Slide 1: On a mission to develop treatments that restore cognitive function
On a mission to develop treatments that restore cognitive function CORPORATE PRESENTATION
Slide 2: Safe harbor statement
Safe harbor statement This document contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended.Our forward-looking statements are based on current beliefs and expectations of our
Slide 3: On a mission to develop treatments that restore cognitive function
On a mission to develop treatments that restore cognitive function Tapping into a fundamental CNS signaling pathway with CY6463, a first-in-class, CNS-penetrant sGC stimulator Executing biomarker-guided development strategy in well-defined populations with cognitive impairment Tackling the enormous
Slide 4: Contents
Contents NO-sGC-cGMP is a fundamental CNS signaling pathway CY6463 translational pharmacology clinical study results Advancing next-generation sGC stimulator program Pipeline centered around improving cognitive function Potential for patient impact: 3 studies underway Executing on our priorities
Slide 5: NO-sGC-cGMP is a fundamental CNS signaling pathway
NO-sGC-cGMP is a fundamental CNS signaling pathway
Slide 6: CY6463 amplifies the fundamental NO-sGC-cGMP signaling pathway
CY6463 amplifies the fundamental NO-sGC-cGMP signaling pathway CY6463First-in-class BBB-permeable, positive allosteric modulator of sGCAmplifies endogenous NO-sGC-CGMP signaling to address central aspects of disease pathophysiology Preclinical data and extensive academic work validate the crucial ro
Slide 7: CY6463 improves endpoints relevant to cognition
CY6463 improves endpoints relevant to cognition Young Control Aged Control Aged CY6463 R6/2 + CY6463 46 nM R6/2 + CY6463 7 nM R6/2 WT Morphological plasticity In-vivo learning and memory Ex-vivo LTP Young rat/Vehicle Aged rat/Vehicle Aged rat/CY6463 Young rat/Vehicle Aged rat/Vehicle Aged rat/CY6463
Slide 8: sGC stimulation amplifies a fundamental CNS signaling pathway
CY6463 amplifies a fundamental CNS signaling pathway NO-sGC-cGMP pathway plays a critical role in brain functionsGC stimulation with CY6463 amplifies NO-sGC-cGMP signalingMorphological, ex vivo and in vivo data demonstrate important role of sGC in synaptic plasticity, learning and memory, and 6463’s
Slide 9: Translational Pharmacology Study Results
CY6463 Translational Pharmacology Study Results
Slide 10: CY6463 showed rapid and persistent improvements in multiple biomarkers
CY6463 showed rapid and persistent improvements in multiple independent biomarkers associated with cognitive impairment In a 15-day study in 24 healthy elderly subjects CY6463 demonstrated: Increased alpha and gamma power Improved N200 latency Faster saccadic eye movement (SEM) reaction time Reduced
Slide 11: Phase 1b translational pharmacology study designed to evaluate CNS activity
Phase 1b translational pharmacology study designed to evaluate CNS activity *due to COVID restrictions, 12 subjects completed only period 1 Healthy elderly population (≥65 years) Objectives washout CY6463 QD CY6463 QD Placebo Placebo 15 days 15 days 24 subjects completed period 1 12 subjects complet
Slide 12: CY6463 showed rapid improvement in biomarkers of cognition
CY6463 showed rapid improvement in biomarkers of cognition Increased alpha and gamma power Faster saccadic eye movement reaction time Improved N200 latency Alpha power: CY6463 vs. placebo Day 15 Improvement Age (years) Untreated CY6463 treated Time (ms) Time (sec) p=0.0216 Placebo CY6463 p=0.0216 Im
Slide 13: Pipeline centered around improving cognitive function
Pipeline centered around improving cognitive Function
Slide 14: CY6463 data point to potential in cognition
CY6463 data point to potential in cognition Preclinical CNS pharmacology Potential to improve cognitive function Neuronal function Neuro-inflammation Bioenergetics Vascular function Increased posterior alpha and gamma power Improved N200 latency Faster saccadic eye movement (SEM) andreaction time Re
Slide 15: Cognitive impairment is a debilitating facet of many CNS diseases
Cognitive impairment is a debilitating facet of many CNS diseases Neurodegenerative Alzheimer’s Disease Parkinson’s Dementia Lewy Body Dementia Neuropsychiatric Major Depressive Disorder Bipolar Disorder Autism Cancer/chemotherapy-induced cognitive impairment Traumatic brain injury Stroke Event-rela
Slide 16: Biomarker-guided development strategy in well-defined populations
