Phase 2 Enabling Studies of a Candidate Drug Therapy (T3D-959) Regulating Neurometabolism for the Treatment of Huntington's Disease

调节神经代谢治疗亨廷顿病的候选药物疗法 (T3D-959) 的 2 期研究

基本信息

批准号：
10480989
负责人：
John Didsbury
金额：
$ 108.88万
依托单位：
T3D THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-21 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10480989
关键词：
Adverse event Affect Age Age of Onset Agonist Alzheimer&apos s Disease Bioenergetics Brain Brain region CD3D gene Certification Chemicals Clinical Clinical Trials Clinical assessments Cyclic GMP Data Development Disease Dose Double-Blind Method Elderly Embryonic Development Embryonic and Fetal Development Energy Metabolism Failure Female Fertility Functional disorder Genetic Transcription Glucose Guidelines Homeostasis Human Huntington Disease Huntington gene Huntington protein Individual Label Metabolic Molecular National Institute of Neurological Disorders and Stroke Neurodegenerative Disorders Neurologic Neurons Neurosciences Nuclear Receptors Oral Oryctolagus cuniculus Outcome PPAR delta PPAR gamma Pathogenesis Pathologic Pathway interactions Patients Performance Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phase Placebo Control Placebos Play Pregnant Women Production Protocols documentation Randomized Rattus Records Regimen Research Research Support Rodent Role Safety Site Small Business Innovation Research Grant Symptoms Target Populations Testing Therapeutic Therapeutic Agents Toxic effect Toxicity Tests Toxicology United States National Institutes of Health Woman Work base brain dysfunction brain metabolism capsule child bearing commercial application design developmental toxicology drug candidate efficacy study improved lipid metabolism mitochondrial dysfunction mutant neurotoxicity novel novel therapeutics open label phase II trial placebo controlled study preclinical trial programs reproductive reproductive toxicity research and development research clinical testing small molecule technological innovation

项目摘要

The recent failure of two clinical trials in Huntington’s disease (HD) aimed at reducing huntingtin protein has emphasized the need to find alternative therapeutic avenues to mitigate the pathological effects of the mutant huntingtin protein that causes this devastating progressive neurodegenerative disorder. T3D-959 is a novel chemical entity with the potential to improve dysfunctional brain glucose energy and lipid metabolism in Alzheimer’s disease (AD). A Phase 2 trial in AD subjects is ongoing. Expansion of the therapeutic utility of this molecule to treat other neurodegenerative diseases is being explored, with Huntington’s disease (HD) of highest priority based on the particularly strong scientific rationale related to its use in HD and the clinical findings in AD subjects treated with T3D-959 which are relevant to HD dysfunction. T3D-959 is an orally delivered small molecule dual nuclear receptor agonist of PPARδ (primary target) and PPARγ (secondary target) that works to restore and maintain brain metabolic homeostasis. PPARδ plays a key role in neuronal bioenergetic pathways and is highly expressed in brain regions affected in HD. Of particular significance, is the finding that the mutant huntingtin protein directly interacts with PPARδ, inhibiting its function. Research on HD has demonstrated a central role for interference with the function of the transcription regulator PPARδ in contributing to HD pathogenesis. A Phase 2 therapeutic proof of concept trial of T3D-959 in HD subjects has been designed and the study protocol approved for advancement by the NIH/NeuroNEXT Executive Committee. The Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) is a program specifically dedicated to expanding the capability of NINDS to test promising new neurological therapies. PASS-HD (PPAR delta/gamma Agonist (T3D- 959) Safety, Tolerability and Efficacy Study in Huntington’s Disease) is a planned randomized, double-blind placebo- controlled study of T3D-959 (1:1 vs. placebo) in early-stage HD subjects. To initiate this clinical trial, there are two pre-requisites: First, a GLP fertility and early embryonic development study in rodents and GLP embryofetal development studies in rodents and non-rodents. These reproductive and developmental toxicology studies are required by the FDA to support the initiation of the PASS-HD trial and were not required for the active and approved IND in AD as all subjects are over age 50. Unlike AD, the average age of onset of HD is 35-50 years. Second, manufacture of capsules containing GMP-grade T3D-959 active pharmaceutical ingredient (API), along with matching placebo capsules, sufficient to dose 120 subjects once daily for 36-weeks, along with a contemplated expanded open label access program, is needed. Aim 1: Conduct Segment I and II reproductive and developmental toxicology studies following ICH guidelines in full compliance with GLP. Aim 2: Production of GMP-grade T3D-959 API containing capsules and matching placebos for use in PASS-HD. Upon successful completion, an IND for HD will be ready to submit, approval of which, will allow initiation of clinical testing.

最近在亨廷顿氏病（HD）中进行了两项临床试验旨在减少亨廷顿蛋白蛋白的失败强调需要找到替代性治疗途径来减轻突变体的病理作用引起这种毁灭性进行性神经退行性疾病的亨廷顿蛋白。 T3D-959是一部小说化学实体具有改善功能失调的脑葡萄糖能量和脂质代谢的潜力阿尔茨海默氏病（AD）。 AD受试者的2期试验正在进行中。扩展此类治疗效用正在探索治疗其他神经退行性疾病的分子，亨廷顿氏病（HD）的最高优先级基于与其在HD中的使用以及AD中的临床发现有关的特别强大的科学原理用T3D-959处理的受试者与HD功能障碍有关。 T3D-959是一个口头交付的小 PPARδ（主要靶标）和PPARγ（次要靶）的分子双核接收器激动剂（次要目标）恢复和维持大脑代谢稳态。 PPARδ在神经元生物能途径中起关键作用并且在HD影响的大脑区域中高度表达。特别重要的是突变体的发现 Huntingtin蛋白直接与PPARδ相互作用，抑制其功能。有关高清的研究表明干扰转录调节剂PPARδ功能的中心作用发病。已经设计了T3D-959的2阶段治疗证明概念验证试验，并且已经设计了 NIH/NEURONEXT执行委员会批准了协议。卓越网络在神经科学临床试验中（Neuronext）是一项专门用于扩展能力的程序 Ninds测试有希望的新神经疗法。 PASS-HD（PPAR Delta/Gamma Agonist（T3D-959）安全性，耐受性和疗效研究中的亨廷顿氏病）是一项计划的随机，双盲安慰剂 - T3D-959（1：1与安慰剂）的对照研究在早期HD受试者中。为了启动这项临床试验，有两个先决条件：首先是啮齿动物和GLP Embryofetal的GLP生育能力和早期胚胎发展研究啮齿动物和非塑料的发展研究。这些生殖和发展毒理学研究是 FDA要求支持PASS-HD试验的计划，并且无需使用Active和Active和 AD中批准的IND，因为所有受试者均超过50岁。与AD不同，HD的平均发作年龄为35 - 50年。其次，沿着含有GMP级T3D-959活性药物成分（API）的胶囊的制造与匹配的安慰剂胶囊相匹配，足以每天为36周剂量120个受试者，以及需要预期的扩展开放标签访问程序。目的1：进行I和II生殖段遵循ICH指南的发育毒理学研究完全符合GLP。目标2：生产 GMP级T3D-959 API包含胶囊和匹配的安慰剂，可用于Pass-HD。成功完成，HD的IND将准备提交，批准将启动临床测试。