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 renewal proposal, we will select a solid oral dosage form based on an accelerated 3-month stability study (under stress conditions) of three candidate formulations currently being developed. With the successful selection of a stable formulation, we will manufacture clinical trial supplies for multi-dose clinical trials (clinical trials not included in this proposal). We will concurrently optimize the crystallization process for Drug Substance to minimize methanol content, a study needed prior to further GMP manufacturing of Drug Substance. We will also conduct a transporter study to examine whether PTI-125 is a substrate or inhibitor of P- glycoprotein (Pgp) and other efflux and uptake transporters, as requested by FDA in pre- IND guidance. Finally, we will conduct chronic repeat dose oral toxicity studies of PTI-125 in rat and dog. Chronic tox studies will support clinical trials for efficacy as well as an eventual NDA. Along with a multi-dose Phase I clinical trial that we plan to conduct separately, the work proposed here will progress the clinical development of PTI-125 and make PTI-125 more attractive to potential commercialization partners.

Public Health Relevance

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 propose to select and manufacture a solid oral dosage form, optimize the crystallization process chemistry to minimize methanol content, and conduct chronic oral toxicity studies in two species.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Martin, Zane
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Pain Therapeutics, Inc.
United States
Zip Code