Evaluation of Clinical Outcome Assessment (COA) and Potential Biomarkers to Facilitate Interventional Trial for Mucopolysaccharidosis IIID Patients

临床结果评估 (COA) 和潜在生物标志物的评估，以促进粘多糖贮积症 IIID 患者的介入试验

• 批准号: 10599310
• 负责人: Srikanth Singamsetty
• 金额: $ 112.56万
• 依托单位: PHOENIX NEST, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10599310
• 关键词: Affect; Authorization documentation; Awareness; Behavior; Behavioral; Biochemical; Biochemical Markers; Brain; CLN2 gene; Case Study; Cessation of life; Childhood; Clinic; Clinical; Clinical Data; Clinical Protocols; Clinical Research; Clinical Services; Clinical Trials; Clinical Trials Design; Cognitive; Collaborations; Communities; Consultations; Contract Services; Data; Data Collection; Dementia; Development; Development Plans; Diagnosis; Dimensions; Disease; Disease Progression; Drug Evaluation; Electrophysiology (science); Emotional; Enrollment; Enzymes; Evaluation; Foundations; Genotype; Goals; Grant; Human; Image; Immobilization; Impaired cognition; Individual; Infusion procedures; International; Intervention; Intervention Studies; Intervention Trial; Investigational Therapies; Legal patent; Letters; Licensing; Literature; Measurable; Measurement; Measures; Medical History; Molecular; Molecular Diagnosis; Monitor; Morals; Motor Skills; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis II; Mucopolysaccharidosis III; Natural History; Nerve Degeneration; Neurocognitive; Neurologic; Neurologic Symptoms; Neuropsychology; Outcome; Outcome Measure; Pathologic; Pathology; Patient Outcomes Assessments; Patients; Phase; Phenotype; Preparation; Principal Investigator; Problem behavior; Program Development; Protocols documentation; Publications; Quality of life; Rare Diseases; Recombinants; Recommendation; Records; Research; Research Design; Research Personnel; Scientist; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Spielmeyer-Vogt Disease; Sulfatases; Surrogate Markers; Surveys; Technology; Time; Treatment Efficacy; Validation; Variant; Visit; Work; Writing; analytical tool; arm; authority; biomarker development; clinical outcome assessment; clinical outcome measures; clinical predictors; clinical trial protocol; clinically relevant; cohort; commercialization; compare effectiveness; control trial; design; disease registry; drug development; efficacy evaluation; enzyme replacement therapy; expectation; experience; innovation; manufacture; meetings; mobile application; molecular marker; outreach; participant enrollment; patient population; phase I trial; potential biomarker; primary endpoint; product development; programs; prospective; randomized placebo controlled study; research clinical testing; service providers; standard of care; success; symposium; symptomatology; timeline; tool; treatment planning; treatment response

