Cyclerion Therapeutics, Inc. participated in a webinar hosted by the United Mitochondrial Disease Foundation (UMDF). The Company shared additional positive clinical data from its signal-seeking study of CY6463, a first-in-class, CNS-penetrant sGC stimulator, in patients with Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS). Data from the 8-participant, open-label study demonstrate CY6463 was well tolerated, with no reports of serious adverse events (SAEs) or treatment discontinuation due to adverse events (AEs), and showed improvements across multiple mitochondrial disease-associated biomarkers, inflammatory biomarkers, cerebral blood flow, and functional connectivity between neural networks.

The webinar included MELAS and mitochondrial disease community insights from Philip Yeske, Ph.D., Science & Alliance Officer of UMDF, and the perspective of MELAS clinician-researcher, Amel Karaa, M.D., Assistant Professor and Director of the Mitochondrial Disease Program and Lysosomal Disorders Program at Harvard Medical School and Massachusetts General Hospital, and recent president of the Mitochondrial Medicine Society, on the implications and potential impact of these data for patients with MELAS. Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is one of the most complex orphan diseases affecting multiple organ systems, including the CNS, with different degrees of severity, and no approved therapies. MELAS is caused by some of the most common mitochondrial DNA mutations affecting the mitochondrial tRNA, and results in large clusters of familial cases of primary mitochondrial diseases (PMD).?It is estimated that about 1 in 4,300 individuals has a mitochondrial disease, and ~80% of individuals with mitochondrial disease have CNS symptoms. The unmet need in MELAS is immense, symptoms can affect virtually any organ and cause intense fatigue, muscle weakness, and pain in addition to neurological manifestations.?Life expectancy is estimated at ~17 years from onset of CNS symptoms.?The disease impedes the individual's ability to live independently, leads to social isolation, and overall reduced quality of life.

CY6463 is the first CNS-penetrant sGC stimulator to be developed as a symptomatic and potentially disease-modifying therapy for serious CNS diseases. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway is a fundamental mechanism that precisely controls key aspects of physiology throughout the body. In the CNS, the NO-sGC-cGMP pathway regulates diverse and critical biological functions including neuronal function, neuroinflammation, cellular bioenergetics, and vascular dynamics.

Although it has been successfully targeted with several drugs in the periphery, this mechanism has yet to be fully leveraged therapeutically in the CNS, where impaired NO-sGC-cGMP signaling is believed to play an important role in the pathogenesis of many neurodegenerative and neuropsychiatric diseases and other disorders associated with cognitive impairment. As an sGC stimulator, CY6463 acts as a positive allosteric modulator to sensitize the sGC enzyme to NO, increase the production of cGMP, and thereby amplify endogenous NO signaling. By compensating for deficient NO-sGC-cGMP signaling, CY6463 and other sGC stimulators may have broad therapeutic potential as a treatment to improve cognition and function in people with serious CNS diseases.