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“同类首创”疗法。冷漠是阿尔茨海默病最常见的神经行为症状之一（约占患者的70%），被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、功能损害加重、照顾者负担加重、更早入院和更高的护理费用有关。多巴胺在动机中的核心作用在机制上得到了很好的认识，哌醋甲酯（MPH），一种多巴胺能兴奋剂药物的有希望的临床数据表明，阿尔茨海默病的冷漠是可以治疗的。三项已发表的临床研究表明，冷漠症状在4周内有显著改善，另外，在12周内认知能力逐渐改善，这是一个有希望的发现。然而，MPH是一种附表ii管制药物，像阿片类药物一样，具有很高的转移，成瘾和滥用风险。PRX-P4-003是一种已知兴奋剂fencamfamine的新型多巴胺能前药，作为一种方便、低风险、每天一次的附表IV治疗，它有改善冷漠症状的潜力。PRX-P4-003的独特结构使其成为一种不溶于水的前药，具有双重保护特性：静脉给药后无活性，口服给药后具有延迟吸收特性。这些保护特性是通过化学配方将前药作为胰脂肪酶特异性激活的底物来实现的，胰脂肪酶几乎全部（bbb99%）位于胰管和小肠。Praxis已经获得了体外和体内安全性和有效性数据，证明了PRX- P4-003下一阶段开发的可行性。这项工作的成功完成将为开发这种治疗阿尔茨海默病冷漠的药物提供关键证据。活动将集中于大规模GMP生产和FDA批准的监管研究，最终用于阿尔茨海默病冷漠患者的人体剂量和调查。

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.