Exhibit 99.2
ON A MISSION TO DEVELOP TREATMENTS THAT RESTORE COGNITIVE FUNCTIONCORPORATE PRESENTATION APRIL 2021
Safe harbor statement 2 © 2021 Cyclerion Therapeutics, Inc 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 management team that involve risks, potential changes in circumstances, assumptions, and uncertainties, including statements about the anticipated timing of release of topline results of our clinical trials; the progression of our discovery programs into clinical development; and the business and operations of the Company. We may, in some cases use terms such as “predicts,” “believes,” “potential,” “continue,” “anticipates,” “estimates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “likely,” “will,” “should” or other words that convey uncertainty of the future events or outcomes to identify these forward-looking statements.Each forward-looking statement is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statement. Applicable risks and uncertainties include those related to the possibility that any results of operations and financial condition of the Company reported are preliminary and subject to final audit and the risks listed under the heading “Risk Factors” and elsewhere in our 2020 Form 10-K filed on February 25, 2021, and our subsequent SEC filings. Investors are cautioned not to place undue reliance on these forward-looking statements. These forward-looking statements (except as otherwise noted) speak only as of the date of this report, and the Company undertakes no obligation to update these forward-looking statements, except as required by law.
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 burden and breadth of cognitive impairment through an innovative portfolio of indications and molecules 2 © 2021 Cyclerion Therapeutics, Inc
Contents NO-sGC-cGMP is a fundamental CNS signaling networkCY6463 translational pharmacology study results Pipeline centered around improving cognitive function Potential for patient impact: our priority indications Next-generation sGC stimulator programExecuting on our priorities 2 © 2021 Cyclerion Therapeutics, Inc
NO-sGC-cGMP IS A FUNDAMENTAL CNS SIGNALING PATHWAY
6 © 2021 Cyclerion Therapeutics, Inc 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 pathophysiologyPreclinical data and extensive academic work validate the crucial role of the NO- sGC-cGMP pathway in brain physiology Synaptic plasticity Neuro- inflammation Bioenergetics Vascular function PKG, PDE, ion channels Downstream targets (e.g., CREB, BDNF) Important role in learning and memory
7 © 2021 Cyclerion Therapeutics, Inc CY6463 improves endpoints relevant to cognition Aged Control Aged CY6463 R6/2R6/2 + CY6463 7 nM R6/2 + CY6463 46 nM WT Morphological plasticityYoung Control 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 10 30 50 70 1.0 1.5 2.0 2.5 �� Time (min) Normalized fEPSP amplitude CY6463 vs WT, p = 0.9811 CY6463 vs R6/2, p = 0.0017 10 30 50 70 1.0 1.5 2.0 2.5 Time (min) Normalized fEPSP amplitude CY6463 vs WT, p = 0.0389 CY6463 vs R6/2, p = 0.265 *p<0.05 vs. the aged control group
8 © 2021 Cyclerion Therapeutics, Inc 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 ability to restore deficits in these endpoints
CY6463 TRANSLATIONAL PHARMACOLOGY STUDY RESULTS
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 powerimproved N200 latency faster saccadic eye movement (SEM) reaction time reduction in neuroinflammatory biomarkers Rapid onset (<15 days)Effect increased with ageBiomarkers linked to AD and aging 10 © 2021 Cyclerion Therapeutics, Inc
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 11 © 2021 Cyclerion Therapeutics, Inc CY6463 QD CY6463 QD Placebo Placebo 15 days 15 days 24 subjects completed period 1 12 subjects completed both periods* Safety and tolerabilityPharmacokinetics Target engagementCNS activity
