Latiglutenase as a Treatment for Celiac Disease

拉蒂谷蛋白酶治疗乳糜泻

• 批准号: 10063458
• 负责人: Joseph A Murray
• 金额: $ 25.91万
• 依托单位: IMMUNOGENICS, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063458
• 关键词: Adherence; Animals; Autoimmune Diseases; Biological; Biological Markers; Biopsy; Blood; Celiac Disease; Clinic; Clinical; Clinical Trials; Data; Deterioration; Development; Diagnosis; Diagnostic; Diet; Digestion; Disease; Disease remission; Enrollment; Enzymes; Esophagogastroduodenoscopy; Exposure to; Funding; Glutamine; Gluten; Goals; Grant; Health; Height; Histologic; Human; Intake; Knowledge; Lead; Life; Measurement; Measures; Modeling; Monitor; Mucous Membrane; Natural Products; Oral; Outcome; Patient Outcomes Assessments; Patients; Peptides; Pharmaceutical Preparations; Phase II Clinical Trials; Placebos; Plasma; Population; Proline; Proteins; Reading; Recovery; Resistance; Safety; Sampling; Serum; Simvastatin; Small Intestines; Stomach; Symptoms; Therapeutic; Time; Villous; Work; arm; base; cost; diaries; dietary supplements; effective therapy; experimental study; factor IXa-factor VIIIa; gastrointestinal; human study; improved; minimally invasive; primary endpoint; product development; reduce symptoms; research clinical testing; response; secondary endpoint; success; symptom treatment; tool

PROJECT SUMMARY/ABSTRACT Original Grant Celiac disease (CD) is an autoimmune disorder of the small intestine, afflicting about 1% of the world's population, for which there is no 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. There is a huge unmet need for a therapeu- tic solution to be used as an adjunct to a GFD. There is a further unmet need for an effective and minimally- invasive tool to monitor small intestinal recovery in CD patients as an alternative to esophagogastroduo- denoscopy (EGD), which is invasive, costly and not generally recommended by clinicians for disease moni- toring. ImmunogenX® is a clinical-stage therapeutic and diagnostic company focused on celiac disease (CD). Our lead product development is the orally administered enzyme product latiglutenase, which has shown evidence for histologic protection and symptom reduction in response to exposure to moderate amounts of dietary gluten. The mechanism of action is the proteolytic digestion along specific glutamine and proline bonds of digestively resistant gluten peptides in the stomach using a combination of two digestive enzymes. Our diagnostic product CypCel is based on a drug biomarker simvastatin (SV) that is highly metabolized in the small intestine and is present in blood at concentrations that are proportional to the extent of villous health. Latiglutenase, a two-enzyme natural product, has a strong scientific premise to justify further clinical testing. It has been shown in a variety of model stomach experiments to detoxify antigenic gluten proteins. Furthermore, there has been sufficient animal and human safety data to be registered as a dietary supple- ment. However, we would first like to obtain more scientific data to inform us on the most responsible and optimal path toward further development and product launch. Previous clinical trials have yielded encourag- ing but inconclusive information regarding its impact on improving mucosal health. We propose to the NCCIH a study to fill this gap in our scientific knowledge. In this application, we propose a human study consisting of a gluten-challenge for diagnosed CD pa- tients in remission. We will employ placebo and latiglutenase arms in a 1:1 ratio and will measure the bio- logical signatures for mucosal changes using biopsy readings of villous height to crypt depth ratio (Vh:Cd) and CypCel measurements (as a minimally-invasive indicator of mucosal health). The trial will be powered to a primary endpoint for biopsy Vh:Cd and secondary endpoint for SV level in serum and plasma samples collected at 5 time points after administration of SV. Our enrollment target based on adequate powering of the primary and secondary endpoints is 42 completed patients. We will also employ the recently validated Celiac Disease Symptom Diary patient reported outcome (CDSD PRO) tool for CD symptoms in order to demonstrate an association between the change in the biological signature (Vh:Cd) and improvement in a clinical outcome (symptoms). We anticipate completing this enrollment at Mayo Clinic (Rochester, MN) where we have already initiated a CypCel trial. This work will provide vital scientific data to help justify fur- ther clinical testing. Supplemental Work We request supplemental funds to extend the trial into a third year. For several unanticipated reasons, the trial planning was more complicated and expensive to start, but is now showing healthy enrollment and operational success. We originally proposed this as a 2-year project with tight funding limits, but accepted that we would have to provide co-funding to meet the cost of a Phase 2 clinical trial. In hindsight we should have recognized that a third year would be needed. We seek a third year of funding to complete this very important and now operationally robust trial. 1

