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.

最近两项旨在减少亨廷顿蛋白的亨廷顿病 (HD) 临床试验失败强调需要寻找替代治疗途径来减轻突变体的病理影响导致这种破坏性进行性神经退行性疾病的亨廷顿蛋白 T3D-959 是一种新型蛋白。具有改善功能失调的大脑葡萄糖能量和脂质代谢潜力的化学实体阿尔茨海默病 (AD) 的 2 期试验正在进行中，以扩大其治疗用途。正在探索治疗其他神经退行性疾病的分子，其中亨廷顿病（HD）的发病率最高优先权基于与其在 HD 中的使用相关的特别强有力的科学原理以及 AD 中的临床发现患有与 HD 功能障碍相关的 T3D-959 的受试者，T3D-959 是一种口服小剂量药物。 PPARδ（主要靶标）和 PPARγ（次要靶标）的分子双核受体激动剂，其作用是恢复和维持大脑代谢稳态在神经元生物能量通路中发挥着关键作用。并且在 HD 受影响的大脑区域中高度表达，这一发现具有特别重要的意义。亨廷顿蛋白直接与 PPARδ 相互作用，抑制其功能，HD 研究已证明。干扰转录调节因子 PPARδ 的功能在 HD 的形成中发挥核心作用发病。 T3D-959 在 HD 受试者中的 2 期治疗概念验证试验已经设计，并且该研究 NIH/NeuroNEXT 执行委员会批准推进协议。神经科学临床试验 (NeuroNEXT) 是一个专门致力于扩展能力的项目 NINDS 测试有前途的神经学新疗法（PPAR δ/γ 激动剂（T3D-959））。亨廷顿病的安全性、耐受性和有效性研究）是一项计划中的随机、双盲安慰剂 T3D-959（1:1 与安慰剂）在早期 HD 受试者中的对照研究为了启动这项临床试验，有：两个先决条件：首先，啮齿动物和 GLP 胚胎胎儿的 GLP 生育力和早期胚胎发育研究这些生殖和发育毒理学研究是啮齿类动物和非啮齿类动物的发育研究。 FDA 要求支持 PASS-HD 试验的启动，但主动和不要求批准 AD 的 IND 是因为所有受试者都超过 50 岁。与 AD 不同，HD 的平均发病年龄为 35-50 岁。其次，生产含有 GMP 级 T3D-959 活性药物成分 (API) 的胶囊，以及与匹配的安慰剂胶囊，足以让 120 名受试者每天服用一次，持续 36 周，以及目标 1：进行 I 段和 II 段生殖和发育毒理学研究遵循 ICH 指南，完全符合 GLP 目标 2：生产。含有胶囊和匹配安慰剂的 GMP 级 T3D-959 API，用于 PASS-HD 成功。完成后，HD 的 IND 将准备好提交，获得批准后将允许启动临床测试。