Scale-up Manufacturing and IND Enabling Studies of Extended-Release Formulation of Mas Receptor Agonist for Treating Vascular Cognitive Impairment and Alzheimer's Disease-Related Dementias

用于治疗血管认知障碍和阿尔茨海默病相关痴呆的 Mas 受体激动剂缓释制剂的放大生产和 IND 启用研究

• 批准号: 10543390
• 负责人: Meredith Hay
• 金额: $ 49.96万
• 依托单位: PRONEUROGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543390
• 关键词: Adsorption; Adverse effects; Agonist; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amendment; Angiotensins; Arizona; Blood; Blood flow; Brain; Bypass; Cardiac; Cells; Cerebrovascular Circulation; Cerebrum; Dementia; Development; Diagnosis; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Encephalitis; Endothelium; Enrollment; Exhibits; FDA approved; Feasibility Studies; Formulation; GTP-Binding Proteins; Gel; Glycolates; Goals; Heart Diseases; Heart failure; Hippocampus (Brain); Human; Hypoxia; Impaired cognition; In Situ; Inflammation; Inflammatory; Injectable; Injection Site Reaction; Injections; Lead; Methods; Microglia; Modeling; National Institute on Aging; Needles; Neurodegenerative Disorders; Neurons; Operative Surgical Procedures; Oxygen; Patients; Peptides; Persons; Phase; Production; Rattus; Reporting; Risk; Small Business Innovation Research Grant; Sterility; Subcutaneous Injections; Syringes; System; Toxic effect; Toxicology; Translating; Treatment Protocols; United States National Institutes of Health; Universities; Vascular Cognitive Impairment; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Vision; cardiovascular risk factor; cerebrovascular; cognitive function; commercialization; compliance behavior; cytokine; design; experience; improved; innovation; lead candidate; link protein; manufacturing scale-up; mouse model; neuroinflammation; novel; peptide drug; pre-clinical; receptor; scale up; subcutaneous; vascular cognitive impairment and dementia; Adsorption; Adverse effects; Agonist; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amendment; Angiotensins; Arizona; Blood; Blood flow; Brain; Bypass; Cardiac; Cells; Cerebrovascular Circulation; Cerebrum; Dementia; Development; Diagnosis; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Encephalitis; Endothelium; Enrollment; Exhibits; FDA approved; Feasibility Studies; Formulation; GTP-Binding Proteins; Gel; Glycolates; Goals; Heart Diseases; Heart failure; Hippocampus (Brain); Human; Hypoxia; Impaired cognition; In Situ; Inflammation; Inflammatory; Injectable; Injection Site Reaction; Injections; Lead; Methods; Microglia; Modeling; National Institute on Aging; Needles; Neurodegenerative Disorders; Neurons; Operative Surgical Procedures; Oxygen; Patients; Peptides; Persons; Phase; Production; Rattus; Reporting; Risk; Small Business Innovation Research Grant; Sterility; Subcutaneous Injections; Syringes; System; Toxic effect; Toxicology; Translating; Treatment Protocols; United States National Institutes of Health; Universities; Vascular Cognitive Impairment; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Vision; cardiovascular risk factor; cerebrovascular; cognitive function; commercialization; compliance behavior; cytokine; design; experience; improved; innovation; lead candidate; link protein; manufacturing scale-up; mouse model; neuroinflammation; novel; peptide drug; pre-clinical; receptor; scale up; subcutaneous; vascular cognitive impairment and dementia

