Novel Dopaminergic Stimulant Prodrug for the Treatment of Apathy in AD

项目总结 该项目的目标是将PRX-P4-003开发为FDA批准的更安全的一流产品 治疗阿尔茨海默病(AD)的冷漠。冷漠是最常见的一种 阿尔茨海默病的神经行为症状(70%的患者)，定义为丧失主动性和 在没有抑郁或其他情绪变化的情况下，对日常活动感兴趣。这些症状 与生活质量下降、功能障碍增加、更多的照顾者 负担、更早的制度化和更高的护理费用。多巴胺在脑内的核心作用 动机是很好的机械理解和有希望的临床数据与哌醋甲酯 多巴胺能兴奋剂(MPH)表明，阿尔茨海默病患者的冷漠是可以治疗的。出版了三本书 临床研究显示，冷漠症状在4周内有显著改善， 此外，一个很有希望的发现是，认知能力在12周内逐渐改善。然而， MPH是一种受附表II控制的药物，与鸦片类药物一样，具有很高的转移注意力、成瘾、 和虐待。PRX-P4-003是已知兴奋剂芬卡那明的新型多巴胺能前药，它 有可能改善冷漠的症状，作为一种方便的低风险，一天一次的时间表 静脉注射治疗。PRX-P4-003的独特结构导致了一种具有双重结构的水不溶前药 保护特性：静脉给药后无效，延迟给药 口服吸收特性。这些保护属性实现了 通过将前药化学配制为由胰腺脂肪酶特异性激活的底物， 几乎全部(&gt；99%)位于胰管和小肠。Praxis有 获得了体外和体内的安全性和有效性数据，证明了PRX-2的可行性。 P4-003，用于下一阶段的开发。圆满完成本建议书中的工作 将提供治疗AD冷漠所需的关键证据。活动将 重点关注大规模GMP制造和FDA批准的最终监管研究 阿尔茨海默病冷漠患者的人体剂量和调查。

PROJECT SUMMARY The goal of this project is to develop PRX-P4-003 as a safer “first-in-class” FDA-approved therapy for apathy in Alzheimer’s Disease (AD). Apathy is one of the most common neurobehavioral symptoms of AD (>70% of patients) and is defined as loss of initiative and interest in daily activity in the absence of depression or other mood changes. These symptoms are associated with reduced quality of life, increased functional impairment, greater caregiver burden, earlier institutionalization and higher costs of care. The central role of dopamine in motivation is well appreciated mechanistically and promising clinical data with methylphenidate (MPH), a dopaminergic stimulant drug, suggests that apathy in AD is treatable. Three published clinical studies have shown meaningful improvement in apathy symptoms by 4 weeks and additionally a promising finding of gradual improvement in cognition by 12 weeks. However, MPH is a Schedule II-controlled drug which, like opiates, has a high risk of diversion, addiction, and abuse. PRX-P4-003 is a novel dopaminergic prodrug of a known stimulant fencamfamine, it has a potential to improve symptoms of apathy as a convenient low risk, once-a-day, Schedule IV treatment. The unique structure of PRX-P4-003 results in a water insoluble prodrug with dual protection properties: it is inactive following intravenous administration and has delayed absorption properties with oral administration. These protection properties were accomplished by chemically formulating the prodrug as a substrate specifically activated by pancreatic lipase, which is almost entirely (>99%) located in the pancreatic duct and small intestine. Praxis has obtained both in vitro and in vivo safety and efficacy data demonstrating the feasibility of PRX- P4-003 for the next stage of development. Successful completion of the work in this proposal will provide key evidence needed to pursue this drug for treating apathy in AD. Activities will focus on large scale GMP manufacturing and FDA approved regulatory studies for eventual human dosing and investigation into patients with apathy in Alzheimer’s Disease.