Novel Dopaminergic Stimulant Prodrug for the Treatment of Apathy in AD

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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.