Slide 1: Clinical Data Update from Study of CY6463 in CIAS
Clinical Data Update from Study of CY6463 in CIAS Thursday, July 28, 2022 8:00 am EDT Exhibit 99.2
Slide 2: Safe harbor statement
Safe harbor statement This presentation is for informational purposes only and is not an offer to sell nor a solicitation of an offer to buy any securities of Cyclerion Therapeutics, Inc. (the “Company”). This presentation includes or may include certain information obtained from trade and statistic
Slide 3: Speakers & Agenda
Steven Hyman, MD Director, The Stanley Center for Psychiatric Research, Broad Institute Board Member, Cyclerion Speakers & Agenda 1 Welcome & introductions A brief overview of CIAS and CY6463 CY6463 clinical data overview Clinical study design Clinical data summary Perspective on CY6463 Q&A 2 3 4 5
Slide 4: Developing therapies to restore cognitive function
Developing therapies to restore cognitive function NO-sGC-cGMP is a fundamental CNS signaling pathway Regulates mitochondrial function, inflammation, neuronal function, and cerebral blood flow CY6463 is a positive allosteric modulator of sGC; oral, QD, small molecule with CNS exposure Promising sign
Slide 5: Advancing parallel clinical studies in priority populations
DISCOVERY IND-ENABLING PHASE 1* PHASE 1b/2a PHASE 2/3 CY6463 MELAS CIAS ADv Multiple under assessment CY3018 Multiple under assessment Advancing parallel clinical studies in priority populations *Two phase 1 studies were completed in healthy young and old (>65 years of age) volunteers confirming tar
Slide 6: Overview of CIAS and CY6463
Overview of CIAS And CY6463 Bruce Kinon, MD Vice President, Clinical Development, Cyclerion
Slide 7: Schizophrenia is one of the top leading causes of disability worldwide
Schizophrenia is one of the top 15 leading causes of disability worldwide1 21M worldwide, 2.7M in US with schizophrenia and growing Schizophrenia is associated with significant health, social, and economic concerns Over three quarters of the estimated US annual cost of schizophrenia ($281B in 2020)
Slide 8: Core cognitive deficits are chief determinant of long-term disability in schizophrenia
Core cognitive deficits are chief determinant of long-term disability in schizophrenia Vast majority of schizophrenia patients suffer with cognitive deficits Deficits overlap with measures of intelligence or IQ1 Cognitive function in schizophrenia may decline at rate of 1 IQ point every 1-2 years 2
Slide 9: Cognitive deficiencies are neurocognitive rate-limiting factors to functioning
Cognitive deficiencies are “neurocognitive rate-limiting factors” to optimal social and vocational functioning 1 Substantial correlation between functional capacity and cognitive performance in schizophrenia 2 Cognitive impairments, negative symptoms but not positive symptoms, are predictive, both c
Slide 10: Current antipsychotic treatment does little to improve cognitive impairment
Current antipsychotic treatment does little to improve cognitive impairment No pharmacologic approaches to improve cognition have yet been successful to yield approved treatments Treatment innovation may depend on search for new disease targets that may mediate CIAS Increasing ability to participate
Slide 11: CY6463 is an sGC stimulator that amplifies endogenous NO-sGC-cGMP signaling
CY6463 is an sGC stimulator that amplifies endogenous NO-sGC-cGMP signaling NO-sGC-cGMP is a fundamental CNS signaling pathway Pathway machinery is broadly expressed (neurons, glial cells, and vasculature) Deficits linked to multiple CNS diseases CY6463 is a positive allosteric modulator (PAM) that
Slide 12: NO-sGC-cGMP dysfunction is implicated in CIAS pathophysiology
NO-sGC-cGMP dysfunction is implicated in CIAS pathophysiology CY6463 improved dendritic spine morphology, increased LTP, increased gamma EEG power, and improved cognitive performance in preclinical models11 Compromised prefrontal and hippocampal NO signaling is implicated in cognitive deficits in sc
Slide 13: Targeting sGC is a promising therapeutic approach in CIAS
Targeting sGC is a promising therapeutic approach in CIAS where new therapies are greatly needed 0 +0.6 +0.2 +0.4 Nearly all people with schizophrenia (98%) have cognitive deficits Core cognitive deficits are chief determinant of long-term disability in schizophrenia NO-sGC-cGMP is a fundamental CNS
Slide 14: CY6463 CIAS Clinical Study
CY6463 CIAS Clinical study Jennifer Chickering, PhD Vice President, Clinical Strategy, Cyclerion
Slide 15: Study to assess effects of once-daily CY6463 on safety, PK, PD, and cognition in CIAS
Study to assess effects of once-daily CY6463 on safety, PK, PD, and cognition in CIAS on standard of care In clinic 1 2 3 4 5 9 10 11 12 13 14 -3 -2 -1 15 -28 to -7 28 Screening Check in Check out Follow up Dosing 6 7 8 Day Randomized, double-blind, placebo-controlled, multiple-ascending-dose, in-cl
Slide 16: Assessments of safety, PK, cognition, and PD
