Cyclerion Therapeutics, Inc. · NASDAQ:CYCN
Cyclerion Therapeutics — Investor Presentation (June 2022)
63 slides from Cyclerion Therapeutics's investor presentation, Jun 10, 2022
Slide 1: Thinking differently about cognition
Thinking differently about cognition CORPORATE Presentation June 2022 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: Developing therapies to restore cognitive function
Developing therapies to restore cognitive function Experienced team of scientific leaders, drug hunters, company builders, and CNS experts Developed and launched first-in-class therapies Raised billions in capital Built leading strategic partnerships Neuroinnovation engine enables faster, more preci
Slide 4: Neuroinnovation Engine
aw 7 = cyclerion “Us NEUROINNOVATION ENGINE
Slide 5: Efficiently developing drugs that matter
Efficiently developing drugs that matter Identify most promising patient populations early, increase signal-to-noise ratio Leverage deep understanding of brain biology, pathobiology of cognitive dysfunction and small molecule mechanisms Partner with academic and industry leaders to access leading-ed
Slide 6: Cyclerion neuroinnovation engine de-risks development at every stage
MOA & biomarker-driven non-clinical validation Identify mechanism- and disease-relevant biomarkers Proof of principle; first-in-human biomarker translation Validate homologous physiological response to drive clinical development Proof of mechanism; biomarker-guided, signal-seeking studies in patient
Slide 7: Deploying our NeuroInnovation ENGINE
Deploying our NeuroInnovation ENGINE
Slide 8: Advancing parallel clinical studies in priority populations
DISCOVERY IND-ENABLING PHASE 1* PHASE 1b/2a PHASE 2 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 targe
Slide 9: CY6463 amplifies the fundamental NO-sGC-cGMP signaling pathway
CY6463 amplifies the fundamental NO-sGC-cGMP signaling pathway CY6463 First-in-class BBB-permeable, positive allosteric modulator of sGC Amplifies endogenous NO-sGC-cGMP signaling to address central aspects of disease pathophysiology sGC stimulators clinically validated in several non-CNS indication
Slide 10: CY6463 improves processes relevant to cognition in preclinical models
CY6463 improves processes relevant to cognition in preclinical models Mitochondrial Function Cerebral Blood Flow Inflammatory Processes Neuronal/Cognitive Function Reticular activating system Thalamus Cortical transition areas Ventral hippocampus Young rat/Vehicle Aged rat/Vehicle Aged rat/CY6463 Sc
Slide 11: CY6463 showed rapid improvement in biomarkers associated with cognitive function
CY6463 showed rapid improvement in biomarkers associated with cognitive function Increased alpha and gamma power Improved N200 latency Alpha power: CY6463 vs. placebo Day 15 Improvement Age (years) Untreated CY6463 treated Time (ms) Reduced neuroinflammatory biomarkers In a 15-day study in 24 health
Slide 12: Biomarker-guided strategy to refine target populations with cognitive impairment
Biomarker-guided strategy to refine target 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 ADv MELAS Mitochondria
Slide 13: MELAS Study Results
aw 7 = cyclerion “Us MELAS STUDY RESULTS
Slide 14: MELAS clinical data demonstrate CY6463 potential as breakthrough CNS therapeutic
MELAS clinical data demonstrate that CY6463 has potential as breakthrough CNS therapeutic MELAS Devastating genetically and phenotypically defined mitochondrial disease (MD) with no approved therapies CY6463 Positive allosteric modulator of sGC which amplifies endogenous NO signaling Study design Op
Slide 15: MELAS: devastating orphan disease, no approved therapies
MELAS*: devastating orphan disease affecting multiple organ systems, no approved therapies Multisystem involvement Skeletal muscle Muscle weakness Myopathy Exercise intolerance Eyes Vision abnormalities Orphan disease MELAS is most common form of primary mitochondrial disease (PMD) Phenotypically an
Slide 16: Strong therapeutic rationale for stimulating NO-sGC-cGMP pathway in mitochondrial disease
Strong therapeutic rationale for stimulating NO-sGC-cGMP pathway to treat mitochondrial disease CY6463 is a positive allosteric modulator of sGC and amplifies endogenous NO signaling Literature links NO-sGC-cGMP pathway to mitochondrial biogenesis and function NO deficiency in mitochondrial disease
Slide 17: Open-label, 29-day study of CY6463 in MELAS patients
Open-label, 29-day study of CY6463 in MELAS patients to assess safety, PK, PD and impact on important domains of mitochondrial disease CNS/PD Safety Safety and tolerability profile with 15-mg QD dosing Safety on top of NO precursors and other stable medications PK Study population (n=8) Genetically
