Cyclerion Announces Positive Data from CNS Translational Study in Healthy Elderly Subjects

Cyclerion Therapeutics announced results from its Phase 1 translational pharmacology study of IW-6463, the first soluble guanylate cyclase (sGC) stimulator in clinical development for CNS disorders.

Treatment with IW-6463 in this 15-day 24-subject crossover study confirmed and extended results seen in earlier Phase 1 studies: once daily oral treatment demonstrated blood-brain-barrier penetration, desired CNS exposure levels and target engagement. In this study, IW-6463 was shown to be safe and generally well-tolerated. Subjects receiving IW-6463 showed meaningful improvements in certain neurophysiological and objective performance measures that are associated with age-related cognitive decline and neurodegenerative diseases. Effects on cerebral blood flow and markers of bioenergetics were not observed in this study.

These results support the ongoing development of IW-6463 in serious CNS diseases. Cyclerion will soon begin enrolling its Phase 2 clinical trial in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS). Over the coming months the company will use the findings of the translational pharmacology study, in addition to observations from the previous Phase 1 study of 110 healthy subjects, to inform further clinical development activities, including the initiation of a planned Phase 2 clinical trial in Alzheimer’s disease with vascular pathology (ADv) in 2021, as well as to explore other potential indications.

"These data show that IW-6463 has a positive effect on brain neurophysiology that has been associated with age-related cognitive decline and neurodegenerative diseases. Furthermore, these data support the role of nitric oxide as an important neurotransmitter whose potential therapeutic benefits remain underexplored,” said Chris Wright, M.D., Ph.D., Cyclerion’s Chief Medical Officer. “We expect to initiate enrollment of the MELAS study later this year and are excited to incorporate the learnings from our translational pharmacology study into the design of our planned Phase 2 ADv study. Looking beyond these studies, we will evaluate the potential of IW-6463 to provide clinical benefit for people suffering from a range of serious CNS diseases. Seeing such robust, consistent and rapidly occurring changes in this study gives us confidence that IW-6463 targets a relevant mechanism in cognition and neurodegeneration.”

The exploratory Phase 1 study conducted in 24 healthy elderly volunteers age 65 and older evaluated safety and tolerability, pharmacokinetics, measures of CNS pharmacodynamic activity, including cerebral blood flow, and a range of measures associated with age-related cognitive decline and neurodegenerative diseases. Participants received study drug once daily across two 15-day dosing periods (Period 1 and Period 2). The dosing periods were separated by a 27-day washout. Participants were randomized to a sequence of receiving IW-6463 for Period 1 and then placebo for Period 2, or vice versa. All 24 subjects completed the first period, and 12 completed the entire crossover due to operational challenges associated with COVID-19.

IW-6463 demonstrated blood-brain-barrier penetration, desired CNS exposure levels and engagement of the targeted nitric oxide (NO)-signaling pathway. Mean concentrations of IW-6463 in cerebrospinal fluid (CSF) achieved levels projected to be pharmacologically active based on preclinical studies. Consistent with this, pathway target engagement was confirmed through monitoring blood pressure and CSF cyclic guanosine monophosphate (cGMP) levels. This study reproduced the brain exposure and safety and tolerability data set of the prior Phase 1 study in young healthy volunteers (n=110).

IW-6463, a CNS-penetrant sGC stimulator, is being developed as a symptomatic and potentially disease modifying therapy for serious CNS diseases. Nitric oxide (NO) is one of several fundamental neurotransmitters, but it has yet to be leveraged for its full CNS therapeutic potential. IW-6463 stimulates sGC, a signaling enzyme that responds to the presence of NO, to enhance the body’s natural ability to produce cyclic guanosine monophosphate (cGMP), an important signaling molecule, naturally. An impaired NO-sGC-cGMP signaling pathway is believed to play an important role in the pathogenesis of neurodegenerative diseases and is critical to basic neuronal functions. Agents that stimulate sGC to produce cGMP may compensate for deficient NO signaling.