12 © 2021 Cyclerion Therapeutics, Inc CY6463 showed rapid improvement in biomarkers of cognition Faster saccadic eye movement reaction time Alpha power: CY6463 vs. placebo Day 15 Improvement Age (years) Untreated CY6463treated Time (ms) Time (sec) p=0.0216 Placebo CY6463 p=0.0216 Improvement 0.02 0.00 -0.02 -0.04 TNFR2 MMP3 PARC (CCL18) MCP1 PAI1 TIMP1 C3 A2M -30 -20 -10 0 10 20 30LS % Mean Difference with 95% CI CSF Biomarkers Reduced neuroinflammatory biomarkersLS % Mean Difference from Placebo at Day 15 In a 15-day study in 24 healthy elderly subjects, CY6463 demonstrated:Increased alpha and gamma power Improved N200 latency
PIPELINE CENTERED AROUND IMPROVING COGNITIVE FUNCTION
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) and reaction time Reduced neuroinflammatory biomarkers in CSF Clinical CNS pharmacology* *In a 15-day study in 24 healthy elderly subjects 14 © 2021 Cyclerion Therapeutics, Inc
Cognitive impairment is a debilitating facet of many CNS diseases Neurodegenerative Alzheimer’s Disease Lewy Body DementiaParkinson’s Dementia Neuropsychiatric Major Depressive Disorder Bipolar DisorderAutism Traumatic brain injury StrokeCancer/chemotherapy-induced cognitive impairment Event-related 15 © 2021 Cyclerion Therapeutics, Inc Mitochondrial Leigh SyndromeKearns-Sayre Syndrome ADv ongoing CIAS ongoing MELAS ongoing ~2M~35M~13M~5M Orphan OrphanOrphan ~21M~150M~27M~10M ~21M (US)~12M~5M (US) References on file.Represents approximate prevalence of patients with cognitive impairment associated with other CNSdiseases, worldwide in millions, except where noted as US prevalence
Biomarker-guided development strategy in well-defined populations with cognitive impairment ADv | Alzheimer’s Disease with vascular pathology (ADv)CIAS | Cognitive Impairment Associated with Schizophrenia MELAS | Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes MELAS ADv Neurodegenerative Neuropsychiatric CIAS Mitochondrial Disease Significant additional opportunities Improving CognitionParallel studies in distinct populationsEfficient, signal-seeking studies inform larger and longer studiesDisease-relevant biomarkers accelerate and guide developmentTranslation of insights across programs increases odds of success 16 © 2021 Cyclerion Therapeutics, Inc
POTENTIAL FOR PATIENT IMPACT: OUR PRIORITY INDICATIONS
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 18 © 2021 Cyclerion Therapeutics, Inc *Two phase 1 studies were completed in healthy young and old (>65 years of age) volunteers confirming targeted CNS exposure and activity
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 trials focused on cognitionInitial approval expected on surrogate, symptomatic or functional endpoints Standard of care for patients with ADvPotential for disease modification and expansion into broader AD Today Tomorrow Future Alzheimer’s Disease Vascular Dementia ADv 19 © 2021 Cyclerion Therapeutics, Inc
ADv study expected to initiate in mid-2021 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 subcortical small-vessel disease on MRIMini mental state exam score (20-26) Objectives Study design Patient targeting Partially funded by the Alzheimer’s Association’s Part the Cloud-Gates PartnershipCollaborating with Dr. Andrew Budson at Boston University on a study to examine the relationship between ERP/EEG and cognitive measures indementias Collaborations 20 © 2021 Cyclerion Therapeutics, Inc
Biomarker-guided development strategy: MELAS Exploratory Phase 2 Near-term impact on disease-specific biomarkers Larger, longer symptomatic trials focused on cognition and stroke-like-episodesPotential for accelerated approval with predictive biomarker Transformative therapy for patients with MELASPotential for expansion into additional mitochondrial diseases Today Tomorrow Future MELAS is a serious orphan disease, with significant CNS impact, no approved treatments 21 © 2021 Cyclerion Therapeutics, Inc
