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

最近两项旨在减少亨廷顿蛋白的亨廷顿病临床试验失败 强调有必要寻找替代治疗途径来减轻突变的病理影响 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是一部小说 具有改善脑功能障碍的葡萄糖、能量和脂肪代谢的化学物质 阿尔茨海默病(AD)。AD受试者的第二阶段试验正在进行中。扩大了这种药物的治疗作用 治疗其他神经退行性疾病的分子正在探索中，亨廷顿病(HD)的发病率最高 优先考虑与HD和AD的临床发现相关的特别有力的科学依据 使用T3D-959治疗的受试者与HD功能障碍相关。T3D-959是一种口服的小型 PPARδ(主要靶点)和PPARγ(次要靶点)的分子双核受体激动剂作用于 恢复和维持大脑代谢动态平衡。PPARδ在神经元生物能量通路中发挥关键作用 并在HD患者受影响的大脑区域高度表达。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。对高清的研究表明， 干扰转录调节因子PPARδ功能在HD发病中的中心作用 发病机制。 T3D-959在HD患者中的第二阶段治疗概念验证试验已经设计完成，该研究 NIH/NeuroNEXT执行委员会批准推进的议定书。卓越网络 在神经科学临床试验中(NeuroNEXT)是一个专门致力于扩展能力的计划 来测试有希望的新的神经疗法。PASS-HD(PPAR Delta/Gamma Agonist(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患者中的对照研究。为了启动这项临床试验，有以下几项 两个先决条件：第一，啮齿动物的GLP生育和早期胚胎发育研究和GLP胚胎胚胎 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需要支持PASS-HD试验的启动，而活动和 在AD中批准IND，因为所有受试者都在50岁以上。与AD不同，HD的平均发病年龄为35-50岁。 第二，生产含有GMP级T3D-959活性药物成分(API)的胶囊，以及 使用匹配的安慰剂胶囊，足以在36周内每天给120名受试者服用一次，以及 需要考虑扩展开放标签访问计划。目标1：进行第一阶段和第二阶段的生殖 和发育毒理学研究完全符合GLP的非物质文化遗产指南。目标2：生产 GMP级T3D-959原料药，包含胶囊和匹配的安慰剂，用于PASS-HD。成功后 完成后，HD的IND将准备提交，批准后，将允许启动临床测试。

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.