ABSTRACT
Objective: To evaluate the safety, tolerability, pharmacokinetics, and central nervous system (CNS) activity of IW-6463, a CNS-penetrant soluble guanylate cyclase (sGC) stimulator in healthy elderly volunteers. Background: IW-6463 is being developed as a symptomatic and potentially disease-modifying therapy for serious CNS diseases. Nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) is a fundamental neurotransmitter system critical to basic neuronal function. Impaired signaling of this pathway is believed to play an important role in the pathogenesis of many neurodegenerative diseases. sGC stimulation by IW-6463 can amplify endogenous NO signaling by increasing cGMP production. Preclinically, IW-6463 improves neuronal function, cerebral blood flow, neuroinflammation, and cellular bioenergetics. Design/Methods: In this double-blind, placebo-controlled, crossover study, 24 healthy elderly (≥65 years) volunteers were randomized to receive study drug once daily across two 15-day dosing periods separated by a washout period. Due to COVID-related restrictions, a total of 24 participants completed period 1 and 12 participants completed period 2. Adverse events were recorded, standard safety assessments were performed, and samples of cerebral spinal fluid (CSF) and plasma were collected. Neuroimaging, electroencephalography (EEG), and cognitive performance measures were conducted at baseline and on Day 15 of each dosing period. Results: IW-6463 was well tolerated with no safety concerns and demonstrated blood-brainbarrier penetration at CSF concentrations predicted to be pharmacologically active based on preclinical studies. Although pharmacological effects were not measurable via neuroimaging, increases in posterior alpha power, trend increases in gamma power, and shortening of N200 auditory event-related potential (ERP) latencies were observed via EEG. Improvements in saccadic reaction time and saccadic peak velocity were also observed. Conclusions: IW-6463's favorable safety profile and impacts on biomarkers of CNS activity after 15 days of dosing in elderly individuals support further evaluation of IW-6463 in patients with serious CNS diseases, including Alzheimer's disease.