项目摘要/摘要 原创赠款 乳糜泻(CD)是一种自身免疫性小肠疾病，困扰着世界上约1%的 人口，这是无法治愈的。目前避免胃肠道相关疾病的唯一治疗选择 症状和潜在的长期健康后果是终生严格坚持无麸质 饮食(GFD)。然而，大多数患者从未完全康复。有一个巨大的未得到满足的治疗需求- 用作GFD附件的TiC溶液。还有一个尚未得到满足的需求，即有效和最低限度地- 有创性监测CD患者小肠恢复情况可替代食道胃十二指肠插管 结肠镜检查(EGD)是一种侵入性的、昂贵的检查方法，通常不被临床医生推荐用于疾病监测。 托林。 免疫原X®是一家专注于乳糜泻(CD)的临床阶段治疗和诊断公司。 我们的主导产品开发是口服酶产品乳谷氨酸酶，它已经表明 组织学保护和症状减轻的证据表明暴露于中等剂量的 膳食面筋。其作用机制是沿着特定的谷氨酰胺和脯氨酸的蛋白质分解消化。 使用两种消化酶的组合在胃中结合抗消化的面筋多肽。 我们的诊断产品CypCel是基于一种药物生物标志物辛伐他汀(SV)，该药物在 小肠，在血液中的浓度与绒毛的范围成正比 健康。 乳酸谷氨酸酶是一种两种酶的天然产物，有很强的科学前提来证明进一步的临床应用是合理的。 测试。它已经在各种模型胃实验中被证明可以解毒抗原性面筋蛋白。 此外，已经有足够的动物和人类安全数据被登记为膳食补充- 门槛。然而，我们首先想要获得更多的科学数据，让我们了解最负责任和 通向进一步开发和产品发布的最佳途径。之前的临床试验已经产生了令人鼓舞的结果-- 关于其对改善粘膜健康的影响的信息尚不明确。我们向 NCCIH进行了一项研究，以填补我们科学知识的这一空白. 在这项应用中，我们提出了一项由面筋挑战诊断CD-PA的人体研究。 病情缓解期。我们将以1：1的比例使用安慰剂和乳胶酶手臂，并将测量生物- 绒毛高度与隐窝深度之比(VH：CD)活检读数的粘膜改变的逻辑征象 和CypCel测量(作为粘膜健康的微创指标)。审判将得到支持 作为活检VH：CD的主要终点和血清和血浆样本中SV水平的次要终点 在给药后5个时间点收集。我们的招生目标是基于足够的电力 主要和次要终点为42例完全性患者。我们还将采用最近经过验证的 乳糜泻症状日记患者报告结局(CDSDPRO)工具用于CD症状，以便 证明生物特征(VH：CD)的变化与 临床结果(症状)。我们预计将在梅奥诊所(明尼苏达州罗切斯特市)完成此次注册。 我们已经启动了CypCel试验。这项工作将提供重要的科学数据，以帮助证明毛皮- 另一项临床试验。 补充工作 我们请求补充资金，以将试验延长到第三年。出于一些意想不到的原因， 试验计划开始时更加复杂和昂贵，但现在显示出良好的登记人数和 运营成功。我们最初提出这是一个有严格资金限制的为期两年的项目，但被接受了 我们将不得不提供共同资金来满足第二阶段临床试验的成本。事后看来，我们应该 已经认识到需要第三个年头。我们寻求第三年的资金来完成这一 这是一项重要的、现在具有强大操作性的试验。 1