Biomarker-guided development strategy in well-defined populations with cognitive impairment ADv | Alzheimer’s Disease with vascular pathology (ADv) CIAS | Cognitive Impairment Associated with SchizophreniaMELAS | Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes MELAS ADv Ne
Slide 17: Potential for patient impact: our priority indications
Potential for patient impact: our priority indications
Slide 18: Pipeline: CY6463 and CY3018 programs
DISCOVERY IND-ENABLING PHASE 1* PHASE 1b/2a PHASE 2 CY6463 MELAS ADv CIAS Multiple under assessment CY3018 Multiple under assessment Advancing parallel, signal-seeking, exploratory studies in priority patient populations *Two phase 1 studies were completed in healthy young and old (>65 years of age)
Slide 19: ADv: growing patient population, limited treatments
Growing patient population, devastating impact, limited treatments Biomarker-guided development strategy: ADv Exploratory Phase 2Near-term impact on disease-specific biomarkers and cognition Larger, longer studies symptomatic trialsfocused on cognition Initial approval expected on surrogate, symptom
Slide 20: ADv study ongoing
ADv study ongoing 20 Exploratory, signal-seeking study to evaluate safety, tolerability, and pharmacodynamic effects (EEG, MRI, neuroinflammatory biomarkers, cognition) Once-daily CY6463 vs. placebo12 weeks30 participants Confirmed AD pathology (PET, CSF)2+ cardiovascular risk factorsMild-moderate s
Slide 21: Biomarker-guided development strategy: MELAS
Biomarker-guided development strategy: MELAS Exploratory Phase 2Near-term impact ondisease-specific biomarkers Larger, longer symptomatic trials focused on cognition and stroke-like-episodes Potential for accelerated approvalwith predictive biomarker Transformative therapy for patients with MELAS Po
Slide 22: MELAS study ongoing; data expected 1H 2022
MELAS study ongoing; data expected 1H 2022 22 Objectives Exploratory, signal-seeking study to evaluate safety, tolerability, and pharmacodynamic effects (MRI, biomarkers) Study design 29-day open label Once-daily CY6463Up to 20 adults (targeting 12 completers) Patient targeting Genetically confirmed
Slide 23: Biomarker-guided development strategy: CIAS
Biomarker-guided development strategy: CIAS Exploratory Phase 1bSafety + near-term impact on disease-relevant biomarkers Larger, longer studies focused on biomarker-identified populations Standard of care adjunctive therapy Improve cognitive impairment and functional outcomes Today Tomorrow Future C
Slide 24: CIAS study ongoing
CIAS study ongoing 24 Objectives Exploratory, signal-seeking study to evaluate safety, tolerability, and pharmacodynamic effects (qEEG, ERP, digital cognitive performance battery) Study design 14-day in clinic, randomized, placebo-controlled, double-blinded Once-daily CY6463Approximately 60 particip
Slide 25: Next generation sGC stimulator program
Next generation sGC stimulator program
Slide 26: CY3018: selectively targeting the CNS
Next generation sGC stimulator CY3018: selectively targeting the CNS Greater relative CNS exposure Greater relative CNS pharmacology Greater CSF:plasma ratio for CY3018 translating into greater relative CNS pharmacologyCY3018 is progressing though IND-enabling developmentOngoing pharmacology studies
Slide 27: Executing on our priorities
WZ ’ = cyclerion TN EXECUTING ON OUR PRIORITIES
Slide 28: 2021: executing on our priorities
2021: executing on our priorities 28 * Preliminary, unaudited unrestricted cash, cash equivalents and restricted cash balance as of March 31, 2021 Clinical andpre-clinical ADv Ph2 study ongoingMELAS Ph2 study data expected H1 2022CIAS Ph1b study ongoingAdvancing CY3018, next-generation development c
Slide 29: On a mission to develop treatments that restore cognitive function
On a mission to develop treatments that restore cognitive function Tapping into a fundamental CNS signaling pathway with CY6463, a first-in-class, CNS-penetrant sGC stimulator Executing biomarker-guided development strategy in well-defined populations with cognitive impairment Tackling the enormous
Slide 30: Appendices
Appendices Preclinical, Phase 1 and translational pharmacology studies, references
Slide 31: Preclinical data
WZ ’ = cyclerion TN PRECLINICAL DATA
Slide 32: CY6463 demonstrated beneficial effects in preclinical studies
CY6463 demonstrated beneficial effects in preclinical studies across multiple domains associated with cognitive disease 32 Cerebral Blood FlowIncreased blood flow in areas associated with memory and arousal by fMRI BOLD imaging IMPROVED CellularBioenergeticsIncreased ATP and restored gene expression
