Evaluation of clinical outcome assessment (COA) and potential biomarkers to Facilitate Interventionaltrial for Mucopolysaccharidosis IIID Patients

项目摘要 Sanfilippo病(粘多糖病III型；MPS III)是一种毁灭性的神经变性溶酶体 儿童期储存障碍，其病理特征为神经系统：发育缓慢，严重 行为问题，进行性认知衰退，痴呆症，以及导致行动不便的运动技能下降， 反应迟钝和死亡。我们关注的是由α-N缺乏引起的MPS IIID。 乙酰氨基葡萄糖-6-硫酸酯酶(GNS)。因为MPS IIID很罕见(百万分之一)，会影响大脑(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又登记了19例病例(见支持函)。Dr。 帕特里夏·迪克森和周翠芬博士(LABioMed)开发了一种酶替代疗法(ERT) 给国会议员IIID的。我们的策略建议将重组人α-N-乙酰氨基葡萄糖-6-硫酸酯酶 脑室注射重组人神经节苷脂(RhGNS)有效治疗神经症状的根本原因 主宰了MPS III的病理。ERT可以对生活质量和患者的发展产生重大影响 尤其是在发育早期给药的时候。有几个成功的例子 商业化的ERT(如丙酮酸酶(MPS I)、艾杜硫酶(MPS II)等)BioMarin最近收到了 批准对一种形式的巴顿病进行ERT，CLN2。MPS I、II和IIIB的其他ERT正在进行第一阶段试验。 FDA和投资者都熟悉ERT及其商业化道路，这将大大增加 进入临床试验的机会。LABioMed已经为rhGNS申请了美国专利，凤巢公司已经 获得了许可。我们关键的非临床和制造计划正在进行中。 我们与FDA进行了积极的互动，并获得了将我们的计划转移到诊所的指导。在……里面 干预性研究的准备建议是在#年进行彻底的自然历史研究(NHS) 可用患者群体具有广泛的网络，以捕获最有可能预测临床 对每个人都有好处。由于确诊患者的数量很少，收集的数据分别来自 个体会在干预时自己对照，在那里患者会接受重组 酵素。大部分工作将由签约服务提供商执行。临床试验本身将是 在刘博士的指导下在纽约大学进行。她有10多项介入临床试验的经验。 和观察力。临床方案是由凤巢的团队在KOL和临床的帮助下设计的 MPS III领域的专家。我们已经聘请了专业的第三方临床服务提供商来帮助 执行、监测和数据收集。从患者那里收集的关于这项研究的关键数据将帮助我们 开发临床结果，这些结果将成为衡量我们的重组人肾小球肾炎治疗有效性的工具，并将是主要的 关键研究的终点。这一试验的成功将使执行关键试验更近一步 评估我们的实验性疗法的疗效及其商业化。

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.