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.

项目概要 血管对认知障碍和痴呆 (VCID) 以及阿尔茨海默病相关痴呆的影响 (ADRD) 为全球 5500 万痴呆症患者做出了重大贡献。这个数字是 预计到 2050 年，这一数字将增加到超过 1.39 亿（世界卫生组织）。多项研究表明 VCID 和 转化为 ADRD 与血管疾病、炎症和脑功能下降密切相关 血流量 1,2,3,4,5,6,7,8。血管疾病、认知功能和进展之间的关系 最近对痴呆症和可能的 AD 进行了审查 9. 这些作者成功地为结案提供了理由 心血管危险因素与 VCID 和 ADRD 风险之间的关系。此外，转化率 据报道，VCI 诊断后 5 年内，VCI 与痴呆的发生率在 40-46% 之间 10,11。有一个 对于预防 VCID 风险个体认知能力下降的治疗药物的迫切未满足的医疗需求。 这项拟议的后期 NIA U01 ADDP 计划的目标是完成 FDA 要求的长期毒理学研究 以及推进抗炎肽 PNA5 的 2 期临床试验所需的安全性研究 患有 MCI 且有 VCID/ADRD 风险的患者的治疗。 PNA5 肽是一种新型多效性抗 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、 减少大脑和脑血管炎症，改善脑血流量并恢复认知功能 在我们的临床前 VCID 模型 12、13、14、15 中。其他已发表的研究均未涉及 Ang-(1-7) 口服制剂 相关肽或小分子18,19,20表现出我们观察到的优异的脑穿透能力 与我们的糖基化肽一起，这将是开发有效的中枢神经系统抗炎、认知功能的关键 保护性治疗。在 NIA 的支持下，我们正在完成早期阶段的 ADDP 计划， 成功完成了 FDA IND 前会议，并将于 2023 年第三季度获得 PNA5 的新 FDA IND。 到本次审查时，我们将完成 PNA5 所需的正式初步 28 天毒理学和安全工作 1a 期首次人体安全研究。在此应用程序中，我们请求支持 1) 额外的长期 术语暴露安全分析，2) 扩大了一个阶段的 GMP 制造以及最终配方和包装 2 试验，以及 3) 进入第 2 阶段所需的 FDA 监管文件和第 2 阶段试验的设计 针对有 VCID/ADRD 风险的 MCI 患者的临床试验。 具体目标 I：对两个物种进行为期六个月的慢性毒理学研究，以确定毒代动力学和 皮下注射 PNA5 的安全性概况。 具体目标二。扩大了 PNA5 的 GMP 制造以及最终灌装和完成，用于 VCID 的第 2 期试验。 具体目标 III：完成监管评估和文件提交给 FDA 和 生成2期临床试验设计和计划。