Project Summary Sanfilippo disease (mucopolysaccharidosis type III; MPS III) is a devastating neurodegenerative lysosomal storage disorder of childhood whose pathologic features are neurologic: slowing of development, severe behavioral problems, progressive cognitive decline, dementia, and decline in motor skills leading to immobility, unresponsiveness, and death. We have focused on MPS IIID caused by a deficiency of alpha-N- acetylglucosamine-6-sulfatase (GNS). Because MPS IIID is rare (1 in a million) and affects the brain (which is difficult to treat) no cure or treatment is available and there are at least five patients in the USA to our knowledge. Sanfilippo patient organizations have 19 additional cases registered around the world (see letter of support). Dr. Patricia Dickson and Dr. Tsui-Fen Chou (LABioMed) have developed an enzyme replacement treatment (ERT) for MPS IIID. Our strategy proposes to deliver recombinant human alpha-N-acetylglucosamine-6-sulfatase (rhGNS) via intracerebroventricular infusion to effectively treat the underlying causes of the neurologic symptoms that dominate MPS III pathology. ERTs can have a dramatic effect on the quality of life and patient development especially when administered early in developments. There are several examples of successfully commercialized ERT’s (e.g. laronidase (MPS I), idursulfase (MPS II), etc.) and BioMarin recently received approval for an ERT for a form of Batten disease, CLN2. Other ERTs for MPS I, II, and IIIB are in Phase I trials. Both the FDA and investors are familiar with ERT and its commercialization path, which will greatly increase the chances of reaching a clinical trial. LABioMed has filed a US patent on rhGNS and Phoenix Nest, Inc. has licensed it. Our pivotal nonclinical and manufacturing plans are on track. We had a positive interaction with the FDA and got guidance for moving our program into the clinics. In preparation for the interventional study the recommendation was for a thorough natural history study (NHS) in the available patient population with a broad net to capture endpoints that are most likely to predict the clinical benefits in each individual. Since the number of diagnosed patients is small the collected data form each individual would be their own control at the time of intervention, where the patient will receive the recombinant enzyme. Most of the work will be executed by contracted service providers. The clinical trial itself will be conducted at NYU under the guidance of Dr. Lau. She has experience with over 10 clinical trials interventional and observational. The clinical protocol was designed by the team at Phoenix Nest with help of KOLs and clinical experts in the MPS III field. We have engaged expert third party clinical service providers to help with the execution, monitoring and data collection. Crucial data collected from the patients on this study will help us develop clinical outcomes that will be tools for measuring the efficacy of our rhGNS therapy and will be primary endpoints on the pivotal study. The success on this trial will put a step closer to executing the pivotal trial to assess the efficacy of our experimental therapy and its commercialization.

项目摘要 圣菲利普病（粘多糖样变性III型; MPS III）是一种破坏性的神经退行性溶酶体疾病， 以神经系统为病理特征的儿童期胆积症：发育迟缓，严重 行为问题、进行性认知下降、痴呆和导致不动的运动技能下降， 反应迟钝和死亡我们关注的是由α-N缺乏引起的MPS III， 乙酰葡糖胺-6-硫酸酯酶（GNS）。因为MPS IIID是罕见的（百万分之一），并影响大脑（这是 难以治疗）没有治愈或治疗方法，据我们所知，美国至少有五名患者。 Sanfilippo患者组织在世界各地登记了另外19例病例（见支持信）。博士 Patricia Dickson和Tsui-Fen Chou博士（LABioMed）开发了一种酶替代治疗（ERT） 对于MPS IIID。我们的策略建议将重组人α-N-乙酰葡糖胺-6-硫酸酯酶 （rhGNS）通过脑室内输注有效地治疗神经系统症状的根本原因 主导MPS III病理学。Erts可以对生活质量和患者的发展产生巨大的影响 尤其是在发育早期给药时。有几个成功的例子 市售ERT（例如，laronidase（MPS I）、艾度硫酸酯酶（MPS II）等）BioMarin最近收到了 批准用于治疗一种形式的巴滕病CLN2的ERT。MPS I、II和IIIB的其他Erts处于I期试验中。 FDA和投资者都熟悉ERT及其商业化路径，这将大大增加 进行临床试验的机会。LABioMed已经申请了rhGNS和Phoenix Nest，Inc.的美国专利。具有 我们关键的非临床和生产计划正在按计划进行。 我们与FDA进行了积极的互动，并获得了将我们的项目推广到诊所的指导。在 为干预性研究做准备，建议进行全面的自然史研究（NHS）， 可用的患者人群，广泛收集最有可能预测临床结局的终点 每个人的利益。由于确诊患者数量较少，因此收集的数据来自每个 个体在干预时将是其自身对照，其中患者将接受重组体 酵素大部分工作将由承包服务提供商执行。临床试验本身将 在刘博士的指导下在纽约大学进行。她有超过10项临床试验的经验 和观察力。临床方案由Phoenix Nest的团队在KOL和临床的帮助下设计， MPS III领域的专家。我们聘请了专业的第三方临床服务提供商， 执行、监测和数据收集。这项研究中从病人身上收集的关键数据将有助于我们 开发临床结果，作为衡量rhGNS治疗疗效的工具， 关键研究的终点。这项试验的成功将使执行关键试验更近一步， 评估我们实验性疗法的疗效及其商业化。