Novel Dopaminergic Stimulant Prodrug for the Treatment of Apathy in AD

用于治疗 AD 冷漠的新型多巴胺能兴奋剂前药

• 批准号: 10438937
• 负责人: Sandeep Patil
• 金额: $ 95.76万
• 依托单位: PRAXIS BIORESEARCH, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438937
• 关键词: Agreement; Alzheimer' s Disease; Alzheimer' s disease patient; Caregiver Burden; Chemicals; Chemistry; Clinical; Clinical Data; Clinical Research; Cognition; Cyclic GMP; Data; Development; Diagnosis; Dopamine; Dose; FDA approved; Florida; Formulation; Fund Raising; Goals; Human; In Vitro; Institutionalization; Intravenous; Investigation; Investigational Drugs; Investigational New Drug Application; Italy; Lipase; Mastication; Memory; Mental Depression; Moods; Motivation; Neurobehavioral Manifestations; Opioid; Oral; Oral Administration; Pancreas; Pancreatic duct; Patients; Pharmaceutical Preparations; Phase; Process; Prodrugs; Property; Psychiatry; Publishing; Quality of life; Research; Risk; Ritalin; Role; Route; Safety; Schedule; Small Business Innovation Research Grant; Small Intestines; Stimulant; Structure; Suspensions; Symptoms; Water; Work; absorption; addiction; associated symptom; base; care costs; common symptom; design; drug candidate; functional disability; high risk; human study; in vivo; interest; intravenous administration; manufacturing process; meetings; novel; novel therapeutics; phase 1 study; pre-clinical; preclinical study; premature; process optimization; programs; scale up; stimulant abuse; success; symptomatic improvement

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.

该项目的目标是将 PRX-P4-003 开发为 FDA 批准的更安全的“一流”疗法，用于治疗阿尔茨海默病 (AD) 的冷漠症。冷漠是 AD 最常见的神经行为症状之一（>70% 的患者），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、功能损伤增加、护理人员负担更大、较早入院和护理成本较高有关。多巴胺在动机中的核心作用在机制上得到了充分认识，哌醋甲酯 (MPH)（一种多巴胺能兴奋剂）的有前景的临床数据表明，AD 中的冷漠是可以治疗的。三项已发表的临床研究显示，在 4 周内，冷漠症状得到了有意义的改善，此外，还有一个令人鼓舞的发现，即在 12 周内，认知能力逐渐改善。然而，MPH 是一种受附表 II 管制的药物，与阿片类药物一样，具有很高的转移、成瘾和滥用风险。 PRX-P4-003 是一种已知兴奋剂芬卡法明的新型多巴胺能前药，作为一种方便的低风险、每日一次的附表 IV 治疗，有可能改善冷漠症状。 PRX-P4-003 的独特结构使其成为具有双重保护特性的水不溶性前药：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制前药作为由胰腺脂肪酶特异性激活的底物来实现的，胰腺脂肪酶几乎完全（> 99％）位于胰管和小肠中。 Praxis 已获得体外和体内安全性和功效数据，证明 PRX-P4-003 下一阶段开发的可行性。该提案中工作的成功完成将为开发这种药物治疗 AD 冷漠所需的关键证据提供依据。活动将集中于大规模 GMP 生产和 FDA 批准的最终人体剂量监管研究以及对阿尔茨海默病冷漠患者的调查。