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，减少脑血流量，增加活性氧 (ROS)和促炎机制加速神经退行性疾病的进展 疾病如阿尔茨海默病和相关痴呆（ADRD），包括血管性痴呆， 对认知障碍的贡献（VCID）1，2，3，4，5。ProNeurogen一直在与我们的 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， VCID。这些新的肽制剂被设计为作用于细胞内的Mas受体（MasR）。 脑血管内皮和神经元细胞以减少脑ROS产生， 神经炎症和改善脑血管血流量。我们已经开始翻译这些 用于治疗炎症相关认知障碍的新型肽治疗剂的临床前发现 存在ADRD或VCID风险的心脏病患者的功能损害。我们有一个 已批准FDA IND # 125320，并支持天然Ang-（1-7）治疗以下疾病的2a期试验： 心力衰竭（HF）患者的认知障碍和NIH对我们心脏搭桥试验的支持 手术患者（CABG）。我们目前正在参与这些研究。我们目前已批准 治疗方案是每天一次，使用标准针皮下注射100微克/千克 和注射器85天。然而，长期给予Ang-（1-7） 保护认知功能的肽需要数月的注射。增加 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”的制剂和注射方法， 需要注射。我们最近完成了可行性研究， Ang-（1-7）缓释制剂（PNA 1-ER），正在向IND提交申请 对于这个新的配方。目前SBIR第一阶段项目的目标是：1）放大批次 我们的缓释聚（乳酸-共-乙醇酸）（PLGA）原位凝胶制剂的开发 对于皮下注射PNA 1-ER，2）开始正式的PK和药物毒性研究， PNA 1-ER需要提交IND。 目标1：我们的主要候选缓释原位凝胶的规模化批量开发 用于皮下注射Ang-（1-7）（PNA 1-ER）的制剂。 目的2：PNA 1-ER单次给药的药代动力学和局部耐受性研究 大鼠 目的3：PNA 1-ER在大鼠体内的重复给药PK和耐受性研究。