MELAS study underway; data expected late 2021 Objectives Exploratory, signal-seeking study to evaluate safety, tolerability, and pharmacodynamic effects (MRI, biomarkers) Study design 29-day open labelOnce-daily CY6463Up to 20 adults (targeting 12 completers) Patient targeting Genetically confirmed mitochondrial disease with neurological features of MELASElevated plasma lactate (disease biomarker) Sites and collaborations Study performed at centers of excellence for mitochondrial medicine: CHOP, MGH, Children’s National Hospital, Columbia University, Johns Hopkins UniversityPreclinical collaboration with Dr. Marni Falk at CHOP to elucidate the role of sGC in mitochondrial disease models 22 © 2021 Cyclerion Therapeutics, Inc
Biomarker-guided development strategy: CIAS Exploratory Phase 1b Safety + 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 CIAS is a debilitating and untreated facet of schizophrenia, with large and growing unmet need 23 © 2021 Cyclerion Therapeutics, Inc
CIAS study expected to initiate in 2H 2021 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-blindedOnce-daily CY6463Approximately 50 participants across sequential cohorts Patient targeting Psychiatrically stable adults with schizophreniaOn stable antipsychotic regimen 24 © 2021 Cyclerion Therapeutics, Inc
NEXT GENERATION sGC STIMULATOR PROGRAM
26 © 2021 Cyclerion Therapeutics, Inc Rat Cyno 0 2 4 6 CSF : Plasma Ratio CY6463 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 to validate amenable CNS indications CY3018 Data displayed as mean+ SEM, Relative pharmacology ratio: 1-hour post-dose with vehicle-subtraction CY3018 CY6463 0.0 0.5 1.0 1.5 Relative Pharmacology% change (gamma : BP)
EXECUTING ON OUR PRIORITIES
28 © 2021 Cyclerion Thera*pePutrieclsi,mInicnar 2021: executing on our priorities Clinical and pre-clinical ADv Ph2 study start mid-2021MELAS Ph2 study data by year end 2021CIAS Ph2b study start in 2H 2021Advancing CY3018, NextGen development candidate Partnerships Explore CNS collaborationsPraliciguat out-license Capabilities and capital Grow external CNS network and augment core team CNS expertiseReduced monthly cash use to ~50% that of 2020Q1 2021 ending cash balance of ~$45M* * Preliminary, unaudited unrestricted cash, cash equivalents and restricted cash balance as of March 31, 2021
29 © 2021 Cyclerion Therapeutics, Inc 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 burden and breadth of cognitive impairment through an innovative portfolio of indications and molecules
APPENDICES Preclinical, Phase 1 andtranslational pharmacology studies, references
PRECLINICAL DATA
CY6463 demonstrated beneficial effects in preclinical studies across multiple domains associated with cognitive disease IM P RO V ED Cerebral Blood FlowIncreased blood flow in areas associated with memory and arousal by fMRI BOLD imaging ENH A NCED Cellular BioenergeticsIncreased ATP and restored gene expression in cells from patients with mitochondrial diseases IM P RO V ED Neuronal FunctionEnhanced memory & spine density in aged animals; increased LTP in neurodegenerative models; affected qEEG spectra RED UCED Neuro- inflammationDecreased markers of LPS-induced neuroinflammation (ICAM1, VCAM1, IL6) invitro 32 © 2021 Cyclerion Therapeutics, Inc
CY6463 improved neuronal functionRestored hippocampal long-term potentiation to wild-type levels in a mouse neurodegenerative model 10 30 50 70 1.0 5 2.0 2.5 Time (min) Normalized fEPSPAmplitude 1. Wild type Disease Disease + CY6463 (46 nM) * Normalized fEPSP Amplitude Time (min) 10 30 50 70 1.0 5 2.0 2.5 ImproveNeuronal Function Reduce Neuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow Hippocampal slices from symptomatic Huntington’s Disease (R6/2) mice incubated with CY6463 for 25-30 minutes before LTP inductionExtracellular field potentials recordings performed using Multi- Electrode Array; **p<0.01 vs. Disease By acting directly on the neurons,CY6463 could restore impaired neurotransmission 33 © 2021 Cyclerion Therapeutics, Inc
