Development of N-tert-(Butyl)hydroxylamine (NtBuHA) as a therapeutic agent for treating Infantile Neuronal Ceroid Lipofuscinosis (INCL)

项目摘要/摘要 对于治疗婴儿神经元性脑炎患者的治疗存在着重大的未得到满足的医疗需求 脂褐素沉着症(包括CLN1巴顿病)在中国，估计每100,000名患者中就有1名 美国目前没有治疗疾病的选择。规避制药公司已经 已完成关键的ADME、PK和毒性研究，能够选择N-(叔丁基)-羟胺 (NtBuHA)/CIRC825作为临床候选。在此SBIR第二阶段计划中，我们建议完成所有 申请研究性新药(IND)所需的研究。组件将是 已完成的内容包括GMP准备好的化学，临床准备好的配方，PK/TK的GLP毒理学，以及 GLP-安全药理学。如果成功，CIRC825将是第一个也是唯一一个治疗 INCL的根本原因，它将改变临床实践范式，从姑息/支持 对治疗策略的关怀。在我们提议的S.A.计划期间，我们将确定一个最佳方案 符合GMP要求的合成路线，获得相关的化学表征和稳定性，以及规模 加快合成，为支持IND的计划提供足够的材料。我们的S.A.2计划将 由于疾病的慢性性质，重点开发口服溶液配方，在那里有更多 对儿科人群的侵入性日常给药模式(例如，S.Q、I.V.、I.T.等)更少了 令人向往。在我们建议的S.A.3计划中，我们计划完成所有符合GLP的体外毒性和 安全性药理检测(HERG、Ames、人外周血淋巴细胞微核率) 是申请IND所必需的。我们建议的S.A.4研究将包括所有活体GLP- 申请IND所需的合规毒理学研究(MTD与PK/TK)。S.A.4研究也将 包括所有符合GLP的体内安全性药理学和遗传毒性研究，这些研究将需要 IND(改良的欧文研究，犬心血管/呼吸安全性，大鼠微核)的文件。 在启动拟议的脊椎动物IND研究之前，根据 FDA罕见病计划，我们将要求与FDA召开正式的IND前会议，以评估 建议的支持IND的研究设计。这项拟议工作的主要目标是确定潜在的安全 危害，临床监测策略，未观察到的不良反应水平(NOAEL)，最低 观察到的不良反应水平(LOAEL)，所有相关的全身暴露，以及预测的人类 开始剂量/人体等量剂量将在第一次人体试验(FIH)中作为靶点。在完成时 这项工作，我们将提交IND申请。在这项拨款之外资助的工作将包括一名慢性青少年 毒理学研究(在毒性物种中)，将使进入儿科患者群体的 关键临床试验：在CLN1疾病模型中建立PK/PD模型以建立最佳剂量/剂量 在INCL的关键临床试验中，方案和血浆/脑暴露达到最佳疗效 患者；IND申请材料准备、FDA会议支持和INDA提交。

PROJECT SUMMARY/ABSTRACT A significant unmet medical need exists for a therapy to treat patients with Infantile Neuronal Ceroid Lipofuscinosis (INCL, or CLN1 Batten Disease.) There are an estimated <1 in 100,000 INCL patients in the United States that have no current disease-treating options. Circumvent Pharmaceuticals has completed key ADME, PK and toxicity studies enabling selection of N-(tert-butyl)-hydroxylamine (NtBuHA)/CIRC825 as a Clinical Candidate. In this SBIR Phase II program, we propose to complete all studies necessary for an Investigational New Drug (IND) application. Components that will be completed include GMP-ready chemistry, clinic-ready formulation, GLP-toxicology with PK/TK, and GLP-safety pharmacology. If successful, CIRC825 will be the first and only option to treat the underlying cause of INCL, and it will change the clinical practice paradigm from palliative/supportive care toward a curative strategy. During our proposed S.A. 1 program, we will identify an optimal synthetic route that is GMP-ready, obtain associated chemical characterizations and stability, and scale up the synthesis to provide sufficient material for an IND-enabling program. Our S.A. 2 program will focus on developing an oral solution formulation owing to the chronic nature of the disease where more invasive modes of daily administration to a pediatric population (e.g., S.Q., I.V., I.T., etc.) are less desirable. In our proposed S.A. 3 program, we plan to complete all GLP-compliant in vitro toxicity and safety pharmacology assays (hERG, Ames, micronucleus in human peripheral blood lymphocytes) that are necessary for applying for an IND. Our proposed S.A. 4 studies will include all in vivo GLP- compliant toxicology studies (MTD with PK/TK) required to file for an IND. S.A. 4 studies will also include all GLP-compliant in vivo safety pharmacology and genotoxicity studies that will be required to file for an IND (Modified Irwin study, Dog Cardiovascular/Respiratory safety, and Rat micronucleus). Prior to initiating the proposed IND-enabling studies in vertebrates, based on recommendation of the FDA Rare Disease Program, we will request a formal pre-IND meeting with the FDA to evaluate the proposed IND-enabling study designs. Key aims of this proposed work are to identify potential safety hazards, clinical monitoring strategies, the No Observed Adverse Effect Level (NOAEL), the Lowest Observed Adverse Effect Level (LOAEL), all associated systemic exposures, and predicted human starting doses/human equivalent doses to be targeted in the first in human (FIH) trial. On completion of this work, we will file an IND application. Work funded outside of this grant will include a chronic juvenile toxicology studies (in tox species) that will enable entrance into the pediatric patient population for the pivotal clinical trial; PK/PD modeling in a CLN1 disease model to establish the optimal dose/dosing regimen and plasma/brain exposure to achieve optimal efficacy in the pivotal clinical trial in INCL patients; and IND application material preparation, FDA meeting support, and INDA submission.