A growing body of evidence indicates that decreased brain blood flow, increased reactive oxygen (ROS) and pro-inflammatory mechanisms accelerate the progression of neurodegenerative diseases such as Alzheimer’s Disease and Related Dementias (ADRD) including Vascular Contributions to Cognitive Impairment (VCID) 1, 2,3,4, 5. ProNeurogen has been working with our University of Arizona collaborators to develop novel Angiotensin 1-7 (Ang-1–7) formulations to treat inflammation-related cognitive impairment in heart disease patients at for risk ADRD and VCID. These novel peptide formulations are designed to act on Mas receptors (MasR) within the brain vascular endothelium and neuronal cells to decrease brain ROS production, neuroinflammation and improve cerebral vascular blood flow. We have begun to translate these preclinical findings into novel peptide therapeutics to treat inflammation related cognitive impairment in patients with heart disease who are at risk for ADRD or VCID. We have an approved FDA IND # 125320 and support for Phase 2a trials for native Ang-(1-7) for treatment of cognitive impairment in heart failure (HF) patients and NIH support for our trial in cardiac bypass surgery patients (CABG). We are currently enrolling in these studies. Our current approved treatment protocol is once a day, subcutaneous 100 microg/kg injection using a standard needle and syringe for 85 days in our HF patients. However, long-term administration of Ang-(1-7) peptides to protect cognitive function will require injections over multiple months. To increase patient compliance as well as accelerate commercialization we are currently investigating new formulations and injection methods that are more “patient friendly” and will decrease the number of injections required. We have recently completed feasibility studies and identified our lead extended-release Ang-(1-7) formulation (PNA1-ER) and are progressing towards IND submission for this new formulation. The goal of the present SBIR Phase I project is to 1) scale-up batch development of our extended-release poly (lactic-co-glycolic acid) (PLGA) in-situ gel formulations for subcutaneous injection of PNA1-ER, 2) begin formal PK and pharmacotoxicity studies of PNA1-ER required for IND submission. Objective 1: Scale-up batch development of our lead candidate extended-release in-situ gel formulations for subcutaneous injection of Ang-(1-7) (PNA1-ER). Objective 2: Single-dose Pharmacokinetics and Local Tolerability Study of PNA1-ER in Rats. Objective 3: Repeat-dose PK and Tolerability Study of PNA1-ER in Rats.

越来越多的证据表明脑血流减少，活性氧增加 （ROS）和促炎机制加速了神经退行性的进展 阿尔茨海默氏病和相关痴呆症（ADRD）等疾病包括血管 认知障碍的贡献（VCID）1、2、3、4、5。 亚利桑那大学合作者开发新型血管紧张素1-7（ANG-1-7）公式 治疗与炎症相关的认知障碍在心脏病患者的风险ADRD和 VCID。这些新颖的肽配方旨在对MAS接收器（MASR）作用 脑血管内皮和神经元细胞以减少脑ROS的产生， 神经炎症并改善脑血管血流。我们已经开始翻译这些 新型肽治疗的临床前发现，以治疗感染相关认知 患有ADRD或VCID风险的心脏病患者的损害。我们有一个 批准的FDA IND＃125320，并支持2A期试验的本地Ang-（1-7）治疗 心力衰竭（HF）患者的认知障碍和对我们心脏旁路试验的NIH支持 手术患者（CABG）。我们目前正在参加这些研究。我们当前的批准 治疗方案是每天一次，使用标准针头皮下100 microg/kg注射 在我们的HF患者中进行了85天的注射器。但是，长期给予Ang-（1-7） 保护认知功能的肽需要在数月内注射。增加 患者合规性以及加速商业化，我们目前正在调查新的 公式和注射方法更“耐心地”，并且会减少数量 需要注射。我们最近完成了可行性研究并确定了我们的潜在客户 扩展释放的Ang-（1-7）公式（PNA1-ER），正在朝着IND提交进展 对于这个新公式。当前SBIR I阶段项目的目标是1）扩展批次 开发我们的扩展释放聚（乳酸 - 乙醇酸）（PLGA）原位凝胶配方 对于皮下注射PNA1-ER，2）开始正式的PK，并开始进行药物毒性研究 提交IND所需的PNA1-ER。 目标1：扩大批次批次开发我们的铅候选延长释放的原位凝胶 皮下注射Ang-（1-7）（PNA1-ER）的公式。 目标2：PNA1-ER中的单剂量药代动力学和局部耐受性研究 老鼠。 目标3：大鼠PNA1-ER的重复剂量PK和耐受性研究。