Slide 33: CY6463 improved neuronal function
CY6463 improved neuronal function Restored hippocampal long-term potentiation to wild-type levels in a mouse neurodegenerative model Wild type Disease Disease + CY6463 (46 nM) * Normalized fEPSPAmplitude Time (min) 10 30 50 70 1.0 5 2.0 2.5 ImproveNeuronal Function ReduceNeuroinflammation EnhanceCel
Slide 34: CY6463 increased qEEG gamma power
CY6463 increased qEEG gamma power No effect seen with PDE9 inhibitor Healthy awake rats were treated with clinically relevant doses of CY6463 (3 mg/kg) or PDE9 inhibitor (10 mg/kg) Graph displays 1-2h post-dose, mean ± SEM ImproveNeuronal Function ReduceNeuroinflammation EnhanceCellular Bioenergetic
Slide 35: CY6463 and donepezil act independently to enhance qEEG signal
CY6463 and donepezil act independently to enhance qEEG signal Combination elicited additive increase in gamma band power in healthy rats ImproveNeuronal Function ReduceNeuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow *p<0.05 vs Veh# p<0.05 CY6463 vs CY6463 +DonepezilHealthy
Slide 36: CY6463 improved learning and memory in aged rats
CY6463 improved learning and memory in aged rats Increased rate of learning in aged rats treated with CY6463 in Morris Water Maze Healthy aged male rats were administered CY6463 (10 mg/kg, p.o.) daily during Morris Water Maze training Young rat/Vehicle Aged rat/Vehicle Aged rat/CY6463 Young rat/Vehi
Slide 37: CY6463 improved cognitive function in pharmacologically impaired rats
CY6463 improved cognitive function in pharmacologically impaired rats ImproveNeuronal Function ReduceNeuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow Rat Novel Object Recognition *p<0.05 vs. VEH + MK-801 rats CY6463 acts downstream of NMDA receptor to reverse deficit induce
Slide 38: CY6463 improved neuronal function: spine density
Mushroom spine density Restoration of spine density has potential to provide neuroprotectiveeffects and improve synaptic function in neurodegenerative diseases CY6463 improved neuronal function Enhanced hippocampal spine density in aged animals treated with CY6463 Young Control Aged Control Aged CY6
Slide 39: CY6463 reduced neuroinflammation
CY6463 reduced neuroinflammation Inhibited in vitro LPS-induction of biomarkers of neuroinflammation 39 *p<0.05 vs. control LPS-treated wellsCY6463 (10 µM) and DETA (30 µM) were incubated with SIM-A9 cells or rat brain 3D microtissues for 30 minutes before LPS (100 ng/ml) incubation and further incu
Slide 40: CY6463 enhanced cellular bioenergetics
CY6463 enhanced cellular bioenergetics Increased ATP and restored decreased gene expression in cells from patients with mitochondrial diseases 40 *p<0.05 vs. vehicle-treated wellsGM13740 Leigh Syndrome patient cells obtained from the Coriell Institute were treated for 24h before ATP quantificationTF
Slide 41: CY6463 improved cerebral blood flow
CY6463 improved cerebral blood flow 41 Increased blood flow in areas associated with memory and arousal by fMRI BOLD imaging Peripherally restricted sGC stimulator CNS-penetrant sGC stimulator CY6463 Reticular activating system Thalamus Cortical transition areas Ventral hippocampus ImproveNeuronal F
Slide 42: Phase 1 study results
WZ ’ = cyclerion TN PHASE 1 STUDY RESULTS
Slide 43: CY6463 Phase 1 showed CNS exposure, target engagement, PK, and safety
Results CY6463 phase 1 showed CNS exposure, target engagement, PK, and safety PHASE 1 (completed) 110 healthy young Age range 18-63 Standard safety Identified safe and well-tolerated dose levels with steady-state CNS exposure in therapeutic target range* Linear, predictable PK, consistentwith QD dos
Slide 44: Translational Pharmacology Study Results
Translational Pharmacology Study Results
Slide 45: CY6463 showed rapid and persistent improvements in multiple biomarkers
CY6463 showed rapid and persistent improvements in multiple independent biomarkers associated with cognitive impairment In a 15-day study in 24 healthy elderly subjects CY6463 demonstrated: Increased alpha and gamma power Improved N200 latency Faster saccadic eye movement (SEM) reaction time Reducti
Slide 46: Biomarker overview: qEEG frequency bands and clinical implications
Biomarker overview: qEEG frequency bands and their clinical implications qEEG is quantitative electroencephalography, an objective method that measures electrical activity and brain wave patterns Resting-state qEEG: subjects sit facing a featureless wall without movingrecorded with eyes open and clo
