Sickle cell and CNS results from Cyclerion

CAMBRIDGE, Mass.—Cyclerion Therapeutics Inc. had a mixed bag of news this week, with data analyzed for two Phase 2 clinical trials: One in sickle cell disease (SCD) and the other in serious central nervous system (CNS) disease, specifically mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes.

The bad news came from the former, as the company noted that top-line results from its STRONG-SCD study of olinciguat, an investigational, orally-administered, once-daily, vascular sGC stimulator for the potential treatment of SCD did not demonstrate adequate activity to support further internal clinical development—although one plus was that olinciguat was generally well tolerated across all dose ranges.

Cyclerion intends to complete its analysis of the study results and present or publish them in a future forum.

“While we are disappointed that we won’t be contributing a much-needed new treatment option for SCD, we are continuing to analyze the data to understand several potential biomarker signals, including inflammation, as we explore partnership options for this program,” said Dr. Peter Hecht, CEO of Cyclerion.

Much better news emerged from an announcement of data from the company’s Phase 1 translational pharmacology study of IW-6463, said to be 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.

According to the company, 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 (collectively referred to as 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)—and possibly other potential indications down the line.

“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 Dr. Chris Wright, 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.”