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

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4700万患有痴呆症的人做出了重大贡献。这个数字 预计到2050年将增加到超过1.3亿人。几项研究表明，VCID和转化率 ADRD与血管疾病、炎症和脑血流减少密切相关。 血管疾病、认知功能与进展为痴呆和可能的AD之间的关系 最近已经进行了审查1，据报道，VCID向痴呆症的转化率约为 45%在诊断VCID的5年内。到目前为止，还没有批准的VCID治疗方法。ProNeurogen具有 一直致力于开发PNA 5，一种新的血管紧张素1-7（Ang-1-7）衍生物，用于治疗认知障碍， 处于ADRD和VCID风险中的人。目前SBIR第一阶段项目的目标是完成GMP 我们的PNA 5的延长释放（ER）皮下注射制剂的配制和开始GLP 针对VCID施用我们的新型肽疗法PNA 5ER的重复剂量毒理学研究。 这些新的肽制剂被设计为作用于神经血管单元内的Mas受体（MasR 包括脑血管内皮细胞、神经元细胞和小胶质细胞，以减少脑活性氧（ROS） 生产，神经炎症和改善脑血流量。我们已经开始将这些临床前 新的肽类药物治疗心脏病患者认知障碍的研究结果， ADRD或VCID风险。在NIA的支持下，我们目前正在完成正式的IND毒理学研究 研究需要推进PNA 5到VCID的人体临床试验，并期望提交我们的IND申请， 2023年第四季度。我们目前计划的VCID患者治疗方案是每天一次，皮下注射100微克/公斤 使用标准针头和注射器注射85天。然而，为了提高患者的依从性， 加速商业化，我们目前正在研究新的配方，更友好的病人， 需要更少的注射。我们将利用Pace Labs（前身为DDE）在以下方面的丰富经验： GMP聚（乳酸-共-乙醇酸）（PLGA）无菌可注射原位凝胶制剂的制剂和 制造专业知识，以完成该项目的3个主要目标。 目标一：开发IND提交所需的PNA 5 ER的GMP生产工艺。 目标二。在大鼠中进行IND重复给药GLP毒理学研究，以确定毒代动力学 和皮下施用PNA 5ER的TK曲线。 目标III：完成CMC监管评估和IND修订文件。 成功完成这些研究后，在II期，我们将完成GLP长期PD/PK研究 以及IND提交所需的安全性研究。

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.