Assessments of safety, PK, cognition, and PD CNS/PD Safety Adverse events, BP/HR, ECGs, PANSS, clinical labs Extrapyramidal sx (AIMS, BARS, SAS), C-SSRS, other vitals, PEs PK Plasma concentrations of CY6463 and associated pharmacokinetics Cognitive performance battery Cognition Inflammation biomarke
Slide 17: Enrolled cognitively impaired, chronic schizophrenia population on standard of care
Enrolled cognitively impaired, chronic schizophrenia population on standard of care Baseline characteristics Total study population (N=48) Sex – male, n (%) 47 (97.9) Race, n (%) Black/African-American 38 (79.2) White 10 (20.8) Hispanic/Latino, n (%) 11 (22.9) Age in years, mean (SD) 36.7 (7.75) BMI
Slide 18: Strong safety, tolerability, and PK profile in participants with schizophrenia
Strong safety, tolerability, and PK profile extended in participants with schizophrenia on standard of care Well tolerated across all dose levels on top of antipsychotic regimen Mostly mild adverse events (AEs), all AEs resolved No SAEs, no severe AEs, no dropouts due to AEs Most common AE was heada
Slide 19: Characterizing effects of CY6463 on cognitive performance
Characterizing effects of CY6463 on cognitive performance In clinic 1 2 3 4 5 9 10 11 12 13 14 -3 -2 -1 15 -28 to -7 28 Screening Check-in Check-out Follow-up 6 7 8 MCCB; Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery Effect size=(Mean
Slide 20: Promising cognition signal after weeks of once-daily dosing with 15mg CY6463
Promising cognition signal after only 2 weeks of once-daily dosing with 15mg CY6463 0.44 0.15 0.44 Attention 0.60 Executive function 0.44 Memory 0.60 General cognition Day 14 Effect size = (Mean CFB CY6463 – mean CFB placebo)/pooled SD; means are least square means from MMRM (mixed-effect model repe
Slide 21: Increase in cognition signal over time
Increase in cognition signal over time Increasing effect size with time on treatment Consistent with pharmacokinetics of CY6463 Benefit expected to be durable and increase with chronic treatment based on: Experience with approved, peripherally active sGC stimulators Multi-dimensional sGC stimulator
Slide 22: CY6463 shows strong cognition signal over placebo after only 2 weeks of dosing
CY6463 shows strong cognition signal over placebo after only 2 weeks of dosing Intervention N Treatment duration Test Effect size Reference CY6463 15mg sGC stimulator 8 active, 16 placebo 2 weeks CSB 0.60 Current study BI 425809 10mg GlyT1 inhibitor ~85 active, 170 pbo 12 weeks MCCB 0.34 Fleishhacke
Slide 23: Characterizing effects of CY6463 on plasma biomarkers of inflammation
Characterizing effects of CY6463 on plasma biomarkers of inflammation In clinic 1 2 3 4 5 9 10 11 12 13 14 -3 -2 -1 15 -28 to -7 28 Screening Check-in Check-out Follow-up 6 7 8 InflammationMAP® v. 1.1, RBM Effect size = (Mean CFB CY6463 – mean CFB placebo)/pooled SD where means are from an ANCOVA (a
Slide 24: Disease-relevant, anti-inflammatory effects for CY6463 15mg
Disease-relevant, anti-inflammatory effects for CY6463 15mg, consistent with CY6463 pharmacology Effect size = (Mean CFB CY6463 – mean CFB placebo)/pooled SD where means are from an ANCOVA (analysis of covariance) with change from baseline as the response variable, treatment group as the main effect
Slide 25: CY6463 shows cognition signal over placebo after only weeks of dosing in CIAS
CY6463 shows cognition signal over placebo after only 2 weeks of dosing in CIAS 0 +0.6 +0.2 +0.4 Well tolerated, no safety signals, on top of stable, single antipsychotic regimen Dose-proportional, once-daily PK profile Robust cognition signal measured on instrument suitable for registration Disease
Slide 26: Perspective on CY6463
Perspective on CY6463 Steven Hyman, MD Director, The Stanley Center for Psychiatric Research, Broad Institute Member, Cyclerion Board of Directors
Slide 27: Summary
summary Peter Hecht, PhD Chief Executive Officer, Cyclerion
Slide 28: CY6463 pharmacology translating from preclinical to clinical, now in two patient populations
CY6463 pharmacology translating from preclinical to clinical, now in two patient populations Known aspects of sGC pharmacology CY6463 studies Mitochondrial function Inflammation Neuronal function Cerebral blood flow Preclinical Healthy elderly (CY6463 15mg) MELAS (CY6463 15mg) CI
Slide 29: Developing therapies to restore cognitive function
Developing therapies to restore cognitive function NO-sGC-cGMP is a fundamental CNS signaling pathway Regulates mitochondrial function, inflammation, neuronal function, and cerebral blood flow CY6463 is a positive allosteric modulator of sGC; oral, QD, small molecule with CNS exposure Promising sign
Slide 30: Q&A and Key Takeaways
Q&A Moderated by Cheryl Gault, Chief Operating Officer, Cyclerion Key Takeaways NO-sGC-cGMP is a fundamental CNS signaling pathway CY6463 is a positive allosteric modulator of sGC; oral, QD, small molecule with CNS exposure, strong safety profile and durable IP Promising signals observed in two dist