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O1 Applying translational approaches for the nonclinical and clinical evaluation of the sGC stimulator CY6463 in CNS diseases Christopher J. Winrow Cyclerion Therapeutics, Cambridge Massachusetts, USA Correspondence: Christopher J. Winrow (cwinrow@cyclerion.com) J Transl Med 2022, 21(1):O1 Introduction: The NO-sGC-cGMP pathway plays a critical role in central nervous system (CNS) function and is impacted across a range of neurological and psychiatric diseases. NO is recognized as a key neu-rotransmitter that is produced on-demand within the CNS and can act through sGC and cGMP to govern a range of downstream effects. We have identified CY6463, a CNS-penetrant sGC stimulator, with demonstrated pharmacological effects in nonclinical and clinical studies. By acting as a selective positive allosteric modulator of sGC, CY6463 can amplify endogenous NO signaling while maintaining upstream spatial and temporal regulation. This enables the on-demand production of cGMP and propagation of downstream signals within the CNS. Methods: A range of nonclinical studies were conducted to understand the in vitro and in vivo properties of CY6463 and supported advancement into clinical development. Phase 1 clinical studies included single-ascending dose, multiple-ascending dose and food interaction studies along with a translational pharmacology study in healthy elderly participants. Results: This presentation will describe the nonclinical pharmacology of CY6463, along with clinical data from Phase 1 studies including the pharmacokinetic, safety, and pharmacodynamic results of our clinical translational pharmacology study in elderly participants. Furthermore, we will discuss our translational biomarker strategy that has been carried through into clinical studies in three separate patient populations and provide outlines of these clinical studies and updates on progress to date. Conclusions: Applying a translational biomarker based approach to the development of CY6463 has enabled advancement of clinical studies in well-defined patient populations to help understand the potential opportunity for modulating sGC function in neuropsychiatric and neurodegenerative diseases. Acknowledgements: CJW is an employee of Cyclerion Therapeutics and gratefully acknowledges the contributions of the Cyclerion team members and collaborators to this project. O2 sGC modulators as cognitive enhancers: neuronal and/ or vascular? Correspondence: Jos Prickaerts (jos.prickaerts@maastrichtuniversity.nl) J Transl Med 2022, 21(1):O2 Introduction: Cognitive impairment is one of the main symptoms of Alzheimer's disease or Vascular dementia, which negatively impacts the quality of life of patients. Therefore, a pharmacological intervention that has memory enhancing effects would be beneficial to patients. Vascular dementia is characterized by impairments in cer-ebral blood flow, endothelial function and blood-brain barrier integrity. These processes are all physiologically regulated by the soluble guanylate cyclase (sGC)-cGMP signaling pathway in blood vessel cells. Additionally, neuronal cGMP signaling plays an important role in long-term potentiation underlying memory formation. Therefore, targeting the NO-sGC-cGMP pathway may be a therapeutic strategy for treating neuronal-and/or vascular-based dementias. Methods: sGC stimulators acting on heme-bound sGC and one sGC activator acting on heme-free sGC were tested in the object location task (OLT) on acquisition memory processes, in healthy rodents and in deficit models. Vascular function and neuroplasticity were assessed. Funding was provided by a restricted research grant from Bayer AG, Pharmaceuticals.

O1 Applying translational approaches for the nonclinical and clinical evaluation of the sGC stimulator CY6463 in CNS diseases Christopher J. Winrow Cyclerion Therapeutics, Cambridge Massachusetts, USA Correspondence: Christopher J. Winrow (cwinrow@cyclerion.com) J Transl Med 2022, 21(1):O1 Introduction: The NO-sGC-cGMP pathway plays a critical role in central nervous system (CNS) function and is impacted across a range of neurological and psychiatric diseases. NO is recognized as a key neu-rotransmitter that is produced on-demand within the CNS and can act through sGC and cGMP to govern a range of downstream effects. We have identified CY6463, a CNS-penetrant sGC stimulator, with demonstrated pharmacological effects in nonclinical and clinical studies. By acting as a selective positive allosteric modulator of sGC, CY6463 can amplify endogenous NO signaling while maintaining upstream spatial and temporal regulation. This enables the on-demand production of cGMP and propagation of downstream signals within the CNS. Methods: A range of nonclinical studies were conducted to understand the in vitro and in vivo properties of CY6463 and supported advancement into clinical development. Phase 1 clinical studies included single-ascending dose, multiple-ascending dose and food interaction studies along with a translational pharmacology study in healthy elderly participants. Results: This presentation will describe the nonclinical pharmacology of CY6463, along with clinical data from Phase 1 studies including the pharmacokinetic, safety, and pharmacodynamic results of our clinical translational pharmacology study in elderly participants. Furthermore, we will discuss our translational biomarker strategy that has been carried through into clinical studies in three separate patient populations and provide outlines of these clinical studies and updates on progress to date. Conclusions: Applying a translational biomarker based approach to the development of CY6463 has enabled advancement of clinical studies in well-defined patient populations to help understand the potential opportunity for modulating sGC function in neuropsychiatric and neurodegenerative diseases. Acknowledgements: CJW is an employee of Cyclerion Therapeutics and gratefully acknowledges the contributions of the Cyclerion team members and collaborators to this project. O2 sGC modulators as cognitive enhancers: neuronal and/ or vascular? Correspondence: Jos Prickaerts (jos.prickaerts@maastrichtuniversity.nl) J Transl Med 2022, 21(1):O2 Introduction: Cognitive impairment is one of the main symptoms of Alzheimer's disease or Vascular dementia, which negatively impacts the quality of life of patients. Therefore, a pharmacological intervention that has memory enhancing effects would be beneficial to patients. Vascular dementia is characterized by impairments in cer-ebral blood flow, endothelial function and blood-brain barrier integrity. These processes are all physiologically regulated by the soluble guanylate cyclase (sGC)-cGMP signaling pathway in blood vessel cells. Additionally, neuronal cGMP signaling plays an important role in long-term potentiation underlying memory formation. Therefore, targeting the NO-sGC-cGMP pathway may be a therapeutic strategy for treating neuronal-and/or vascular-based dementias. Methods: sGC stimulators acting on heme-bound sGC and one sGC activator acting on heme-free sGC were tested in the object location task (OLT) on acquisition memory processes, in healthy rodents and in deficit models. Vascular function and neuroplasticity were assessed. Funding was in part supported by a restricted grant from Bayer AG and Merck Sharp & Dohme Corp.