Open-label extension of a 3-month blinded clinical trial of PTI-125 - Project Summary/Abstract
PTI-125 is a novel small molecule Alzheimer'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 Aβ42's tight binding to
and toxic signaling via the α7-nicotinic acetylcholine receptor (α7nAChR) as well as Aβ42'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 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.