CY6463 increased qEEG gamma powerNo 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 Reduce Neuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow CY6463 isdifferentiated from PDE9 inhibitor, which showed no effect on gamma power Vehicle PDE9i CY6463 CY6463 +PDE9i 0 5 10 15 GammaPower Gamma Power Vehicle PDE9i CY6463 CY6463+ PDE9i 34 © 2021 Cyclerion Therapeutics, Inc
CY6463 and donepezil act independently to enhance qEEG signalCombination elicited additive increase in gamma band power in healthy rats ImproveNeuronal Function Reduce Neuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow *p<0.05 vs Veh# p<0.05 CY6463 vs CY6463 +DonepezilHealthy rats orally administered CY6463 (10mg/kg), Donepezil (1mg/kg), or a combination. Graph displays 1-2h post-dose, mean ± SEM CY6463 may offer opportunity to enhance attention and cognitive performance alone and on top of standard of care Vehicle Donepezil IW-6463 IW-6463+Donepezil 0.0 0.5 2.0 2.5 rewo PmmaaG * * # Gamma 1.5Power1.0 Vehicle Donepezil CY6463 CY6463 +Donepezil 35 © 2021 Cyclerion Therapeutics, Inc
36 © 2021 Cyclerion Therapdeautiliycs, uInrcin CY6463 improved learning and memory in aged ratsIncreased rate of learning in aged rats treated with CY6463 in Morris Water Maze Young rat/Vehicle Aged rat/Vehicle Aged rat/CY6463 Young rat/Vehicle Aged rat/Vehicle Aged rat/CY6463 *p<0.05 vs. Aged vehicle-treated ImproveNeuronal Function Reduce Neuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow
37 © 2021 Cyclerion Therapeutics, Inc CY6463 improved cognitive function in pharmacologically impaired rats ImproveNeuronal Function Reduce Neuroinflammation 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 induced by NMDA antagonist (MK-801) 0 20 80 VEH-SAL VEH + MK-801 Galantamine + MK-801 0.01mg/kg 0.1mg/kg 1mg/kg 40 60Recognition Index (% of time exploring novel object) * * * * CY6463 (oral)+ MK-801
38 © 2021 Cyclerion Therapeutics, Inc Mushroom spine density Restoration of spine density has potential to provide neuroprotective effects and improve synaptic function in neurodegenerative diseases CY6463 improved neuronal functionEnhanced hippocampal spine density in aged animals treated with CY6463 Young Control Aged Control Aged CY6463 86420 Spines/10 μm of dendrite Control Young CY6463 Control Aged * * ImproveNeuronal Function Reduce Neuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow *p<0.05 vs. Aged3-month old (young) or 16-month old (aged) healthy mice at study initiation Aged mice treated for 4 months with 1 mg/kg CY6463
CY6463 reduced neuroinflammationInhibited in vitro LPS-induction of biomarkers of neuroinflammation *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 incubated for 18-20h at 37oC before IL-6 quantification in the media Neuroinflammation in mouse microglial cells Neuroinflammation in rat brain 3D microtissues ImproveNeuronal Function Reduce Neuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow CY6463 Control Control CY6463 Control Control * * 39 © 2021 Cyclerion Therapeutics, Inc
Vehicle Healthy CY6463 (10uM) 0.0 0.2 Normalized gene expression 0.4 0.6 0.8 * * TFAM CY6463 enhanced cellular bioenergeticsIncreased ATP and restored decreased gene expression in cells from patients with mitochondrial diseases *p<0.05 vs. vehicle-treated wellsGM13740 Leigh Syndrome patient cells obtained from the Coriell Institute were treated for 24h before ATP quantificationTFAM: mitochondrial transcriptional factor A, a key activator of mitochondrial transcription as well as a participant in mitochondrial genome replication. ImproveNeuronal Function Reduce Neuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow Vehicle AMPKactivator FCCP (10M) CY6463 (0.1M) 0 100 200 300 ATP(pmole/ug protein) * * TFAM Mitochondrial disease patient cells * * * * 40 © 2021 Cyclerion Therapeutics, Inc
