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

这项工作的目标是开发一种治疗药物，将保护个人与腹腔疾病 (CD)他们因摄入麸质蛋白而遭受肠道和症状性痛苦。CD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， 没有已知的治疗方法。目前唯一的治疗选择，以避免胃肠道相关的症状 和潜在的长期健康后果是终身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 平均而言，患者继续无意中消耗不安全水平的谷蛋白，同时试图坚持 a GFD（参考文献13）。对于用作药物组合物的辅助剂的治疗溶液存在相当大的未满足的需求。 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 治疗乳糜泻我们的领导开发，latiglutenase，是一种口服酶产品 临床证据表明CD患者的组织学保护和症状减轻。FDA，类型 C与ImmunogenX会面，支持公司的试验策略，症状标签和结果测量 仪器ImmunogenX的团队在临床开发和运营、监管、 生物统计学和营销策略。 麦谷蛋白酶是一种双酶药物产品，有很强的科学前提来证明进一步的临床试验是合理的。 以前的临床试验已经产生了令人鼓舞的，但不确定的信息，其影响， 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 这一点在审查审判结果时变得显而易见。粘膜愈合相对缓慢。 相对于安慰剂，观察到拉替谷蛋白酶引起的症状缓解的更强有力的证据;然而， 这一益处几乎仅在CD患者亚群中发现， 遵守GFD。我们开始更好地理解这种选择性的原因， 更多地了解GFD期间持续血清阳性的患病率。拟议的NIAID 试验将重点关注CD患者亚群的多种症状缓解，该亚群约包括 20%的CD患者。 在本SBIR快速通道（I+II期）U44提案中，我们提出了一项随机、双盲、安慰剂对照， 一项针对确诊的CD患者的剂量范围交叉研究，这些患者尽管坚持治疗但仍有症状 无麸质饮食我们的入组目标是基于症状主要终点的充分把握度 还原我们预计需要对600名患者进行预筛选，以将120名血清阳性患者纳入研究。 筛选期（约20%的CD患者在接受GFD治疗1年后仍持续血清阳性），最终 完成60例患者。受试者招募将涉及四家研究中心， 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）工具用于CD症状。第一阶段将提供完善的试验设计， 结果测量开发、统计工具和最终制剂开发，以证明临床 试验在第二阶段进行。

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.