Background

CY6463 is a brain-penetrant, positive allosteric modulator of the soluble guanylate cyclase (sGC). It amplifies endogenous nitrous oxide signaling to increase production of the second message cGMP. This signaling pathway regulates regional blood flow and inflammation, among other processes. Impaired NO signaling has been implicated in neurodegenerative disease.

Other sGC modulators are used to treat heart failure due to pulmonary hypertension; CY6463 is the first CNS-accessible sGC stimulator to enter clinical trials.

In preclinical work, CY6463 was reported to raise cGMP levels in cerebrospinal fluid and to elicite changes in CNS function. In rats, it increased fMRI-BOLD signals and EEG gamma band power, and reversed an experimental learning deficit induced an NMDA receptor antagonist. It slowed the loss of dendritic spines in aging mice and in an APP/PS1 transgenic mouse model of AD, and increased synaptic long-term potentiation in hippocampal slices from mice carrying the huntingtin gene expansion known to cause Huntington's disease. The compound reportedly also demonstrated anti-inflammatory activity in obese mice. It lowered blood pressure in rats and mice, as expected for sGC stimulators (Correia et al., 2021).

A related modulator, CYR119, reduced CNS neuroinflammation in cell and animal models (Correia et al., 2021).

Findings

In 2019, Cyclerion ran a first Phase 1 study, evaluating safety, tolerability, and effects on food of single and multiple ascending oral doses in 110 healthy volunteers. According to a January 2020 press release, they drug was well-tolerated, suitable for once-daily dosing with or without food, and achieved CSF levels sufficient for pharmacological activity. No serious adverse events were noted. The drug caused a mild reduction in blood pressure, as expected due to its mechanism of action.

In January 2020, a second Phase 1 began to measure the effects of 15 days of drug or placebo on brain blood flow in 24 healthy elderly volunteers. This trial ended in May 2020 when the study site closed due to COVID-19. In October 2020, the company announced results (press release). All 24 subjects completed at least one arm in the crossover study; 12 completed both. The trial reproduced the pharmacokinetic, brain-penetration, and pharmacodynamic results of the prior Phase 1. No effects were seen on blood flow, but the drug did improve some quantitative EEG parameters, and reduced CSF neuroinflammatory biomarkers

In June 2021, Cyclerion began a Phase 2 study in people with Alzheimer’s disease and vascular pathology (see company website). The planned 40 participants are 60 years or older with confirmed AD pathology and mild to moderate dementia, cardiovascular risk factors (e.g., high blood pressure, diabetes, obesity), and MRI evidence of subcortical vascular disease. They were randomized to a three-month course of once-daily drug or placebo, against a primary outcome of adverse events. Other endpoints include imaging, quantitative EEG, CSF biomarkers of neuroinflammation, and cognitive performance (Glasser et al., 2021). The trial was slated for completion in July 2022.

In June 2022, the company announced positive top-line results for two different indications, an inherited mitochondrial disease called MELAS, and cognitive impairment associated with schizophrenia. The press release claimed improvement in biomarkers of mitochondrial function and inflammation, cerebral blood flow, and neural network connectivity after one month of open-label CY6463 in eight mitochondrial disease patients (press release). In the placebo-controlled schizophrenia trial, two weeks of 15 mg daily were said to improve cognitive performance and inflammatory biomarkers in 48 participants (press release). Higher doses of 30 and 60 mg CY6463 had no effect on cognition. For details of both studies, see company presentation.

In October 2022, Cyclerion announced a decision to focus development of CY6463 on mitochondrial disease, saying it had stopped enrollment in the AD study and expected data in the first half of 2023 (press release).

For details, see clinicaltrials.gov.