CY6463 improved cerebral blood flowIncreased blood flow in areas associated with memory and arousal by fMRI BOLD imaging Peripherally restricted sGC stimulator CNS-penetrant sGC stimulator CY6463 Cortical transition areas ThalamusVentral hippocampus Reticular activating system ImproveNeuronal Function Reduce Neuroinflammation EnhanceCellular Bioenergetics ImproveCerebral Blood Flow Healthy awake male rats treated with 0.3 mg/kg iv; image quantification 20-30 minutes post-dose 41 © 2021 Cyclerion Therapeutics, Inc
PHASE 1 STUDY RESULTS
43 © 2021 Cyclerion Therapeutics, Inc PHASE 1 (completed Jan. 2020) Results CY6463 phase 1 showed CNS exposure, target engagement, PK, and safety 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, consistent with QD dosing CNS exposure confirmed Evidence of target engagement (blood pressure) Goals Achieved Study designThree stages:SAD MAD Food Interaction110 healthy young PK (blood & CSF) Wide dose range tested Well tolerated at all dose levels, no safety signals May be taken with or without food *Based on positive CNS pharmacology in multiple preclinical models
TRANSLATIONAL PHARMACOLOGY STUDY RESULTS
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 powerimproved N200 latency faster saccadic eye movement (SEM) reaction time reduction in neuroinflammatory biomarkers Rapid onset (<15 days)Effect increased with ageBiomarkers linked to AD and aging 45 © 2021 Cyclerion Therapeutics, Inc
Biomarker overview: qEEG frequency bands and their clinical implications qEEG is quantitative electroencephalography, an objective method that measures electrical activity and brain wave patterns Band Frequency Hz associated withDelta 0-4 Deep sleep Theta 4-8 Waking/falling asleep, some with cognition Alpha 8-14 Passive wakefulnessAttention and cognitive processing Beta 14-30 Alert, concentration Gamma 30-80 Higher cognitive functionResting-state qEEG:subjects sit facing a featureless wall without movingrecorded with eyes open and closed for 5 minutes each Associated with:Cognitive decline in aging and ADGenetic risk factors for AD (ApoE4)AD pathological protein levels(Aβ, tau)Improvement with approved AD treatments 46 © 2021 Cyclerion Therapeutics, Inc
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 vs. placebo change (%) in alpha power on day 15 47 © 2021 Cyclerion Therapeutics, Inc
CY6463’s consistent alpha power effects across repeat sessions indicate stable and robust signal Footer CY6463 relative to placebo DAY 1baseline DAY 15change from baseline CY6463 Placebo Pre- Pre-dose 1 dose 2 Pre-dose 2 hr 3 hr 6 hr last dose post-dose post-dose post-dose Magnitude of improvement equivalent to decline seen after 2 years of aging 48 © 2021 Cyclerion Therapeutics, Inc
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 Placebo CY6463 Increase in alpha powerDay 15 change from baseline in mean closed-eye alpha (8-12 Hz) Power Consistent individual treatment responsesPosterior Closed-Eye Alpha (8-12 Hz) Power p = 0.0197%Placebo CY6463Posterior BL D15 BL D15Placebo CY6463 17% treatment effect • Similar increase in anterior over placebo alpha power observed(p=0.0752) 13/18 participants increase • Overall effect not driven with CY6463, vs 5/18 with by outliersplacebo1 49 © 2021 Cyclerion Therapeutics, Inc
CY6463 treatment associated with trend improvement in gamma power Change in Closed-Eye Gamma (25-45 Hz) Power Placebo CY6463Anterior (p = 0.081) Placebo CY6463Posterior (p = 0.1163) 200150100500 -50-100 Change from baseline (%) 50 © 2021 Cyclerion Therapeutics, Inc
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 identification and distinctionAffected in aging, neurodegenerative and neuropsychiatric diseases with cognitive impairment, and other CNS diseases ParametersLatency: time after the stimulus to peak signalAmplitude: size of peak signal 51 © 2021 Cyclerion Therapeutics, Inc
CY6463 improved N200 latency and effect increased with age Day 15 Improvement Age (years) Time (ms) Effect of age on N200 latencyUntreated CY6463 treated Overall decrease in N200 latency for CY6463 treated vs untreated on day 15 (p<0.02)Effect more pronounced in older subjects 52 © 2021 Cyclerion Therapeutics, Inc
