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

• 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
• 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' 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

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 亨廷顿蛋白导致这种毁灭性的进行性神经退行性疾病。 T3D-959是一本小说 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）。 AD 受试者的 2 期试验正在进行中。扩大该药物的治疗效用 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 接受 T3D-959 治疗的受试者与 HD 功能障碍相关。 T3D-959是一种口服小剂量 PPARδ（主要靶标）和 PPARγ（次要靶标）分子双核受体激动剂，其作用是 恢复和维持大脑代谢稳态。 PPARδ 在神经元生物能量通路中发挥关键作用 在 HD 受影响的大脑区域中高度表达。特别重要的是，发现突变体 亨廷顿蛋白直接与 PPARδ 相互作用，抑制其功能。高清研究表明 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。卓越网络 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 测试有前景的新神经疗法。 PASS-HD（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 啮齿动物和非啮齿动物的发育研究。这些生殖和发育毒理学研究是 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 需要考虑扩大开放标签访问计划。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 GMP 级 T3D-959 API，包含用于 PASS-HD 的胶囊和匹配的安慰剂。成功后 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。