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

开发 N-叔丁基羟胺 (NtBuHA) 作为治疗婴儿神经元蜡质脂褐质沉积症 (INCL) 的药物

• 批准号: 9254294
• 负责人: Andrew Lim
• 金额: $ 19.88万
• 依托单位: CIRCUMVENT PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9254294
• 关键词: 13 year old; Adolescent; Adsorption; Ames Assay; Animals; Antiepileptic Agents; Baclofen; Behavior; Benchmarking; Binding; Binding Proteins; Biodistribution; Blood - brain barrier anatomy; Brain; Canis familiaris; Cardiac; Cardiotoxicity; Cessation of life; Chemicals; Child; Childhood; Cleaved cell; Clinical; Clinical Trials; Complex; Data; Dependency; Development; Diagnosis; Disease; Dose; Drug Interactions; Drug Kinetics; Ensure; Excretory function; Exposure to; Family; Fentanyl; Formulation; Functional disorder; Half-Life; Hepatocyte; Hereditary Disease; Human; Hydroxylamine; In Vitro; Infantile neuronal ceroid lipofuscinosis; Intestines; Intravenous; Kinetics; Lead; Liver; Liver Microsomes; Longevity; Lysosomes; Maximum Tolerated Dose; Mediating; Medical; Metabolic; Metabolism; Micronucleus Tests; Microsomes; Modeling; Motor; Mus; National Institute of Child Health and Human Development; Nerve Degeneration; Neurologic; Oral; Organ; Pain; Palmitates; Patients; Performance; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Plasma; Plasma Proteins; Preparation; Property; Proteins; Protocols documentation; Rattus; Regimen; Reporting; Research Personnel; Risk; Rodent; Route; Safety; Sampling; Small Business Innovation Research Grant; Solubility; Spastic; Spielmeyer-Vogt Disease; Sprague-Dawley Rats; Supportive care; Testing; Therapeutic; Therapeutic Agents; Thermodynamics; Toxic effect; Toxicology; United States; United States National Institutes of Health; Work; absorption; animal data; aqueous; brain tissue; chemical property; chemical reaction; clinical practice; efficacy evaluation; genotoxicity; improved; in vivo; infancy; lipophilicity; palliative; palmitoyl-protein hydrolase; phase 2 study; phase II trial; pre-clinical; programs; respiratory; response; safety study; small molecule; small molecule therapeutics; spasticity; success; thioester; thioesterase PPT1 gene product; tizanidine; valproate

PROJECT SUMMARY/ABSTRACT There is a significant unmet medical need for a therapy to treat patients with Infantile Neuronal Ceroid Lipofuscinosis (type CLN1 Batten Disease), for which there are (<1 in 100,000) estimated patients in the United States that have no current disease-treating options. We will begin a pre-clinical program on one small molecule that has been selected as a lead compound by a senior investigator at the NICHD, Dr. Anil Mukherjee. This small molecule, N-(tert-butyl)-hydroxylamine (NtBuHA), has been selected amongst a panel of 12 hydroxylamine derivatives for its minimal in-vitro and in-vivo toxicity profile, its solubility in aqueous solution, and its superior chemical activity in replacing deficient Palmitoyl-Protein Thioesterase 1 (PPT1) activity, that underlies the pathophysiology of INCL patients. In preparation for an IND-enabling program, we will de-risk NtBuHA by completing physiochemical analysis, DMPK studies, biodistribution studies, and pilot toxicology studies. Solubility, stability, and lipophilicity studies will be conducted in-vitro to confirm NtBuHA has adequate chemical properties prior to further in-vivo work. Plasma protein binding studies from four species (mouse, rat, dog, human) will determine thermodynamic binding parameters of NtBuHA to be used in PK analyses and that will help provide an estimation of human systemic exposure from animal data. Metabolic stability will be performed in microsomes and hepatocytes of four species (mouse, rat, dog, human) to estimate cross-species-to- human phase I and phase II metabolism, respectively. Metabolite profiling in hepatocytes of four species (mouse, rat, dog, human) will be performed to aid in the selection of toxicology species, and to identify any human specific metabolites. INCL patients are often treated with a combination of anti- epileptic, pain, and anti-spasticity medications (e.g. valproate, fentanyl, baclofen, tizanidine), thus necessitating drug-drug interaction (CYP inhibition and induction) studies that will be performed in human liver samples. We will complete PK studies in rats to determine the dose dependent pharmacokinetic parameters that are both adsorption dependent (via oral gavage route) and adsorption independent (via intravenous route), as well as to estimate both human PK parameters and dose regimen needed for pharmacological response. Dose-escalating biodistribution studies in rats will be conducted with focus on accumulation of NtBuHA within the brain, in order to determine the minimum dose required to achieve therapeutically relevant concentrations in brain tissues. A 7-day maximum tolerated dose (MTD) study will be completed to establish the therapeutic window for NtBuHA, and ensure therapeutically relevant brain concentrations can be safely achieved. The hERG, AMES and micronucleus tests will be completed as in-vitro toxicology gating studies that will aid in determining whether a phase II SBIR submission is merited. Upon the conclusion the proposed work, we will have a lead compound that is characterized for more comprehensive formulation, safety and efficacy evaluation in vivo. Upon successful completion of these studies, we intend to enter into Phase II SBIR studies that will employ GLP facilities and GMP materials, longer repeat dosing toxicity protocols in large animals, and safety studies (cardiac, respiratory, etc.), that will more precisely predict NtBuHA behavior in humans and that will support a subsequent IND application. Ultimately, we hope NtBuHA can become a marketed product that has clinically meaningful impact on INCL patients.