65 to 69yn=10 ≥70 yn=14 p=0.016 CY6463 improved N200 latency, driven by response in older subjects Greater decrease in ≥70y vs <70yDay 15 change from baseline Latency response was greater insubjects ≥70y vs 65-69y (p=0.016) Narrowing of variance in ≥ 70ysupports a drug effect In ≥ 70y, magnitude of improvement after 2 weeks of treatment with CY6463 represents ~10y age-related change in N200 latency Time (ms) 3.0 1.5 0.0 1.5 53 © 2021 Cyclerion Therapeutics, Inc
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 amygdalaConsidered to be reflective of attention / arousal and influenced by motivation, time on task, and task difficulty Sensitive to sedation, fatigue, and CNS depressants and cognitive enhancers, and is affected by aging Peak Velocity Amplitude Latency Duration T=0ms Eye Position 54 © 2021 Cyclerion Therapeutics, Inc Eye Velocity https://www.liverpool.ac.uk/~pcknox/teaching/Eymovs/params.htm
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 neurophysiologyCognitive enhancers (e.g., modafinil) also positively impact saccadic eye movements Time (sec) p=0.0216 Placebo CY6463 Placebo CY6463 p=0.0216 p=0.07 Improvement Velocity (deg/sec) 55 © 2021 Cyclerion Therapeutics, Inc Improvement Mean change from baseline on day 15 post-dose 0.02 0.00 -0.02 -0.04 150 100 50 0
PAI1MCP1 PARC (CCL18)MMP3 TNFR2 TIMP1 C3 A2M LS % Mean Difference from Placebo at Day 15 LS % Mean Difference with 95% CI CSF Biomarkers CY6463 improved neuroinflammatory biomarkers A2M and C3 are associated with pathological aging and Alzheimer’s Disease -30 -20 -10 0 10 20 30LS % Mean Difference from placebo at Day 15 (95% CI) 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 tangles; involved in synaptic remodeling and degeneration 56 © 2021 Cyclerion Therapeutics, Inc
RELEVANT REFERENCE PUBLICATIONS
Relevant reference publications (1 of 2) 58 © 2021 Cyclerion Therapeutics, Inc NO-sGC-cGMP signaling in the CNSGarthwaite, John. “Nitric oxide as a multimodal brain transmitter.” Brain and neuroscience advances vol. 2 2398212818810683. 4 Dec. 2018Kleppisch T, Feil R. cGMP signaling in the mammalian brain: role in synaptic plasticity and behaviour. Handb Exp Pharmacol. 2009;(191):549- 79Ben Aissa M, Lee SH, Bennett BM, Thatcher GR. Targeting NO/cGMP Signaling in the CNS for Neurodegeneration and Alzheimer’s Disease. Curr Med Chem. 2016;23(24):2770-2788Hollas MA, Ben Aissa M, Lee SH, Gordon-Blake JM, Thatcher GRJ. Pharmacological manipulation of cGMP and NO/cGMP in CNS drug discovery. Nitric Oxide. 2019 Jan 1;82:59-74qEEG spectral frequency analysisIshii et al. Healthy and Pathological Brain Aging: From the Perspective of Oscillations, Functional Connectivity, and Signal Complexity. Neuropsychobiology, 2018Babiloni, et al. Resting-state posterior alpha rhythms are abnormal in subjective memory complaint seniors with preclinical Alzheimer’s neuropathology and high education level: the INSIGHT-preAD study. Neurobiol Aging. 2020;90:43-59
Relevant reference publications (2 of 2) 59 © 2021 Cyclerion Therapeutics, Inc 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;24:405–12Fruehwirt et al. Associations of event-related brain potentials and Alzheimer’s disease severity: A longitudinal study. Progress in Neuropsychopharmacology and Biological Psychiatry 92 (2019) 31-38Saccadic eye movement (SEM)Wilcockson et al. Abnormalities of saccadic eye movements in dementia due to Alzheimer’s disease and mild cognitive impairment. Aging 2019, Vol.11, No.15James A. Sharpe & David H. Zackon (1987) Senescent Saccades: Effects of Aging on Their Accuracy, Latency and Velocity, Acta Oto- Laryngologica, 104:5-6, 422-428ADvCortes-Canteli M, Iadecola C. Alzheimer’s Disease and Vascular Aging: JACC Focus Seminar. J Am Coll Cardiol. 2020;75(8):942-951MELASEl-Hattab AW, Adesina AM, Jones J, Scaglia F. MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab. 2015;116(1-2):4-12CIASKeefe RS, Harvey PD. Cognitive impairment in schizophrenia. Handb Exp Pharmacol. 2012;(213):11-37