A 26-week rat toxicity study and efficacy and biomarker studies in Tau-APP Alzheimer's mouse model to support a Phase 1b clinical study

一项为期 26 周的大鼠毒性研究以及 Tau-APP 阿尔茨海默病小鼠模型的功效和生物标志物研究，以支持 1b 期临床研究

• 批准号: 10710197
• 负责人: JAMES G. MOE
• 金额: $ 136.8万
• 依托单位: OLIGOMERIX, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10710197
• 关键词: Acute; Adverse effects; Age Months; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; American; Biochemical; Biological Assay; Biological Markers; Blinded; Brain; Canis familiaris; Cardiopulmonary; Cardiovascular system; Caregivers; Cause of Death; Chronic; Clinical; Clinical Research; Data; Dementia; Development; Diet; Disease; Dose; Double-Blind Method; Drug Kinetics; Electronics; Event; Formulation; Future; Goals; Human; In Vitro; Incidence; Inflammation; Isomerism; Kilogram; Lead; Liquid substance; Lung; Metabolism; Mission; Modeling; Mus; Mutation; National Institute on Aging; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Oral; Outcome; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phosphorylation; Preparation; Prevalence; Preventive; Process; Rattus; Recovery; Research; Safety; Self Administration; Series; Serum; Signal Transduction; Specimen; Sprague-Dawley Rats; System; Tauopathies; Technology; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Studies; Toxic effect; Toxicology; Transgenic Mice; Translating; Treatment Efficacy; United States; Validation; Work; beta amyloid pathology; bioprinting; clinical candidate; cognitive testing; cost; cost effective; design; efficacy study; first-in-human; genotoxicity; healthy volunteer; in vivo; innovation; manufacture; manufacturing scale-up; method development; mouse model; novel; pharmacokinetic characteristic; pharmacologic; pre-clinical; preclinical development; preclinical study; prevent; process improvement; programs; research and development; safety study; small molecule; small molecule inhibitor; tau Proteins; tau aggregation; therapy development; treatment response

PROJECT SUMMARY: This R44 application is focused on preparations for a phase 1b clinical study to look for early clinical signs of efficacy/proof-of-concept by evaluating the response to treatment of relevant serum and CSF biomarkers in a double blinded study of patients with Alzheimer’s Disease. The proposed work is designed to support longer term dosing required to see an effect on biomarkers. The prevalence of AD is increasing worldwide. There remains an urgent need for disease modifying drugs for AD that are cost-effective and easy to administer. This program is progressing to fill the need with an economical, disease-modifying drug that is stable, oral, and can be self-administered. If successful, it will have a tremendous impact on the more than 6.5 million Americans who currently have AD (projected to be 12.7 million by 2050) and their caregivers, and will help reduce the current cost of $321 billion (projected to be $1 trillion by 2050) to our nation (Alzheimer's Association 2022 Alzheimer's Disease Facts and Figures). We have now completed all preclinical work for our IND application to FDA for our first-in-human phase 1a study. A summary of this work follows: TO-0582 demonstrated pharmacologic activity in two mouse models of tauopathy (the htau model that has human tau with all 6 isomers best representing tau aggregation in AD and in the JNPL3 mouse model that has a P301L mutation and represents four-repeat tauopathies), reasonable pharmacokinetic characteristics, minimal DDI potential, lack/minimal effects on cardiovascular, pulmonary and CNS systems, and a lack of genotoxicity. Relatively modest, non-adverse toxicity was observed in 28-day rat and dog GLP toxicity studies. The no adverse effect level for both the rat and dog 28 day studies were the highest dose tested. Thus, TO- 0582 is an excellent candidate for clinical development for treatment of neurodegenerative diseases. Manufacture of kilogram quantities for non-clinical safety studies (NCSS) and drug pre-formulation work has been completed. A GMP batch was also prepared for the manufacture of our drug product OLX-07010. We are preparing our electronic IND application for our phase 1a study that will be submitted to FDA by mid-April 2022 and anticipate first-in-human studies will begin in June of 2022. The Aims of the proposed program are: Aim 1 Perform 26-weeks oral toxicity study (GLP) in Rats with a four-week recovery period (GLP). This includes scaling up the manufacture of TO-0582 to 5 kg level. Aim 2: Conduct a therapeutic therapeutic efficacy study in TAPP mice; and Aim 3: Conduct an acute therapeutic efficacy study TAPP mice. The second and third Aims will evaluate biomarkers that could translate into the planned Phase 1b clinical AD study and to show efficacy of the compound in a mouse model with tau and amyloid beta pathology, acute and chronic dosing studies will be performed in the tau-APP (TAPP) mice which will support transition of clinical work from healthy volunteers to patients. As the National Institute on Aging is the primary Federal agency for AD research, the development of a DMT for AD, has the highest relevance for its mission.

项目概述：该R44申请的重点是为1b期临床研究做准备