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
• 负责人: John Didsbury
• 金额: $ 52.98万
• 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/10708865
• 关键词: Adverse event; Affect; Age; Age of Onset; Agonist; Alzheimer' s Disease; Bioenergetics; Brain; Brain region; CD3D gene; Chemicals; Clinical; Clinical Trials; Clinical assessments; Cyclic GMP; Dedications; Development; Disease; Dose; Double-Blind Method; Elderly; Embryonic Development; Embryonic and Fetal Development; Energy Metabolism; Failure; Female; Fertility; Functional disorder; Genetic Transcription; Guidelines; Homeostasis; Human; Huntington Disease; Huntington gene; 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; brain dysfunction; brain metabolism; capsule; child bearing; commercial application; data submission; design; developmental toxicology; drug candidate; efficacy study; glucose metabolism; improved; lipid metabolism; manufacture; mitochondrial dysfunction; mutant; neurotoxicity; new chemical entity; 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舞蹈病（HD）的临床试验失败