Dosing Begins in Trial of CY6463 for Patients With Cardiovascular Risk

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by Patricia Inacio PhD |

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Patient dosing has begun in Cyclerion Therapeutic’s Phase 2a trial testing CY6463, a disease-modifying therapy for people with Alzheimer’s disease who have cardiovascular risk factors — health conditions that increase the risk of heart disease.

The experimental oral therapy is designed to improve cognition and function in people with Alzheimer’s.

“We believe that CY6463 has potential to provide meaningful cognitive benefits and are very pleased to have initiated this important clinical study,” Andreas Busch, PhD, chief scientific officer of Cyclerion, said in a press release.

“The need for effective new treatments for Alzheimer’s disease is immense, and, given the aging population demographics and increasing rate of diagnosis, this need will continue to expand,” Busch added.

The study (NCT04798989), targeting Alzheimer’s with vascular pathology, aims to recruit approximately 30 patients with the disease, ages 65 and older. Participants should have Alzheimer’s confirmed by PET imaging scans or by measuring disease biomarkers in the cerebrospinal fluid or CSF — the fluid surrounding the brain and spinal cord — and at least two cardiovascular risk factors.

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Additionally, patients must have signs of mild-to-moderate small-vessel disease affecting the subcortical region of the brain, as shown by MRI, among other eligibility criteria.

The trial is being conducted at four U.S. clinical sites, three of which are actively enrolling. More information is available here.

“The ongoing Phase 2a study will focus on a segment of the Alzheimer’s disease population where we believe our therapeutic candidate has the best opportunity to provide a clinical benefit,” Busch said. “We expect this trial to deliver a rich dataset that will deepen our understanding of the therapeutic potential of CY6463 and will enable well-informed decisions regarding further development.”

The trial’s main goal is to evaluate CY6463’s safety, tolerability, and pharmacokinetics — essentially, how the body affects the medicine. Exploratory measures include the therapy’s potential impact on disease-relevant biomarkers and cognitive performance.

Participants will be randomly assigned to receive a placebo or CY6463, delivered orally once daily for approximately three months.

Alzheimer’s and vascular dementia are the two most common forms of dementia. More than half of those diagnosed with Alzheimer’s also have signs of vascular dementia, with these patients often having more rapidly progressing disease and higher symptom severity. Cyclerion believes that CY6463 has the potential to address the processes that drive disease in this particular population of patients with dementia.

CY6463, previously called IW-6463, is an oral therapy that stimulates an enzyme called soluble guanylate cyclase (sGC), known to play a key role in the production of nitric oxide (NO).

The nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway has been shown to play a key role in several physiological aspects, and its deregulation has been linked with several disorders, including Alzheimer’s. While prior therapies were successful at targeting the pathway outside the central nervous system (CNS), comprised of the brain and spinal cord, CY6463 is the first to be able to penetrate the CNS and cross the blood-brain barrier, a semi-permeable membrane that shields the CNS from the general blood circulation.

The stimulation of sGC by CY6463 can boost the levels of NO, and consequently of cGMP, amplifying its signal.

Prior preclinical studies have shown that stimulating sGC induces a panoply of benefits across the CNS, including boosting memory in aged animals and increasing blood flow. Also, in lab-grown cells, it reduced the levels of neuroinflammation markers and increased the cells’ ability to produce energy.

“Our CY6463 development efforts are supported by preclinical data which demonstrate beneficial effects on cognition measures and the neuronal and microglia cellular [considered the immune cells of the brain] activity thought to have a central role in the pathology and the cognitive dysfunction experienced by individuals living with [Alzheimer’s disease with vascular pathology],” said Busch.

According to Cyclerion, results from a Phase 1 trial in elderly healthy individuals showed CY6463 was safe and generally well-tolerated. Moreover, it led to meaningful improvements in neurophysiological and biomarkers associated with age-related cognitive decline and neurodegenerative diseases.

“A Phase 1 study in elderly subjects demonstrated an impact on biomarkers relevant to neurodegeneration and cognitive impairment,” Busch said.