Novel Dopaminergic Stimulant Prodrug for the Treatment of Apathy in AD

该项目的目标是开发PRX-P4-003作为FDA批准的治疗阿尔茨海默病(AD)冷漠的更安全的“一流”疗法。冷漠是阿尔茨海默病最常见的神经行为症状之一(70%的患者)，定义为在没有抑郁或其他情绪变化的情况下对日常活动失去主动性和兴趣。这些症状与生活质量下降、功能障碍增加、照顾者负担更重、更早住院和更高的护理成本有关。多巴胺在动机中的中心作用在机制上得到了很好的认识，多巴胺能兴奋剂哌醋甲酯(MPH)有希望的临床数据表明，AD的冷漠是可以治疗的。发表的三项临床研究表明，冷漠症状在4周后有显著改善，另外一个有希望的发现是，12周后认知能力逐渐改善。然而，MPH是一种受附表II控制的药物，与阿片类药物一样，具有很高的分流、成瘾和滥用风险。PRX-P4-003是一种已知兴奋剂fencamlamine的新型多巴胺能前药，它作为一种方便的低风险、每天一次的方案IV治疗，具有改善冷漠症状的潜力。PRX-P4-003的独特结构导致了一种具有双重保护性质的水不溶前药：静脉给药后它是不活跃的，口服给药时具有延迟吸收特性。这些保护特性是通过化学方式将前药作为由胰腺脂肪酶特异性激活的底物来实现的，胰腺脂肪酶几乎全部(99%)位于胰管和小肠中。PRAXIS已经获得了体外和体内的安全性和有效性数据，证明了PRX-P4-003用于下一阶段开发的可行性。这项提案中的工作的成功完成将为研究这种治疗AD冷漠的药物提供必要的关键证据。活动将集中在大规模的GMP制造和FDA批准的最终人类剂量的监管研究，以及对阿尔茨海默病患者冷漠的调查。

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.