Cyclerion Therapeutics, Inc. · NASDAQ:CYCN
Cyclerion Therapeutics — Investor Presentation (April 2021)
59 slides from Cyclerion Therapeutics's investor presentation, Apr 27, 2021
Slide 1: On a mission to develop treatments that restore cognitive function
ON A MISSION TO DEVELOP TREATMENTS THAT RESTORE COGNITIVE FUNCTIONCORPORATE PRESENTATION APRIL 2021
Slide 2: Safe harbor statement
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 cur
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 enormou
Slide 4: Contents
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
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
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 a
Slide 7: CY6463 improves endpoints relevant to cognition
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/Vehic
Slide 8: CY6463 amplifies a fundamental CNS signaling pathway
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 plast
Slide 9: CY6463 translational pharmacology study results
CY6463 TRANSLATIONAL PHARMACOLOGY STUDY RESULTS
Slide 10: CY6463 showed rapid and persistent improvements in multiple independent 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 powerimproved N200 latency faster saccadic eye movement (SEM) reaction time reductio
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 11 © 2021 Cyclerion Therapeutics, Inc CY6463 QD CY6463 QD Placebo Placebo 15 days 15 days 24 subjects
Slide 12: CY6463 showed rapid improvement in biomarkers of cognition
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.
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) and reaction time R
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 Lewy Body DementiaParkinson’s Dementia Neuropsychiatric Major Depressive Disorder Bipolar DisorderAutism Traumatic brain injury StrokeCancer/chemotherapy-induced cognitive impairment Event-related
Slide 16: Biomarker-guided development strategy in well-defined populations with cognitive impairment
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 Ne
Slide 17: Potential for patient impact: our priority indications
POTENTIAL FOR PATIENT IMPACT: OUR PRIORITY INDICATIONS
Slide 18: Advancing parallel, signal-seeking, exploratory studies in priority patient populations
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 he
Slide 19: Growing patient population, devastating impact, limited treatments (ADv)
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, symptom
Slide 20: ADv study expected to initiate in mid-2021
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
Slide 21: Biomarker-guided development strategy: MELAS
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 MELASP
Slide 22: MELAS study underway; data expected late 2021
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
Slide 23: Biomarker-guided development strategy: CIAS
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
Slide 24: CIAS study expected to initiate in 2H 2021
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 CY6463Appro
Slide 25: Next generation sGC stimulator program
NEXT GENERATION sGC STIMULATOR PROGRAM
Slide 26: CY3018: selectively targeting the CNS
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 pharmacology
Slide 27: Executing on our priorities
WZ . = cyclerion A EXECUTING ON OUR PRIORITIES
Slide 28: 2021: 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 collaborationsPralicig
Slide 29: On a mission to develop treatments that restore cognitive function
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 cog
Slide 30: Appendices
APPENDICES Preclinical, Phase 1 andtranslational pharmacology studies, references
Slide 31: Preclinical data
WZ . = cyclerion A PRECLINICAL DATA
Slide 32: CY6463 demonstrated beneficial effects in preclinical studies across multiple domains
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 ge
Slide 33: CY6463 improved neuronal function
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
Slide 34: CY6463 increased qEEG gamma power
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 Bioenergetic
Slide 35: CY6463 and donepezil act independently to enhance qEEG signal
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
Slide 36: CY6463 improved learning and memory in aged rats
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 vehic
Slide 37: CY6463 improved cognitive function in pharmacologically impaired rats
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
Slide 38: CY6463 improved neuronal function: spine density
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 CY64
Slide 39: CY6463 reduced neuroinflammation
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 incubate
Slide 40: CY6463 enhanced cellular bioenergetics
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 ob
Slide 41: CY6463 improved cerebral blood flow
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 Functi
Slide 42: Phase 1 study results
WZ . = cyclerion “AN PHASE 1 STUDY RESULTS
Slide 43: Phase 1 results: CNS exposure, target engagement, PK, and safety
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, predict
Slide 44: Translational pharmacology study results
TRANSLATIONAL PHARMACOLOGY STUDY RESULTS
Slide 45: CY6463 showed rapid and persistent improvements in multiple independent 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 powerimproved N200 latency faster saccadic eye movement (SEM) reaction time reductio
Slide 46: Biomarker overview: qEEG frequency bands and their 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 Band Frequency Hz associated withDelta 0-4 Deep sleep Theta 4-8 Waking/falling asleep, some with cogniti
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 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 e
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 Placebo CY6463 Increase in alpha powerDay 15 change from baseline in mean closed-eye alpha (8-12 Hz) Power Consistent individual treatment responsesPost
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 CY6463Anterior (p = 0.081) Placebo CY6463Posterior (p = 0.1163) 200150100500 -50-100 Change from baseline (%) 50 © 2021 Cyclerion Therapeutics, Inc
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) 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 Th
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 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
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 amygdalaConsidered to be reflective of attent
Slide 55: CY6463 improved saccadic eye movement, an objective functional measure
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
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 f
Slide 57: Relevant reference publications
RELEVANT REFERENCE PUBLICATIONS
Slide 58: Relevant reference publications (1 of 2)
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
Slide 59: Relevant reference publications (2 of 2)
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
Cyclerion Therapeutics — Investor Presentation (April 2021) on 6ix