germany; the Division of Gastroenterology and Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston (D.S.); the Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital (M.M., A.P., M.-L.L.), the Faculty of Medicine and Health Technology, Tampere University (J.I., J.T.), Jilab (J.I.), and the Department of Pediatrics, Tampere University Hospital (M.-L.L.), Tampere, the Department of Internal Medicine, Central Finland Central Hospital, Jyväskylä (J.T.), Lääkärikeskus Aava Helsinki Kamppi, Helsinki (J. Koskenpato), and Clinical Research Services Turku, Turku (M. Scheinin) - all in Finland; Oslo University Hospital, Rikshospitalet, and Stiftelsen K.G. Jebsen Celiac Disease Research Center, University of Oslo, Oslo (K.E.A.L.), the Medical Department, Innlandet Hospital Trust, Gjøvik (O.H.), and Akershus University Hospital, Lørenskog (J.J.) - all in Norway; the University of Medicine and Pharmacy "Carol Davila" and the National Institute for Mother and Child Health "Alessandrescu-Rusescu," Bucharest, Romania (A.P.); the Gastroenterology Department and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania (J. Kupcinskas); the Department of Gastroenterology, Internal Medicine Clinic, Tartu University Hospital, Tartu, Estonia (K.K.); the Department of Gastroenterology and Hepatology, University Hospital Zurich (L.B., J.Z.), and the Swiss Celiac Center, Center of Gastroenterology, Clinic Hirslanden (J.Z.) - both in Zurich, Switzerland; and University College Hospital Galway, Galway, Ireland (V.B.).

出版信息

N Engl J Med. 2021 Jul 1;385(1):35-45. doi: 10.1056/NEJMoa2032441.

DOI:10.1056/NEJMoa2032441

PMID:34192430

Abstract

BACKGROUND

In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease.

METHODS

In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life).

RESULTS

Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P = 0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI, -7.6 to 2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI, -8.9 to 0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI, -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group.

CONCLUSIONS

In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease. (Funded by Dr. Falk Pharma; CEC-3 EudraCT number, 2017-002241-30.).

摘要

背景

在乳糜泻中，小肠转谷氨酰胺酶 2 导致麸质肽中的谷氨酰胺残基脱酰胺，从而增强 T 细胞的刺激作用，并导致黏膜损伤。转谷氨酰胺酶 2 的抑制作用可能是治疗乳糜泻的一种方法。

方法

在一项概念验证试验中，我们评估了三种剂量的 ZED1227（一种选择性口服转谷氨酰胺酶 2 抑制剂）与安慰剂相比，在接受每日麸质挑战的病情控制良好的乳糜泻患者中，为期 6 周的治疗的疗效和安全性。主要终点是绒毛高度与隐窝深度之比评估的麸质诱导的黏膜损伤的衰减。次要终点包括上皮内淋巴细胞密度、乳糜泻症状指数评分和乳糜泻问卷评分（用于评估健康相关生活质量）。

结果

在分配至 10mg ZED1227 组的 41 例患者、分配至 50mg 组的 41 例患者、分配至 100mg 组的 41 例患者和分配至安慰剂组的 40 例患者中，分别有 35、39、38 和 30 例患者有足够的十二指肠活检样本用于评估主要终点。在所有三个剂量组中，ZED1227 治疗均减轻了麸质诱导的十二指肠黏膜损伤。与安慰剂相比，从基线到第 6 周，绒毛高度与隐窝深度比值的平均变化在 10mg 组为 0.44（95%置信区间，0.15 至 0.73）（P=0.001），在 50mg 组为 0.49（95%置信区间，0.20 至 0.77）（P<0.001），在 100mg 组为 0.48（95%置信区间，0.20 至 0.77）（P<0.001）。与安慰剂相比，上皮内淋巴细胞密度的变化在 10mg 组为-2.7 个/100 个上皮细胞（95%置信区间，-7.6 至 2.2），在 50mg 组为-4.2 个/100 个上皮细胞（95%置信区间，-8.9 至 0.6），在 100mg 组为-9.6 个/100 个上皮细胞（95%置信区间，-14.4 至-4.8）。使用 100mg 剂量可能改善了症状和生活质量评分。最常见的不良反应是头痛、恶心、腹泻、呕吐和腹痛，在所有组中发生率相似。皮疹在 100mg 组的 40 例患者（8%）中出现。