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（CLN 1型Batten病），估计有（<1/100，000）患者， 美国目前没有治疗疾病的选择。我们将开始一个临床前项目， 一种小分子被NICHD的高级研究员选为先导化合物， 博士阿尼尔·慕克吉这种小分子，N-（叔丁基）-羟胺（NtBuHA），已被选中 在一组12种羟胺衍生物中，其体外和体内毒性最小， 在水溶液中溶解性，以及其在替代缺乏的棕榈酰蛋白质中的上级化学活性 硫酯酶1（PPT 1）活性，是INCL患者病理生理学的基础。为筹备 作为一项IND支持计划，我们将通过完成理化分析、DMPK 研究、生物分布研究和初步毒理学研究。溶解度、稳定性和亲脂性研究 将在体外进行，以确认NtBuHA在进一步体内研究之前具有足够的化学性质 工作4个种属（小鼠、大鼠、犬、人）的血浆蛋白结合研究将确定 在PK分析中使用的NtBuHA的热力学结合参数，这将有助于提供 根据动物数据估计人体全身暴露量。代谢稳定性将在 四个种属（小鼠、大鼠、犬、人）的微粒体和肝细胞，以估计跨种属- 人I期和II期代谢。四种动物肝细胞中的代谢产物谱 将对种属（小鼠、大鼠、犬、人）进行毒理学试验，以帮助选择毒理学种属，并 确定任何人类特定代谢物。INCL患者通常使用抗- 癫痫、疼痛和抗痉挛药物（例如丙戊酸盐、芬太尼、巴氯芬、替扎尼定），因此 需要进行药物相互作用（抑制和诱导）研究， 人类肝脏样本我们将完成大鼠PK研究，以确定剂量依赖性 具有吸附依赖性（经口灌胃途径）和吸附依赖性的药代动力学参数 独立（通过静脉途径），以及估计人体PK参数和剂量 药理学反应所需的方案。将在大鼠中进行剂量递增生物分布研究， 重点关注NtBuHA在脑内的蓄积，以确定最小 在脑组织中达到治疗相关浓度所需的剂量。最多7天 将完成耐受剂量（MTD）研究，以确定NtBuHA的治疗窗，以及 确保可以安全地达到治疗相关的脑浓度。hERG、艾姆斯和 微核试验将作为体外毒理学门控研究完成，这将有助于确定 是否需要提交第二阶段SBIR。在完成拟议的工作后，我们将有一个 先导化合物具有更全面的配方、安全性和有效性 体内评价。在成功完成这些研究后，我们打算进行第二阶段SBIR 将采用GLP设施和GMP材料的研究， 大型动物和安全性研究（心脏、呼吸系统等），可以更精确地预测NtBuHA 人类的行为，并将支持随后的IND申请。最终，我们希望NtBuHA 可以成为对INCL患者有临床意义影响的上市产品。