A Phase 2a study evaluating the safety, tolerability, pharmacokinetics, and central nervous system activity of CY6463 when administered to participants with Alzheimer’s disease with vascular pathology

Abstract

AbstractBackgroundThe soluble guanylate cyclase (sGC) stimulator, CY6463, is being developed as a symptomatic and potentially disease‐modifying therapy for serious central nervous system (CNS) diseases, including Alzheimer’s disease (AD). Nitric oxide (NO)‐sGC‐cyclic guanosine monophosphate (cGMP) is a fundamental neurotransmitter system critical to neuronal function. Impaired signaling of this pathway is known to play 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.CY6463 has been evaluated in two Phase 1 studies (110 healthy younger adult volunteers and 24 healthy elderly volunteers >65 years of age) assessing the safety, tolerability, pharmacokinetics (PK), and CNS activity of CY6463. Once‐daily CY6463 administration was well tolerated across dose levels, led to target CNS concentrations, achieved predictable/linear food‐independent PK, and had positive impacts on saccadic eye movements as well as brain neurophysiology as measured by electroencephalography (EEG).MethodThis 12‐week, randomized, placebo‐controlled study will evaluate safety, tolerability, PK, and CNS activity of CY6463 in approximately 40 patients with a combination of AD pathology, sub‐cortical vascular disease, and cardiovascular risk factors. This defined subset of the larger AD population, referred to as AD with vascular pathology (ADv), is hypothesized to be more likely to respond to CY6463 treatment due to CY6463’s expected impact on vascular and CNS biology. This study is funded in part by a Translational Research Award from the Alzheimer’s Association Part the Cloud‐Gates Partnership Grant Program.ResultThe primary objective, safety and tolerability, will be evaluated based on adverse event reporting. Exploratory evaluations assessed variously at baseline and weeks 2, 4, 8, and 12, will include plasma and CSF biomarkers of disease; PK; quantitative EEG and event related potentials as biomarkers of neurophysiology; functional magnetic resonance imaging measures of cerebral perfusion and brain connectivity; and cognitive performance tests of attention, executive function, and memory.ConclusionResults from this study in patients with ADv will inform the design of larger, longer studies evaluating the potential for CY6463 to improve cognition in this patient population.