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:
- 金额:$ 108.88万
- 依托单位:
- 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:
- 关键词:Adverse eventAffectAgeAge of OnsetAgonistAlzheimer&aposs DiseaseBioenergeticsBrainBrain regionCD3D geneCertificationChemicalsClinicalClinical TrialsClinical assessmentsCyclic GMPDataDevelopmentDiseaseDoseDouble-Blind MethodElderlyEmbryonic DevelopmentEmbryonic and Fetal DevelopmentEnergy MetabolismFailureFemaleFertilityFunctional disorderGenetic TranscriptionGlucoseGuidelinesHomeostasisHumanHuntington DiseaseHuntington geneHuntington proteinIndividualLabelMetabolicMolecularNational Institute of Neurological Disorders and StrokeNeurodegenerative DisordersNeurologicNeuronsNeurosciencesNuclear ReceptorsOralOryctolagus cuniculusOutcomePPAR deltaPPAR gammaPathogenesisPathologicPathway interactionsPatientsPerformancePharmaceutical PreparationsPharmacologic SubstancePharmacotherapyPhasePlacebo ControlPlacebosPlayPregnant WomenProductionProtocols documentationRandomizedRattusRecordsRegimenResearchResearch SupportRodentRoleSafetySiteSmall Business Innovation Research GrantSymptomsTarget PopulationsTestingTherapeuticTherapeutic AgentsToxic effectToxicity TestsToxicologyUnited States National Institutes of HealthWomanWorkbasebrain dysfunctionbrain metabolismcapsulechild bearingcommercial applicationdesigndevelopmental toxicologydrug candidateefficacy studyimprovedlipid metabolismmitochondrial dysfunctionmutantneurotoxicitynovelnovel therapeuticsopen labelphase II trialplacebo controlled studypreclinical trialprogramsreproductivereproductive toxicityresearch and developmentresearch clinical testingsmall moleculetechnological 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
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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John Didsbury其他文献
John Didsbury的其他文献
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{{ truncateString('John Didsbury', 18)}}的其他基金
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:
10708865 - 财政年份:2022
- 资助金额:
$ 108.88万 - 项目类别:
Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial of T3D-959 in Mild to Moderate Alzheimer's Disease Subjects
T3D-959 在轻度至中度阿尔茨海默病受试者中的 2 期随机、双盲、安慰剂对照临床试验
- 批准号:
9918832 - 财政年份:2019
- 资助金额:
$ 108.88万 - 项目类别:
Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial of T3D-959 in Mild to Moderate Alzheimer's Disease Subjects
T3D-959 在轻度至中度阿尔茨海默病受试者中的 2 期随机、双盲、安慰剂对照临床试验
- 批准号:
10444130 - 财政年份:2019
- 资助金额:
$ 108.88万 - 项目类别:
Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial of T3D-959 in Mild to Moderate Alzheimer's Disease Subjects
T3D-959 在轻度至中度阿尔茨海默病受试者中的 2 期随机、双盲、安慰剂对照临床试验
- 批准号:
10357575 - 财政年份:2019
- 资助金额:
$ 108.88万 - 项目类别:
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