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能够保护乳糜泻患者的治疗药物。 (CD)因少量摄入面筋蛋白而遭受肠道和症状性窘迫。CD是 一种影响小肠的自身免疫性疾病，困扰着大约1%的世界人口，为此 目前还没有已知的治疗方法。目前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，患者继续无意中摄入不安全水平的面筋，同时试图坚持 参考文献13.有一个相当大的未得到满足的需求，需要一种治疗溶液作为一种辅助手段 GFD。 免疫原X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。我们开发的乳胶酶是一种口服酶产品。 为CD患者的组织学保护和症状减轻提供临床证据。美国食品药品监督管理局，类型 C与免疫原X会面，支持公司的试验战略、症状标签和结果衡量 乐器。免疫原X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。 拉替谷氨酸酶是一种双酶药物产品，它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非决定性的信息，关于它对 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。粘膜愈合相对较慢。 与安慰剂相比，观察到更有力的证据表明，乳谷氨酸酶可以缓解症状；然而， 这一益处几乎只出现在CD患者的亚群中，这些患者尽管 坚持使用GFD。我们开始更好地理解这种选择性的原因，并获得了 更多地了解在GFD期间持续血清阳性的流行率。拟议的NIAID 试验将侧重于缓解这一亚群CD患者的多种症状，包括大约 占所有CD患者的20%。 在这项SBIR Fast Track(阶段I+II)U44方案中，我们提出了一种随机、双盲、安慰剂对照、 对确诊的CD患者进行剂量范围交叉研究，这些患者尽管坚持服用但仍有症状 无麸质饮食。我们的登记目标基于针对症状的主要终端的足够供电 还原。我们预计需要对600名患者进行预筛查，以登记120名血清阳性患者加入 筛查期(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例病人入院。学科招聘将涉及四个学习中心，并将跨越 大约18个月。我们将采用最近经过验证的腹水症症状日记患者-报告 结果(CDSDPRO)CD症状测试仪。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 在第二阶段进行试验。

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.