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

项目总结/摘要 婴儿神经元性蜡样瘤患者的治疗存在显著的未满足的医疗需求 脂褐质沉积症（INCL或CLN 1 Batten病。）据估计，在100，000名INCL患者中， 美国目前没有治疗疾病的选择。Circumvent制药公司 完成关键ADME、PK和毒性研究，选择N-叔丁基羟胺 （NtBuHA）/CIRC 825作为临床候选药物。在SBIR第二阶段计划中，我们建议完成所有 研究新药（IND）申请所需的研究。组件将 已完成的研究包括GMP就绪化学、临床就绪制剂、GLP毒理学和PK/TK，以及 GLP-安全药理学。如果成功的话，CIRC 825将是第一个也是唯一的选择， INCL的根本原因，它将改变临床实践范式，从姑息/支持 关注治疗策略。在我们提议的SA期间。1方案，我们将确定一个最佳的 合成路线是GMP就绪，获得相关的化学表征和稳定性，以及规模 为IND启动计划提供足够的材料。我们的SA 2计划将 由于该疾病的慢性性质， 对儿科群体每日给药的侵入性模式（例如，S.Q.：静脉注射，IT等等）。不太 令人向往在我们提议的SA。3计划，我们计划完成所有符合GLP的体外毒性试验， 安全药理学试验（hERG、艾姆斯、人外周血淋巴细胞微核）， 是申请IND所必需的。我们建议的S.A. 4项研究将包括所有体内GLP- 要求提交IND. S.A.的合规毒理学研究（MTD和PK/TK）。4项研究还将 包括所有GLP合规性体内安全药理学和遗传毒性研究， IND文件（改良欧文研究，犬心血管/呼吸系统安全性和大鼠微核）。 在启动拟议的脊椎动物IND赋能研究之前， FDA罕见病项目，我们将要求与FDA举行正式的IND前会议，以评估 拟定IND使能研究设计。这项拟议工作的主要目标是确定潜在的安全性 危害、临床监测策略、无明显不良作用水平（NOAEL）、最低 观察到的不良作用水平（LOAEL）、所有相关全身暴露量和预测的人体暴露量 起始剂量/首次人体试验（FIH）中靶向的人体等效剂量。完成后 我们将提交IND申请。这项补助金以外资助的工作将包括一个慢性青少年 毒理学研究（毒性种属），将使进入儿科患者人群， 关键性临床试验; CLN 1疾病模型中的PK/PD建模，以确定最佳剂量/给药 在INCL关键临床试验中实现最佳疗效的方案和血浆/脑暴露量 患者;以及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.