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

项目摘要 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）对全世界5500万患有痴呆症的人做出了重大贡献。这个数字 估计到2050年将增加到1.39亿人以上（世卫组织）。一些研究表明，VCID和 转化为ADRD与血管疾病、炎症和脑功能减退密切相关。 血流量12345678血管疾病、认知功能和进展之间的关系 痴呆症和可能的AD最近已被审查9。这些作者成功地为结束 心血管危险因素与VCID和ADRD风险之间的关系。此外， 据报道，在诊断为VCI的5年内，痴呆的VCI发生率在40-46%之间10，11。有一个 对预防有VCID风险的个体的认知下降的治疗剂的迫切未满足的医疗需求。 该拟议的后期NIA U 01 ADDP项目的目标是完成FDA要求的长期毒理学研究。 和安全性研究，需要推进到抗炎肽PNA 5的2期临床试验， 治疗MCI患者，并有VCID/ADRD风险。肽PNA 5是一种新型多效性抗- 炎性血管紧张素-（1-7）/MasR激动剂，具有显著脑渗透性、增强的生物利用度 减少大脑和脑血管炎症，改善脑血流量，恢复认知功能 在我们的临床前VCID模型中12，13，14，15.其他已发表的关于Ang-（1-7）口服制剂的研究 相关的肽或小分子18、19、20显示出我们观察到的极好的脑渗透性 与我们的糖基化肽，这将是关键的发展有效的中枢神经系统抗炎，认知 保护性治疗在NIA的支持下，我们正在完成ADDP项目的早期阶段， 成功完成了我们的FDA pre-IND会议，并将在2023年第三季度之前获得新的FDA IND PNA 5。由 到本次审查时，我们将完成PNA 5所需的正式初步28天毒理学和安全性工作 用于1a期首次人体安全性研究。在此应用程序中，我们请求支持1）额外的长- 长期暴露安全性分析，2）阶段的扩大GMP生产和最终制剂和包装 2期试验，3）FDA监管文件和进入II期试验所需的II期试验设计 在有VCID/ADRD风险的MCI患者中进行的临床试验。 具体目标I：在两个物种中进行6个月的慢性毒理学研究，以确定毒代动力学和 皮下施用PNA的安全性特征5. 具体目标二。用于VCID II期试验的PNA 5的扩大GMP生产和最终灌装和成品。 具体目标III：完成监管评估和文件，以提交给FDA和 制定II期临床试验设计和计划。

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.