Novel Dopaminergic Stimulant Prodrug for the Treatment of Apathy in AD

项目摘要 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。 阿尔茨海默病（AD）的冷漠治疗。冷漠是最常见的 AD的神经行为症状（>70%的患者），定义为主动性丧失， 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、照顾者更多有关。 负担、较早的机构化和较高的护理费用。多巴胺的中心作用 动机是很好的赞赏机制和有前途的临床数据与哌甲酯 (MPH)一种多巴胺能兴奋剂药物，表明AD中的冷漠是可以治疗的。3篇出版 临床研究显示，4周后冷漠症状有显著改善， 此外，在12周内逐渐改善认知的有希望的发现。然而，在这方面， MPH是一种附表II管制药物，与阿片类药物一样，具有很高的转移、成瘾、 和虐待PRX-P4-003是已知兴奋剂芬坎法明的新型多巴胺能前药， 作为一种方便的低风险，每天一次的时间表， 静脉注射治疗。PRX-P4-003的独特结构导致具有双重结构的水不溶性前药。 保护特性：静脉给药后无活性， 口服给药的吸收特性。这些保护特性是通过 通过将前药化学配制为被胰脂肪酶特异性活化的底物， 其几乎全部（>99%）位于胰管和小肠中。普拉西斯已经 获得了体外和体内安全性和有效性数据，证明了PRX的可行性- P4-003用于下一阶段的开发。成功完成本提案中的工作 将提供关键的证据，需要追求这种药物治疗冷漠的AD。活动将 专注于大规模GMP生产和FDA批准的监管研究， 人类剂量和调查与阿尔茨海默病的冷漠患者。

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.