GMP Production of a Tau Oligomer Inhibitor to Enable Clinical Development for ADRD
Tau 寡聚物抑制剂的 GMP 生产促进 ADRD 的临床开发
基本信息
- 批准号:9908941
- 负责人:
- 金额:$ 122.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-30 至 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAmericanBiological AssayCaregiversCause of DeathCellular AssayChemistryChronicChronic DiseaseClinical ProtocolsClinical TrialsCyclic GMPDementiaDevelopmentDiseaseDoctor of PhilosophyDoseExcipientsFormulationFundingFunding OpportunitiesGoalsHumanIn VitroKilogramLaboratoriesLeadMicrotubule StabilizationNerve DegenerationPathologyPharmaceutical PreparationsPharmacologyPharmacology and ToxicologyPhasePowder dose formPreparationPreventiveProcessProductionReportingResearchSafetySeriesSmall Business Innovation Research GrantSolubilityTauopathiesTechniquesTherapeuticTransgenic MiceTranslatingUnited StatesUnited States National Institutes of HealthWorkaggregation pathwayanalytical methodcapsuleclinical developmentcostefficacy studyimprovedin vitro activityin vitro testingin vivoin vivo Modelinhibitor/antagonistmethod developmentmouse modelnovelpreventprogramsprototypesafety studysafety testingscale upscreeningsmall moleculesmall molecule inhibitorsynaptic functiontau Proteinstau aggregationtreatment strategyverification and validation
项目摘要
TITLE: GMP Synthesis of a Tau Oligomer Inhibitor to Enable Clinical Development for ADRD
PROJECT SUMMARY - SBIR Funding Opportunity: NIA PAS-18-187, "Advancing Research on Alzheimer's
Disease (AD) & AD-Related Dementias (ADRD) (R43/R44 Clinical Trial Optional)"
The long-term goal of this program is to develop a disease-modifying, small molecule drug for
Alzheimer’s disease (AD) and related dementias (ADRD). There is a critical unmet need for a disease
modifying drug for AD. Chronic treatment strategies require economically feasible approaches such as small
molecule drugs. This program is progressing to fill this need with a disease modifying drug that, if successful,
will have a tremendous impact on the more than 5.8 million Americans who currently have AD (projected to be
14 million by 2050) and their caregivers, and will help reduce the current cost of $290 billion (projected to be
$1.1 trillion by 2050) to our nation. Our small molecule leads target tau self-association into oligomers for
neurodegeneration. Tau protein’s normal function is to stabilize microtubules thereby enabling synaptic
function. Tau oligomers are the acutely toxic species of tau and their reduction will modify the course of AD.
Our in vivo efficacy studies were carried out blindly and independently by Peter Davies, Ph.D., a key opinion
leader in the tau targeting field. The lead compound inhibited tau aggregation in transgenic mice expressing
human tau (htau), best representing tau aggregation in AD using a preventive paradigm. These results
demonstrate that our lead compound reduced self-association of tau and inhibited formation of insoluble tau
aggregates. The activity translated from in vitro and cellular assays to an in vivo model of tau aggregation
validating our screening approach and showing that targeting oligomer formation can inhibit the entire tau
aggregation pathway. Furthermore, preliminary safety testing showed a good profile in terms of MTD, Ames,
hERG, 14 day dose range finding study, and safety pharmacology. This application is for the cGMP
manufacture of 2 - 3 kilograms of our lead (TO-0582AQ) for use in clinical development. Further, we will
develop the IND package for FDA that will be supported by the GLP safety studies that are presently being
carried out under a parallel NIH funded program (AG062021). We will also perform pre-formulation work under
the proposed program and will qualify activity of API, formulated API and any intermediates using our
proprietary in-vitro screening assays. Additional activities to be taken include managing all subcontractors and
consultants and responsibility for all reporting requirements to NH for the proposed program. Our collaborators
include Edward Cheesman, Ph.D., Chemistry and Manufacturing Controls Consultant who managed our scale
up for the non-clinical safety studies, will also help oversee the GMP scale-up of our lead compound for clinical
development. Pre-formulation work will be carried out by Rajaram Vaidyanathan, RPh, Ph.D., at Gram
Laboratories, Inc. Timothy J. Kachmar, M.S., McCormick LifeSciences, LLC will be our regulatory consultant.
