A Clinical Study of Latiglutenase as a Treatment for Symptom Reduction for Celiac Disease

拉蒂谷蛋白酶治疗乳糜泻症状的临床研究

• 批准号: 10116258
• 负责人: Joseph A Murray
• 金额: $ 99.86万
• 依托单位: IMMUNOGENICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-08 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116258
• 关键词: Abdominal Pain; Adherence; Affect; Autoimmune Diseases; Back; Biological Products; Biometry; Celiac Disease; Chemistry; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Conduct Clinical Trials; Consumption; Cross-Over Studies; Deterioration; Development; Diagnosis; Diagnostic; Distress; Documentation; Dose; Double-Blind Method; Drug Formulations; Eating; Enrollment; Enzymes; Exposure to; Family; Funding; Gluten; Gluten-free diet; Goals; Health; Histologic; Immunoglobulin A; Immunoglobulin G; Individual; Ingestion; Intellectual Property; Intestinal Diseases; Intestines; Label; Lead; Legal patent; Life; Marketing; Measurement; Measures; Mucous Membrane; National Institute of Allergy and Infectious Disease; Online Systems; Oral; Outcome; Outcome Measure; Patient Outcomes Assessments; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II/III Clinical Trial; Placebos; Population; Powder dose form; Prevalence; Production; Proteins; Publishing; Randomized; Regulatory Affairs; Research Design; Safety; Secure; Serology; Site; Small Business Innovation Research Grant; Small Intestines; Solid; Statistical Data Interpretation; Stomach; Subgroup; Symptoms; System; Therapeutic; Tissue Transglutaminase Antibodies; Water; Work; base; clinical development; clinical efficacy; clinically relevant; commercialization; diaries; dietary; effective therapy; efficacy study; experience; gastrointestinal; healing; improved; innovation; instrument; meetings; operation; patient stratification; phase III trial; preclinical study; primary endpoint; product development; programs; prospective; recruit; reduce symptoms; research clinical testing; response; safety study; screening; seropositive; symptom treatment; symptomatic improvement; tool; trial design

The goal of this work is to develop a therapeutic drug that will protect individuals with celiac disease (CD) from intestinal and symptomatic distress they suffer due to minute ingestion of gluten protein. CD is an autoimmune disorder affecting the small intestine, afflicting about 1% of the world’s population, for which there is no known cure. Currently the only therapeutic option to avoid gastrointestinal-related symptoms and potentially long-term health consequences is the life-long strict adherence to a gluten-free diet (GFD). However, a majority of patients never fully recover. Furthermore, recent published analyses indicate that CD patients on average continue to inadvertently consume unsafe levels of gluten while attempting to adhere to a GFD (Ref 13). There is a considerable unmet need for a therapeutic solution to be used as an adjunct to a GFD. ImmunogenX is a clinical-stage biopharmaceutical company developing therapeutic and diagnostic solutions for celiac disease. Our lead development, latiglutenase, is an orally administered enzyme product with clinical evidence for histologic protection and symptomatic reduction in CD patients. The FDA, in Type C meetings with ImmunogenX, supports the company’s trial strategy, symptom label, and outcome measuring instrument. ImmunogenX’s team has extensive experience in clinical development and operations, regulatory affairs, biostatistics, and marketing strategy. Latiglutenase, a dual-enzyme drug product, has a strong scientific premise to justify further clinical testing. Previous clinical trials have yielded encouraging but inconclusive information regarding its impact on improving mucosal health. The indeterminacy is mostly attributable to shortcomings in one of the trial designs that became evident upon review of the trial results. Mucosal healing is relatively slow to manifest. Much stronger evidence was observed for symptom relief due to latiglutenase relative to placebo; however, this benefit was almost exclusively found in a subpopulation of CD patients who remained seropositive despite adhering to a GFD. We are beginning to better understand the reasons for this selectivity and also gaining more understanding of the prevalence of persistent seropositivity while on a GFD. The proposed NIAID trial will focus on multiple symptom relief for this subpopulation of CD patients, which comprises approximately 20% of all CD patients. In this SBIR Fast Track (Phase I+II) U44 proposal, we propose a randomized, double-blind, placebo-controlled, dose-ranging crossover study for diagnosed CD patients who remain symptomatic despite adhering to a gluten free diet. Our enrollment target is based on adequate powering of the primary endpoint for symptom reduction. We anticipate the need to prescreen 600 patients to enroll 120 seropositive patients into the screening period (about 20 % of CD patients after 1 year on a GFD remain persistently seropositive), ultimately achieving 60 completed patients. Subject recruitment will involve four study centers and will span approximately 18 months. We will employ the recently validated Celiac Disease Symptom Diary patient-reported outcome (CDSD© PRO) instrument for CD symptoms. Phase I will provide a refined trial design, outcome measurement development, statistical tools, and final drug product development to justify clinical trial conduct in Phase II.

这项工作的目的是开发一种治疗性药物，以保护患有腹腔疾病的人 （CD）由于小小的摄入麸质蛋白而遭受的肠和有症状困扰。 CD是 一种自身免疫性疾病，影响了小肠，遭受了大约1％的世界人口的痛苦，为此 没有已知的治愈方法。目前，避免胃肠道相关符号的唯一热量选项 潜在的长期健康后果是终身严格遵守无麸质饮食（GFD）。 但是，大多数患者从未完全康复。此外，最近发表的分析表明CD 平均而言，患者在试图遵守的同时，不经意间消耗不安全的面筋水平 GFD（参考13）。需要将治疗溶液用作辅助剂 GFD。 Immunogenx是一家临床阶段生物制药公司，开发治疗和诊断解决方案 用于腹腔疾病。我们的铅开发Latiglutenase是一种口服酶的酶产物 CD患者的组织学保护和症状减少的临床证据。 FDA，类型 C与Immunogenx的C会议，支持公司的试用策略，症状标签和结果测量 乐器。 Immunogenx的团队在临床开发和运营，监管方面拥有丰富的经验 事务，生物统计学和营销策略。 Latiglutenase是一种双酶药物产品，具有强大的科学前提，可以证明进一步的临床测试是合理的。 先前的临床试验对其对其影响的影响产生了令人鼓舞但尚无定论的信息 改善粘膜健康。不确定性主要归因于一个试验设计中的缺点 审查了试验结果，这成为证据。粘膜愈合相对较慢。 观察到由于安慰剂而言，由于拉丁木素酶导致的症状缓解，有更强的证据。然而， 在仍然是血清阳性目的地的CD患者的亚群中几乎完全发现了这种好处 坚持GFD。我们开始更好地理解这种选择性的原因并获得了 在GFD上，更多地了解持续的血清阳性流行率。提议的尼亚德 试验将重点介绍CD患者的这种亚群的多种症状缓解，该症状大致包括 所有CD患者中有20％。 在此SBIR快速轨道（I阶段+II）U44提案中，我们提出了一个随机，双盲，安慰剂对照， 诊断性CD患者的剂量延伸跨界研究 无麸质饮食。我们的入学目标是基于症状的主要终点的足够动力 减少。我们预计有必要将600名患者预先招募120名血清阳性患者进入 筛查期（GFD 1年后约有20％的CD患者保持持续性血清阳性），最终 达到60个完整的患者。主题招聘将涉及四个研究中心，并将涉及 大约18个月。我们将采用最近验证的乳糜泻症状日记患者报告 结果（CDSD©Pro）CD符号的仪器。第一阶段将提供精致的试用设计， 结果测量开发，统计工具和最终药物开发，以证明临床合理 在第二阶段的试验。