Wednesday, September 18, 2024
9/18/2024
Project Summary/Abstract PTI-125 (sumifilam) 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 Aß42’s tight binding to and toxic signaling via the a7-nicotinic acetylcholine receptor (a7nAChR) as well as Aß42’s aberrant activation of toll-like receptor 4 (TLR4). 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 a7nAChR, NMDAR and insulin receptors, suggesting symptomatic improvement. Under a US IND, the first-in-human clinical trial showed no drug-related adverse effects and dose proportional pharmacokinetics. Our first-in-patient clinical trial in mild-to-moderate AD patients demonstrated 20-34% reductions in established CSF biomarkers P-tau181, total tau, neurogranin and neurofilament light chain, as well as 5-15% reductions neuroinflammatory markers. Replicating these results in a 1-month placebo-controlled clinical trial in 62 patients, both 50 mg and 100 mg doses significantly improved 7 CSF biomarkers compared to placebo, including the desired increase in CSF Aß42. In a cognitive assessment of episodic memory, the 50 and 100 mg doses produced 37% and 23% effect sizes, respectively, versus placebo. Improvement on this primary cognitive endpoint correlated with improvements in biomarkers. With these highly encouraging clinical results, PTI-125 is ready for a large Phase 2/3 clinical trial and partnering efforts. We propose here a Phase 3 readiness scope of work. We will conduct a clinical study to determine the effect of concomitant food on absorption of PTI-125, as required by FDA. We will also scale-up manufacturing and analytical methods of PTI-125 oral tablets to Phase 3 (commercial) standards and manufacture drug supply to initiate a large Phase 2/3 trial. Finally, we will select clinical trial sites, patient recruitment methods and an electronic clinical outcome assessment (eCOA) platform.
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