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

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，脑血流量减少，活性氧增加 （ROS）和促炎机制加速神经退行性疾病的进展 阿尔茨海默病和相关痴呆症 (ADRD) 等疾病，包括血管疾病 对认知障碍 (VCID) 的贡献 1、2、3、4、5。ProNeurogen 一直在与我们合作 亚利桑那大学合作者开发新型血管紧张素 1-7 (Ang-1–7) 制剂 治疗有 ADRD 风险的心脏病患者的炎症相关认知障碍和 这些新型肽制剂旨在作用于体内的 Mas 受体 (MasR)。 脑血管内皮和神经元细胞减少脑活性氧的产生， 我们已经开始转化这些神经炎症和改善脑血管血流。 治疗炎症相关认知的新型肽疗法的临床前发现 有 ADRD 或 VCID 风险的心脏病患者的损伤。 批准 FDA IND # 125320 并支持天然 Ang-(1-7) 治疗的 2a 期试验 心力衰竭 (HF) 患者的认知障碍和 NIH 对我们的心脏搭桥试验的支持 我们目前正在招募接受手术的患者（CABG）。 治疗方案是每天一次，使用标准针头皮下注射100微克/公斤 然而，我们的 HF 患者需要长期注射 Ang-(1-7)。 保护认知功能的肽需要注射数月。 患者依从性以及加速商业化，我们目前正在研究新的 更“患者友好”的配方和注射方法将减少数量 我们最近完成了可行性研究并确定了我们的领先优势。 缓释Ang-(1-7)制剂(PNA1-ER)并正在向IND提交进展 目前 SBIR 第一阶段项目的目标是 1) 扩大批量。 开发我们的缓释聚乳酸乙醇酸 (PLGA) 原位凝胶配方 对于皮下注射 PNA1-ER，2) 开始正式的 PK 和药物毒性研究 IND 提交需要 PNA1-ER。 目标 1：我们的主要候选缓释原位凝胶的放大批量开发 用于皮下注射Ang-(1-7) (PNA1-ER)的制剂。 目标 2：PNA1-ER 在患者中的单剂量药代动力学和局部耐受性研究 老鼠。 目标 3：PNA1-ER 在大鼠中的重复剂量 PK 和耐受性研究。