Abstract Details

Title Design and methods of a Phase 2a study evaluating the safety, tolerability, pharmacokinetics, and CNS activity of CY6463 in participants with Alzheimer’s disease with vascular pathology

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P6 - Poster Session 6 (5:30 PM-6:30 PM)

Poster/Presentation
Number 3-005

Background

CY6463 is being developed as an oral symptomatic- and potentially disease-modifying therapy for serious CNS diseases. Nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) is a fundamental signaling system critical to neuronal function. Impaired signaling of this pathway plays a role in the pathogenesis of many neurodegenerative diseases. CY6463, a positive allosteric modulator of sGC, amplifies endogenous NO signaling to increase cGMP production. In preclinical models, CY6463 improved neuronal function, cerebral blood flow, neuroinflammation, and cellular bioenergetics.

In two Phase 1 studies, CY6463 was well tolerated, led to target CNS concentrations, achieved predictable/linear food-independent PK, and had positive impacts on saccadic eye movements and brain neurophysiology as measured by electroencephalography (EEG).

Objective To evaluate the safety, tolerability, pharmacokinetics (PK), and central nervous system (CNS) activity of CY6463, a CNS-penetrant soluble guanylate cyclase (sGC) stimulator in participants with Alzheimer’s disease (AD) with vascular pathology (ADv).

Design/Methods This 12-week, randomized, placebo-controlled study will evaluate CY6463 in approximately 30 patients with a combination of AD pathology, sub-cortical vascular disease, and cardiovascular risk factors. This defined subset of the larger AD population is hypothesized to be more likely to respond to CY6463 treatment due to CY6463’s expected impact on vascular and CNS biology. This work was supported by an Alzheimer’s Association Grant (PTCG-20-707481).

Results Safety and tolerability will be evaluated based on adverse events and standard safety measures. Exploratory evaluations assessed variously at baseline and weeks 2, 4, 8, and 12, will include CSF biomarkers of disease; PK; quantitative EEG and event-related potentials as biomarkers of neurophysiology; functional magnetic resonance imaging measures of brain perfusion and connectivity; and cognitive performance tests of attention, executive function, and memory.

Conclusions Results from this study will inform the design of larger, longer studies evaluating the potential for CY6463 to improve cognition in ADv.

Authors/Disclosures
Chad E Glasser, PharmD (Cyclerion Therapeutics) PRESENTER	Mr. Glasser has received personal compensation for serving as an employee of Cyclerion Therapeutics. Inc. Mr. Glasser has stock in Cyclerion Therapeutics Inc.. Mr. Glasser has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Christopher Wright	Christopher Wright has received personal compensation for serving as an employee of Cyclerion. Christopher Wright has received personal compensation for serving as an employee of AavantiBio. Christopher Wright has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cyclerion. Christopher Wright has received stock or an ownership interest from Cyclerion. Christopher Wright has received stock or an ownership interest from AavantiBio. The institution of Christopher Wright has received research support from Alzheimer's Association.
	No disclosure on file