PNA5: A Novel Mas Receptor Agonist for Treatment of Cognitive Impairment in Patients at Risk for Vascular Dementia and Alzheimer's Disease Related Dementia: an FDA required Toxicology Study

PNA5：一种新型 Mas 受体激动剂，用于治疗有血管性痴呆和阿尔茨海默氏病相关痴呆风险的患者的认知障碍：FDA 要求的毒理学研究

• 批准号: 10705874
• 负责人: Meredith Hay
• 金额: $ 220.81万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705874
• 关键词: AGTR2 gene; Acceleration; Agonist; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amendment; Anti-Inflammatory Agents; Arizona; Australia; Award; Binding; Biological Availability; Biological Markers; Brain; Cerebrovascular Circulation; Cerebrum; China; Chronic; Clinical; Clinical Protocols; Clinical Research; Clinical Trials Design; Cognitive; Data; Dementia; Development; Diagnosis; Disease; Documentation; Dose; Drug Industry; Drug Kinetics; Europe; Exhibits; Formulation; GTP-Binding Proteins; Glycopeptides; Goals; Human; Impaired cognition; Individual; Inflammation; Inflammatory; Japan; Kilogram; Legal patent; Licensing; Link; Medical; Medicine; Modeling; Nature; Nerve Degeneration; Neurodegenerative Disorders; Oral; Oxygen; Patients; Penetration; Peptides; Persons; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Production; Protocols documentation; Publishing; Receptor Activation; Reporting; Request for Applications; Risk; Safety; Schedule; Solubility; Specialist; Structure; Therapeutic; Time; Toxic effect; Toxicokinetics; Toxicology; Treatment Protocols; Universities; Vascular Dementia; Vascular Diseases; Vision; Work; angiotensin I (1-7); aqueous; cardiovascular risk factor; cerebrovascular; cognitive function; experience; first-in-human; glycosylation; improved; link protein; manufacturability; manufacture; neuroprotection; novel; novel strategies; phase 2 designs; phase II trial; pre-Investigational New Drug meeting; pre-clinical; preclinical efficacy; prevent; programs; receptor; safety study; small molecule; subcutaneous; trial planning; vascular cognitive impairment and dementia

PROJECT SUMMARY Vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease related dementias (ADRD) significantly contribute to the 55 million people world-wide who suffer with dementia. This number is estimated to increase to over 139 million people by 2050 (WHO). A number of studies have shown that VCID and conversion to ADRD are strongly correlated with vascular disease, inflammation and decreased cerebral brain blood flow 1,2,3, 4,5,6, 7,8. The relationship between vascular disease, cognitive function and progression to dementia and possible AD have been recently reviewed 9. These authors successfully make the case for a close relationship between cardiovascular risk factors and risk for VCID and ADRD. Furthermore, conversion rates of VCI to dementia has been reported to be within 40-46% within 5 years of diagnosis of VCI 10,11. There is an urgent unmet medical need for therapeutics to prevent cognitive decline in individuals at risk for VCID. The goal of this proposed late-stage NIA U01 ADDP program is to complete FDA-required long-term toxicology and safety studies required to advance to a Phase 2 clinical trial of the anti-inflammatory peptide, PNA5, for treatment of persons with MCI and are at risk for VCID/ADRD. The peptide PNA5 is a novel pleotropic anti- inflammatory Angiotensin-(1-7)/MasR agonist that has outstanding brain penetration, enhanced bioavailability, decreases brain and cerebrovascular inflammation, improves cerebral blood flow and restores cognitive function in our preclinical VCID model 12,13,14,15. None of the other published studies with oral formulations of Ang-(1-7) related peptides or small molecules 18,19,20 have exhibited the excellent brain penetration that we have observed with our glycosylated peptides, which will be key for developing an effective CNS anti-inflammatory, cognitive protective therapeutic. With support from the NIA, we are completing our early stage ADDP program, have successfully completed our FDA pre-IND meeting, and will have our new FDA IND for PNA5 by Q3 2023. By the time of this review, we will have completed our formal initial 28-day toxicology and safety work for PNA5 required for Phase 1a first-in-human safety studies. In this application we are requesting support for 1) additional long- term exposure safety analysis,2) expanded GMP manufacturing and final formulation and packaging for a Phase 2 trial, and 3) FDA regulatory documentation and design of the Phase 2 trial required to advance to Phase 2 clinical trials in persons with MCI at risk for VCID/ADRD. Specific Aim I: Conduct six-month chronic toxicology studies in two species to determine the toxicokinetic and safety profiles for subcutaneously administered PNA5. Specific Aim II. Expanded GMP manufacturing and final fill and finish of PNA5 for Phase 2 trials in VCID. Specific Aim III: Complete regulatory assessments and documentation for submission to FDA and to generate Phase 2 clinical trial design and plan.

项目总结 血管对认知损害和痴呆(VCID)和阿尔茨海默病相关痴呆的贡献 (ADRD)对全球5500万痴呆症患者做出了重大贡献。这个号码是 估计到2050年将增加到超过1.39亿人(世卫组织)。多项研究表明，VCID和 转换为ADRD与血管疾病、炎症和脑功能减退密切相关 血流1，2，3，4，5，6，7，8。血管疾病、认知功能与疾病进展的关系 最近回顾了痴呆症和可能的阿尔茨海默病9。这些作者成功地提出了结束语 心血管危险因素与VCID和ADRD发病风险的关系此外，转换率 据报道，在被诊断为VCI 10，11的5年内，VCI对痴呆症的发病率在40%-46%之间。 迫切需要未得到满足的治疗方法，以防止VCID风险人群的认知能力下降。 这项拟议的晚期NIA U01 ADDP计划的目标是完成FDA要求的长期毒理学 以及进入抗炎肽PNA5的第二阶段临床试验所需的安全性研究，用于 MCI患者和有VCID/ADRD风险的人的治疗。多肽PNA5是一种新的多效性抗肿瘤药物 炎症性血管紧张素-(1-7)/MASR激动剂，具有出色的脑渗透性，增强的生物利用度， 减少脑血管炎症，改善脑血流，恢复认知功能 在我们的临床前VCID模型中，12，13，14，15。没有其他已发表的关于Ang-(1-7)口服制剂的研究 相关的多肽或小分子18，19，20已经显示出我们观察到的良好的脑穿透能力 与我们的糖基化多肽，这将是开发有效的中枢抗炎，认知 保护性治疗。在NIA的支持下，我们正在完成我们的早期ADDP计划， 我们成功地完成了FDA的Pre-IND会议，并将在2023年第三季度之前为PNA5提供我们新的FDA IND。由 在本次审查期间，我们将完成PNA5所需的为期28天的正式初步毒理学和安全工作 用于1a期首个人类安全研究。在此应用程序中，我们请求支持1)额外的长时间- 术语暴露安全分析，2)扩展的GMP制造和最终配方和阶段包装 2个试验，以及3)FDA法规文件和进入第二阶段所需的第二阶段试验设计 有VCID/ADRD风险的MCI患者的临床试验。 具体目标一：对两个物种进行为期六个月的慢性毒理学研究，以确定其毒代动力学和 皮下注射PNA5的安全性概况。 具体目标二。扩大VCID第二阶段试验PNA5的GMP制造和最终填充和完成。 具体目标三：完成监管评估和文件，以提交给林业局和 制定第二阶段临床试验设计和计划。