Slide 47: CY6463 improved qEEG measures: significant increase in alpha power
CY6463 improved qEEG measures: significant increase in alpha power qEEG is quantitative electroencephalography, an objective method that measures electrical activity and brain wave patterns CY6463 vs. baseline Significant increase in EEG alpha power No effect of placebo Placebo vs. baseline CY6463 v
Slide 48: CY6463's consistent alpha power effects across repeat sessions
CY6463’s consistent alpha power effects across repeat sessions indicate stable and robust signal Footer DAY 1baseline DAY 15change from baseline CY6463 relative to placebo CY6463 Placebo Pre-dose 1 Pre-dose 2 Pre-doselast dose 2 hr post-dose 3 hr post-dose 6 hr post-dose Magnitude of improvement equ
Slide 49: CY6463 increased alpha power with high responder rate
CY6463 increased alpha power with high responder rate (>70%) 1. Includes all subjects. For CY6463 and pbo each: n=12 for period 1, n=6 for period 2 Increase in alpha powerDay 15 change from baseline in mean closed-eye alpha (8-12 Hz) Power Consistent individual treatment responsesPosterior Closed-Ey
Slide 50: CY6463 treatment associated with trend improvement in gamma power
CY6463 treatment associated with trend improvement in gamma power Change in Closed-Eye Gamma (25-45 Hz) Power Placebo CY6463 Placebo CY6463 200 150 100 50 0 -50 -100 Anterior (p = 0.081) Posterior (p = 0.1163) Change from baseline (%)
Slide 51: Biomarker overview: event-related potential (ERP)
Biomarker overview: event-related potential (ERP) Trial: 500 tones80% standard, 20% deviant Deviant Standard ERP oddball paradigmSubjects wear EEG cap and headphones, hear tones with instruction to press a button upon deviant tones P300 N200 N200Stable component of ERP waveformStimulus identificatio
Slide 52: CY6463 improved N200 latency and effect increased with age
CY6463 improved N200 latency and effect increased with age Day 15 Improvement Age (years) Untreated CY6463 treated Time (ms) Effect of age on N200 latency Overall decrease in N200 latency for CY6463 treated vs untreated on day 15 (p<0.02) Effect more pronouncedin older subjects
Slide 53: CY6463 improved N200 latency, driven by response in older subjects
65 to 69yn=10 ≥70 yn=14 p=0.016 CY6463 improved N200 latency, driven byresponse in older subjects Greater decrease in ≥70y vs <70yDay 15 change from baseline Latency response was greater in subjects ≥70y vs 65-69y (p=0.016) Narrowing of variance in ≥ 70y supports a drug effect In ≥ 70y, magnitude of
Slide 54: Biomarker overview: saccadic eye movement
Biomarker overview: saccadic eye movement as an objective measure of attention and cognition Short, fast, simultaneous tracking of both eyes in the same direction Brain areas involved include the frontal cortex, superior colliculus, substantia nigra, and amygdala Considered to be reflective of atten
Slide 55: CY6463 improved saccadic eye movement
CY6463 improved saccadic eye movement, an objective functional measure Decrease in saccadic reaction time Increase in saccadic peak velocity Shorter saccadic reaction times and faster saccadic velocities indicate that CY6463 is improving CNS functional performance – motor output – in addition to CNS
Slide 56: CY6463 improved neuroinflammatory biomarkers
CY6463 improved neuroinflammatory biomarkers A2M and C3 are associated with pathological aging and Alzheimer’s Disease Alpha-2-macroglobulin (A2M) levels predict cognitive decline and development of AD; may lead to tau hyperphosphorylation Complement C3 (C3) colocalizes with Aβ plaques and tau tangl
Slide 57: Relevant reference publications
Relevant reference publications
Slide 58: Relevant reference publications (1 of 2)
Relevant reference publications (1 of 2) NO-sGC-cGMP signaling in the CNSCorreia S, et al. “The CNS-penetrant soluble guanylate cyclase stimulators CY6463 reveals its therapeutic potential in neurodegenerative diseases.” Frontiers in Pharmacology. 2021;12(1014)Correia S, et al. “The CNS-penetrant so
Slide 59: Relevant reference publications (2 of 2)
Relevant reference publications (2 of 2) Event-related potential (ERP): MMN, N200 and P300Bennys K, Portet F, Touchon J. Diagnostic value of event-related evoked potentials N200 and P300 subcomponents in early diagnosis of Alzheimer’s disease and mild cognitive impairment. J Clin Neurophysiol 2007;2