PTI-125 is a novel small molecule AD therapeutic candidate with a novel target and mechanism of action. PTI-125 binds and reverses an altered conformation of the scaffolding protein filamin A (FLNA) to prevent A?42?s tight binding to and toxic signaling via the ?7-nicotinic acetylcholine receptor (?7nAChR) as well as A?42?s aberrant activation of toll-like receptor 4 (TLR4). Hence, by restoring FLNA?s native shape and blocking these two toxic cascades, PTI-125 reduces both tau hyperphosphorylation and neuroinflammation. Downstream effects include reduced neurofibrillary lesions and amyloid deposits, suggesting disease modification, and improved synaptic plasticity and function of ?7nAChR, NMDAR and insulin receptors, suggesting symptomatic improvement. We will pursue a label claim of symptomatic improvement instead of the more difficult claim of disease modification. An IND has been filed and the first-inhuman trial will start August 9, 2017. The current administrative supplement proposal includes additional development work related to this first-in-human clinical trial and the ongoing interim 3-month oral toxicity study in dog. These activities include 1) the Data and Safety Monitoring Board, 2) the bioanalytical method adaptation and validation for use in human plasma, 3) the bioanalysis of plasma samples from the 3-month dog study, 4) the dose analysis for the dosing solutions used in the 3-month dog study, required by GLP regulations, and 5) the cost of the recently completed independent audit of the previous SBIR grant that closed Dec. 31, 2016. All these activities are necessary for the continued development of this novel AD therapeutic candidate.
PTI-125 is a novel compound has been shown to alleviate multiple pathological features of AD in mouse models and in postmortem AD brain tissue, including receptor dysfunctions, inflammation, impaired synaptic plasticity, and the hallmark plaques and tangles. These multiple therapeutic benefits suggest PTI-125 may improve cognitive function as well as slow the course of the disease. Activities in this proposal are related to the first-in-human clinical trial and the 3- month interim oral toxicity study in dog.