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 initially pursue a label claim of symptomatic improvement instead of the more difficult claim of disease modification and will therefore conduct clinical studies in mild-to-moderate AD. Conducted under a US IND, the first-in-human clinical trial showed no drug-related adverse effects (AEs) and dose proportional pharmacokinetics (PK) of the oral solution. In this administrative supplement proposal, we include costs of additional pilot tableting and coating that solved an issue related to the high water solubility of the compound. We also include the cost of labeling and preparing randomization kits for a 3-month trial, dose analysis for the chronic toxicity studies, analytical method adaptation to human CSF (so we can measure CSF levels of PTI-125 in the upcoming multi-dose clinical trial), electronic submission costs in submitting a request for advice and the annual submission to FDA, the cost of the DSMB for this trial, the cost of an annual audit for a prior NIA grant, and other ongoing expenses relating to stability assessments, bulk drug storage and intellectual property.
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. We additional costs in this administrative supplement were unforeseen or not included in other grant proposals.