标题:GMP合成Tau寡聚体抑制剂以实现ADRD的临床开发
项目摘要- SBIR资助机会:NIA PAS-18-187,“推进阿尔茨海默氏症研究
疾病(AD)和AD相关痴呆(ADRD)(R43/R44临床试验可选)”
该计划的长期目标是开发一种改善疾病的小分子药物,
阿尔茨海默病(AD)和相关痴呆(ADRD)。有一个关键的未满足的需要,
AD的修饰药物。慢性治疗策略需要经济上可行的方法,如小型
分子药物该计划正在进行,以满足这种疾病修饰药物的需求,如果成功,
将对目前患有AD的580多万美国人产生巨大影响(预计将在2020年
到2050年将有1400万人)及其护理人员,并将有助于减少目前2900亿美元的成本(预计2050年将达到1400万美元)。
到2050年将达到1.1万亿美元)。我们的小分子导致靶tau自缔合成寡聚体,
神经变性Tau蛋白的正常功能是稳定微管,从而使突触
功能Tau寡聚体是tau的急性毒性物质,其减少将改变AD的进程。
我们的体内功效研究由Peter Davies,Ph.D.,关键意见
Tau靶向领域的领导者先导化合物抑制了转基因小鼠中tau蛋白的聚集,
人tau(htau),使用预防性范例最好地代表AD中的tau聚集。这些结果
证明我们的先导化合物减少了tau的自缔合并抑制了不溶性tau的形成
集料.活性从体外和细胞测定转化为tau聚集的体内模型
验证了我们的筛选方法,并显示靶向寡聚体的形成可以抑制整个tau蛋白,
聚集途径此外,初步安全性试验显示MTD、艾姆斯、
hERG、14天剂量范围探索研究和安全性药理学。此应用程序适用于cGMP
生产2 - 3千克的电极导线(TO-0582 AQ)用于临床开发。此外,我们将
为FDA开发IND包,该IND包将得到目前正在进行的GLP安全性研究的支持。
在NIH资助的平行项目(AG 062021)下进行。我们亦会根据
拟定的计划,并将使用我们的产品对API、配制API和任何中间体的活性进行鉴定。
专有的体外筛选试验。其他活动包括管理所有分包商,
顾问和责任的所有报告要求NH为拟议的计划。我们的合作者
包括Edward Cheesman博士,化学和制造控制顾问,负责管理我们的规模
非临床安全性研究,也将有助于监督我们的临床先导化合物的GMP规模扩大
发展配制前工作将由Rajaram Vaidyanathan,RPh,Ph.D.进行,关于Gram
laboratories公司Timothy J. Kachmar,M.S.,McCormick LifeSciences,LLC将担任我们的监管顾问。
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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JAMES G. MOE其他文献
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{{ truncateString('JAMES G. MOE', 18)}}的其他基金
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:
10603544 - 财政年份:2022
- 资助金额:
$ 122.89万 - 项目类别:
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 - 财政年份:2022
- 资助金额:
$ 122.89万 - 项目类别:
GMP Production of a Tau Oligomer Inhibitor to Enable Clinical Development forADRD
Tau 寡聚物抑制剂的 GMP 生产促进 ADRD 的临床开发
- 批准号:
10759200 - 财政年份:2019
- 资助金额:
$ 122.89万 - 项目类别:
GMP Production of a Tau Oligomer Inhibitor to Enable Clinical Development for ADRD
Tau 寡聚物抑制剂的 GMP 生产促进 ADRD 的临床开发
- 批准号:
10025563 - 财政年份:2019
- 资助金额:
$ 122.89万 - 项目类别:
Scale-up and Synthesis of a Tau Oligomer Inhibitor to initiate IND enabling studies for AD and ADRD
Tau 寡聚体抑制剂的放大和合成,启动 IND 使 AD 和 ADRD 研究成为可能
- 批准号:
9922201 - 财政年份:2018
- 资助金额:
$ 122.89万 - 项目类别:
Scale-up and Synthesis of a Tau Oligomer Inhibitor to initiate IND enabling studies for AD and ADRD
Tau 寡聚体抑制剂的放大和合成,启动 IND 使 AD 和 ADRD 研究成为可能
- 批准号:
9902254 - 财政年份:2018
- 资助金额:
$ 122.89万 - 项目类别:
Development of an Alzheimer's disease specific antibody biomarker for a tau oligomer fragment
开发 tau 寡聚体片段的阿尔茨海默病特异性抗体生物标志物
- 批准号:
9409478 - 财政年份:2017
- 资助金额:
$ 122.89万 - 项目类别:
Development and Commercialization of a Tau Oligomer Inhibitor for AD/RD
用于 AD/RD 的 Tau 寡聚体抑制剂的开发和商业化
- 批准号:
10408166 - 财政年份:2016
- 资助金额:
$ 122.89万 - 项目类别:
Tau Oligomer Platform Validation Using Lead Series Candidate in htau Mice
使用先导系列候选物在 htau 小鼠中进行 Tau 寡聚物平台验证
- 批准号:
9141080 - 财政年份:2016
- 资助金额:
$ 122.89万 - 项目类别:
Development and Commercialization of a Tau Oligomer Inhibitor for AD/RD
用于 AD/RD 的 Tau 寡聚体抑制剂的开发和商业化
- 批准号:
10641495 - 财政年份:2016
- 资助金额:
$ 122.89万 - 项目类别: