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.

项目摘要 对认知障碍和痴呆（VCID）和阿尔茨海默氏病有关的血管贡献 （ADRD）为全球遭受痴呆症患者的5500万人做出了巨大贡献。这个数字是 到2050年，估计将增加到超过1.39亿人（WHO）。许多研究表明VCID和 转化为ADRD与血管疾病，炎症和脑大脑降低密切相关 血流1,2,3，4,5,6，7,8。血管疾病，认知功能和发展到 最近对痴呆症和可能的广告进行了审查9。这些作者成功地将其结束了 心血管危险因素与VCID和ADRD风险之间的关系。此外，转换率 据报道，VCI到痴呆症在VCI 10,11诊断后的5年内在40-46％以内。有一个 紧急未满足的医学需求需要治疗，以防止患有VCID风险的人的认知能力下降。 该提议的后期NIA U01 ADDP程序的目标是完成FDA要求的长期毒理学 和安全研究需要前进到抗炎肽PNA5的2期临床试验中 对患有MCI的人的治疗，有VCID/ADRD的风险。肽PNA5是一种新型的多元性抗 炎症性血管紧张素 - （1-7）/MASR激动剂具有出色的脑穿透力，增强的生物利用度， 减少大脑和脑血管炎症，改善脑血流并恢复认知功能 在我们的临床前VCID型号12,13,14,15中。其他发表的研究都没有Ang（1-7）的口服表述 相关的肽或小分子18,19,20表现出了我们观察到的出色的大脑穿透力 使用我们的糖基化肽，这将是开发有效CNS抗炎，认知的关键 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， 成功完成了我们的FDA预印度会议，并将在第三季度为PNA5提供新的FDA IND。 审查的时间，我们将完成我们需要PNA5的正式初始28天毒理学和安全工作 对于第1A阶段的人类安全研究。在此应用程序中，我们要求支持1）额外的长期 定期暴露安全分析，2）扩展GMP制造和最终配方和包装 2试验和3）FDA调节文档和设计2阶段试验的设计 MCI患有VCID/ADRD风险的人的临床试验。 特定目的I：在两个物种中进行六个月的慢性毒理学研究，以确定毒素动力学和 皮下施用PNA5的安全概况。 具体目标II。在VCID中进行了2阶段试验的GMP制造和PNA5的最终填充和饰面。 特定目标III：完整的监管评估和文件，以提交给FDA和 生成2期临床试验设计和计划。