GMP Manufacturing and IND Enabling Studies of Extended-Release PNA5: A Novel Therapeutic for Treating Cognitive Impairment in Patients at-risk for Alzheimer's Disease-Related Dementias and Vascular

缓释 PNA5 的 GMP 生产和 IND 启用研究：一种治疗阿尔茨海默氏病相关痴呆和血管性认知障碍患者认知障碍的新疗法

• 批准号: 10819329
• 负责人: Meredith Hay
• 金额: $ 49.95万
• 依托单位: PRONEUROGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10819329
• 关键词: Acceleration; Agonist; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amendment; Angiotensins; Anti-Inflammatory Agents; Arizona; Biological Availability; Biological Markers; Blood Vessels; Brain; Cells; Cerebrovascular Circulation; Cerebrum; Clinical; Clinical Trials; Cognitive; Data; Dementia; Development; Diagnosis; Disease; Documentation; Dose; Drug Kinetics; Exhibits; Formulation; Friends; GTP-Binding Proteins; Gel; Glycolates; Glycopeptides; Goals; Heart Diseases; Human; Impaired cognition; In Situ; In Vitro; Inflammation; Inflammatory; Injectable; Injections; Link; Methods; Microglia; Modeling; Needles; Nerve Degeneration; Neurons; Oral; Oxygen; Patients; Penetration; Peptides; Persons; Pharmaceutical Preparations; Phase; Populations at Risk; Production; Publishing; Rattus; Reactive Oxygen Species; Receptor Activation; Reporting; Research; Risk; Schedule; Small Business Innovation Research Grant; Sterility; Structure; Subcutaneous Injections; Syringes; Therapeutic; Toxic effect; Toxicokinetics; Toxicology; Translating; Treatment Protocols; Universities; Vascular Diseases; Vascular Endothelium; Vision; cardiovascular risk factor; cognitive function; commercialization; compliance behavior; design; experience; glycosylation; improved; in vivo; innovation; link protein; manufacturability; manufacture; manufacturing process; neuroinflammation; neurovascular unit; novel; novel therapeutics; peptide drug; pre-Investigational New Drug meeting; pre-clinical; preclinical efficacy; programs; receptor; safety study; small molecule; subcutaneous; treatment planning; vascular cognitive impairment and dementia

Vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer’s disease related dementias (ADRD) significantly contribute to the 47 million people world-wide who suffer with dementia. This number is estimated to increase to over 130 million people by 2050. Several studies have shown that VCID and conversion to ADRD are strongly correlated with vascular disease, inflammation and decreased cerebral brain blood flow. The relationship between vascular disease, cognitive function and progression to dementia and possible AD have been recently reviewed 1 and conversion rates of VCID to dementia have been reported to be approximately 45% within 5 years of diagnosis of VCID. To date, there are no approved therapies for VCID. ProNeurogen has been working to develop PNA5, a novel Angiotensin 1-7 (Ang-1–7) derivative, to treat cognitive impairment in persons at for risk ADRD and VCID. The goal of the present SBIR Phase I project is to complete GMP formulation of our extended-release (ER) subcutaneous injection formulation of PNA5 and begin GLP repeat-dose toxicology studies for the administration of our novel peptide therapy, PNA5ER, for VCID. These novel peptide formulations are designed to act on Mas receptors (MasR) within the neurovascular unit including brain vascular endothelium, neuronal cells and microglia to decrease brain reactive oxygen (ROS) production, neuroinflammation and improved brain blood flow. We have begun to translate these preclinical findings into novel peptide therapeutics to treat cognitive impairment in patients with heart disease who are at risk for ADRD or VCID. With support from NIA, we are currently completing our formal IND enabling toxicology studies required to advance PNA5 to human clinical trials for VCID and expect to submit our IND application by Q4 2023. Our current planned treatment protocol for VCID patients is once a day, subcutaneous 100 microg/kg injection using a standard needle and syringe for 85 days. However, to increase patient compliance as well as accelerate commercialization we are currently investigating new formulations that are more patient friendly and require fewer injections. We will take advantage of Pace Labs (formerly DDE) extensive experience in the formulation of GMP poly(lactic-co-glycolic acid) (PLGA) sterile injectable in-situ gel formulations and manufacturing expertise to complete the 3 principal objectives of this project. Objective I: Develop GMP manufacturing processes for PNA5ER required for IND submission. Objective II. Conduct IND enabling repeat-dose GLP toxicology studies in rats to determine the toxicokinetic and TK profiles for subcutaneously administered PNA5ER. Objective III: Complete CMC regulatory assessments and documentation for an IND amendment. Following successful completion of these studies, in Phase II we will complete GLP long-term PD/PK studies and safety studies required for IND submission.

对认知障碍和痴呆（VCID）和阿尔茨海默氏病有关的血管贡献 （ADRD）为全球4700万人造成痴呆症患者的贡献。这个数字是 到2050年，估计将增加到超过1.3亿人。几项研究表明，VCID和转换 ADRD与血管疾病，感染和大脑血液流动的改善密切相关。 血管疾病，认知功能和对痴呆症的发展与可能的AD之间的关系 最近已经审查了1个，据报道VCID的转化率近似 诊断为VCID的5年内45％。迄今为止，尚无批准的VCID疗法。下尿原具有 一直在努力开发PNA5，一种新型血管紧张素1-7（Ang-1-7）衍生物，以治疗认知障碍 为风险addrd和vcid的人。当前SBIR I阶段项目的目标是完成GMP 我们的扩展释放（ER）皮下注射式PNA5的形成并开始GLP 重复剂量毒理学研究，用于用于VCID的新型肽治疗PNA5ER。 这些新型的肽配方旨在对神经血管中的MAS受体（MASR）作用 包括脑血管内皮，神经元细胞和小胶质细胞，以减少大脑活性氧（ROS） 产生，神经炎症和改善的脑血流。我们已经开始翻译这些临床前 新型肽疗法的发现，以治疗心脏病患者的认知障碍 ADRD或VCID的风险。在NIA的支持下，我们目前正在完成正式的IND促进毒理学 需要将PNA5推向人类临床试验所需的研究，并期望通过 Q4 2023。我们目前针对VCID患者的计划治疗方案是每天一次，皮下100 microg/kg 使用标准针和注射器注射85天。但是，提高患者合规性以及 加速商业化我们目前正在调查更耐心的新公式，并且 需要更少的注射。我们将利用PACE LABS（以前是DDE）丰富的经验 GMP聚（乳酸 - 乙醇酸）（PLGA）无菌注射的原位凝胶配方和 制造专业知识以完成该项目的3个主要目标。 目标I：为IND提交所需的PNA5ER开发GMP制造过程。 目标II。在大鼠中进行IND启用重复剂量GLP毒理学研究以确定有毒动力学 和皮下给药的TK曲线。 目标III：完整的CMC监管评估和文档，以进行IND修正案。 成功完成这些研究后，在第二阶段，我们将完成GLP长期PD/PK研究 和提交所需的安全研究。