Open-label extension of a 3-month blinded clinical trial of PTI-125

Project Summary/Abstract PTI-125 is a novel small molecule Alzheimerandapos;s disease (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 Aβ42andapos;s tight binding to and toxic signaling via the α7-nicotinic acetylcholine receptor (α7nAChR) as well as Aβ42andapos;s aberrant activation of toll-like receptor 4 (TLR4). Hence, by restoring FLNAandapos;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 α7nAChR, 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 and will therefore conduct clinical studies in mild-to-moderate AD. Under a US IND, the first-in-human clinical trial showed no drug- related adverse effects (AEs) and dose proportional pharmacokinetics (PK). Two Phase 2 multidose studies in mild-to-moderate AD patients of 1-month and 3-month duration, respectively, will measure CSF and plasma/lymphocyte biomarkers and psychiatric/behavioral measures. The already underway 1-month study, a 12-patient open-label study, will also assess PK of twice daily oral dosing of the tablet formulation. The upcoming 3-month blinded study will additionally assess cognition, but not PK. Excellent safety margins have been demonstrated in a 3-month toxicity study in dog and in a 6-month toxicity study in rat. The completion of the 9-month dog toxicity study in May 2019, along with the 6-month rat study, will support clinical trials of any duration. We therefore propose to add a 1-year open-label extension to the 3-month clinical trial both to encourage enrollment and to start our safety database required by FDA. This proposal also includes scale-up and manufacture of PTI-125 tablets to supply this clinical trial, as well as analytical method improvement for PTI-125 Drug Substance to Phase 2/3 standards. The faster acquisition of endpoints for the 3-month blinded clinical trial, along with longer-term dosing for safety and monitoring of disease progression, should greatly enhance interest by potential pharma partners.Project Narrative PTI-125 is a novel compound that 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. With Phase 1 safety demonstrated and a Phase 2 study in two parts underway, we propose to add a 1-year open-label extension to the latter Phase 2 study, including the scale- up and manufacture of PTI-125 tablets to supply this study. Analytical method improvement for the Drug Substance to Phase 2/3 standards is also proposed.