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（HD）临床试验失败， 强调需要找到替代的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是一部小说 具有改善脑葡萄糖能量和脂质代谢功能障碍的潜力的化学实体， 阿尔茨海默病（AD）。正在AD受试者中进行II期试验。扩大这一治疗效用 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）的最高 基于与其在HD中的使用和AD中的临床结果相关的特别强有力的科学依据， 与HD功能障碍相关的T3D-959治疗受试者。T3D-959是一种口服给药的小分子 分子双核受体激动剂的过氧化物酶体增殖物激活受体δ（主要目标）和过氧化物酶体增殖物激活受体γ（次要目标）的工作， 恢复和维持大脑代谢平衡。过氧化物酶体增殖物激活受体δ在神经元生物能量通路中起关键作用 并且在HD中受影响的脑区域中高度表达。特别重要的是，发现突变体 亨廷顿蛋白直接与PPAR δ相互作用，抑制其功能。HD的研究表明， 干扰转录调节因子过氧化物酶体增殖物激活受体δ在HD中的作用 发病机制 设计了一项在HD受试者中进行的T3D-959的II期治疗概念验证试验， NIH/NeuroNEXT执行委员会批准的推进方案。卓越网络 神经科学临床试验（NeuroNEXT）是一个专门致力于扩大能力的计划， NINDS来测试有前途的新神经疗法。PASS-HD（PPAR δ/γ激动剂（T3D-959） 亨廷顿病的安全性、耐受性和疗效研究）是一项计划随机、双盲安慰剂- 在早期HD受试者中进行的T3D-959（1：1 vs.安慰剂）对照研究。为了启动这项临床试验，有 两项前期研究：首先，在啮齿动物和GLP胚胎胎仔中进行的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 FDA要求支持启动PASS-HD试验，但活性药物和 由于所有受试者年龄均超过50岁，因此已批准IND治疗AD。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，沿着 与匹配的安慰剂胶囊，足以给药120名受试者每天一次，持续36周，以及 预期的扩大的开放标签获取计划是必要的。目标1：开展第一和第二阶段生殖活动 以及完全符合GLP的ICH指导原则的发育毒理学研究。目标2：生产 含GMP级T3D-959 API的胶囊和匹配安慰剂，用于PASS-HD。一旦成功 完成后，将准备提交HD IND，批准后将允许启动临床试验。

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.