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.

这项工作的目标是开发一种治疗药物来保护乳糜泻患者 （CD）他们因摄入少量麸质蛋白而遭受肠道和症状困扰。光盘是 一种影响小肠的自身免疫性疾病，困扰着世界上约 1% 的人口，为此 目前还没有已知的治疗方法。目前是避免胃肠道相关症状的唯一治疗选择 潜在的长期健康后果是终生严格遵守无麸质饮食（GFD）。 然而，大多数患者从未完全康复。此外，最近发表的分析表明 CD 患者在尝试坚持饮食的同时，平均仍会无意中摄入不安全水平的麸质 GFD（参考文献 13）。对于用作辅助治疗的治疗解决方案，存在相当大的未满足需求 GFD。 ImmunogenX 是一家临床阶段的生物制药公司，开发治疗和诊断解决方案 用于乳糜泻。我们的主导开发产品 latiglutenase 是一种口服酶产品 具有对 CD 患者进行组织学保护和症状减轻的临床证据。 FDA，类型 C 与 ImmunogenX 举行会议，支持公司的试验策略、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，具有强有力的科学前提来证明进一步的临床测试是合理的。 先前的临床试验已就其对健康的影响提供了令人鼓舞但非结论性的信息。 改善粘膜健康。不确定性主要归因于其中一项试验设计的缺陷 在审查试验结果后，这一点变得显而易见。粘膜愈合的表现相对较慢。 相对于安慰剂，观察到更有力的证据表明拉谷蛋白酶可缓解症状；然而， 这种益处几乎只出现在 CD 患者亚群中，尽管这些患者仍保持血清反应阳性 遵守 GFD。我们开始更好地理解这种选择性的原因，并且也获得了 更好地了解 GFD 期间持续血清阳性的发生率。拟议的 NIAID 试验将重点关注 CD 患者亚群的多种症状缓解，其中大约包括 占所有 CD 患者的 20%。 在此 SBIR 快速通道（I+II 期）U44 提案中，我们提出了一种随机、双盲、安慰剂对照、 针对确诊 CD 患者的剂量范围交叉研究，这些患者尽管坚持服用但仍存在症状 无麸质饮食。我们的入组目标是基于症状主要终点的充足动力 减少。我们预计需要对 600 名患者进行预筛查，以便将 120 名血清反应呈阳性的患者纳入研究中。 筛查期（大约 20% 的 CD 患者在接受 GFD 1 年后仍持续血清反应呈阳性），最终 完成 60 名患者。受试者招募将涉及四个研究中心，并将跨越 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 CD 症状的结果 (CDSD© PRO) 工具。第一阶段将提供完善的试验设计， 结果测量开发、统计工具和最终药物产品开发，以证明临床合理性 第二阶段的试验进行。