Slide 18: Strong safety/tolerability and once-daily profile in MELAS
Strong safety/tolerability and once-daily profile extended to participants with MELAS CY6463 well tolerated with and without NO precursors (L-arginine and L-citrulline) Mostly mild adverse events (AEs), no severe AEs No SAEs, no discontinuations due to AEs Most common AE was headache, all but 1 mild
Slide 19: Improvement in biomarkers of mitochondrial function
Lactate (mmol/L) (effect size = -0.5) GDF-15 (ng/mL) (effect size = -0.5) FGF-21 (ng/mL) (effect size = -0.2) Improvement in biomarkers of mitochondrial function that are affected in MELAS disease Mitochondrial function effects Blood biomarkers linked to mitochondrial function were elevated at basel
Slide 20: Broad improvement of inflammatory biomarkers
B2M (μg/mL) (effect size = -1.0) SAP (μg/mL) (effect size = -0.9) Broad improvement of inflammatory biomarkers Anti-inflammatory effects ~65% of 40 inflammatory biomarkers with effect sizes |value|≥0.3 Central and peripheral inflammation is upregulated in patients with mitochondrial dysfunction TNFR
Slide 21: Increased cerebral blood flow across all regions analyzed
Increased cerebral blood flow across all regions analyzed Blood flow effects Neuronal and/or glial injury due to mitochondrial failure, nitric oxide deficiency and cerebrovascular angiopathy reduce cerebral blood flow Dysregulated cerebral blood flow is linked to stroke-like episodes and CNS symptom
Slide 22: CY6463 enhanced functional connectivity and visual activation in CNS
CY6463 enhanced functional connectivity and visual activation in CNS, which is impaired in MELAS Task-free fMRI (resting state) shows enhanced functional connectivity: Increased signals across several resting state networks including those involved in: executive function sensorimotor processing Task
Slide 23: Improvements supported by correlation across endpoints
Improvements after 29-day dosing supported by correlation across endpoints Correlations (r) between CBF and clinical improvement as assessed by the patient global impression of change (PGIC) Correlations (r) between changes in blood biomarkers and plasma concentrations Biomarker parameters Fibroblas
Slide 24: Ongoing Clinical Trials
aw 7 = cyclerion “Us ONGOING CLINICAL TRIALS
Slide 25: CIAS study ongoing; data expected Q3 2022
CIAS study ongoing; data expected Q3 2022 Objectives Exploratory, signal-seeking study to evaluate safety, tolerability, and pharmacodynamic effects (qEEG, ERP, digital cognitive performance battery) Study design In-clinic, randomized, placebo-controlled, double-blind, multiple-ascending-dose design
Slide 26: ADv study ongoing
ADv study ongoing Exploratory, signal-seeking study to evaluate safety, tolerability, and pharmacodynamic effects (EEG, MRI, neuroinflammatory biomarkers, cognition) Once-daily CY6463 vs. placebo 12 weeks 30 participants Confirmed AD pathology (PET, CSF) 2+ cardiovascular risk factors Mild-moderate
Slide 27: Next-generation sGC stimulator program
Next-generation sGC stimulator program
Slide 28: Applying the neuroinnovation engine to CY3018
Applying the neuroinnovation engine to CY3018 – a differentiated sGC stimulator In mice, rats, and non-human primates, CY3018 has greater partitioning into the brain than CY6463 CY3018 elicited unique patterns of activation and deactivation in rodent imaging studies demonstrating differentiation fro
Slide 29: Track Record of Success
aw 7 = cyclerion “Us TRACK RECORD OF SUCCESS
Slide 30: Leadership Team with Track Record of Success
Leadership Team with Track Record of Success Peter Hecht, PhD Chief Executive Officer Andy Busch, PhD Chief Scientific Officer Chris Winrow, PhD Vice President, Translational Medicine & Development Program Lead Jennifer Chickering, PhD Vice President, Clinical Strategy Anjeza Gjino, MBA Chief Financ
Slide 31: Experienced Board of Directors and Scientific Advisors
George Conrades Errol De Souza, PhD Marsha Fanucci, Chair Peter Hecht, PhD, CEO Ole Isacson, MD, PhD Stephanie Lovell Terrance McGuire Michael Mendelsohn, MD Experienced Board of Directors and Scientific Advisors Board of Directors Scientific Advisors Claudio Babiloni, PhD University of Rome Andrew
Slide 32: Developing therapies to restore cognitive function
Developing therapies to restore cognitive function Experienced team of scientific leaders, drug hunters, company builders, and CNS experts Developed and launched first-in-class therapies Raised billions in capital Built leading strategic partnerships Neuroinnovation engine enables faster, more preci
Slide 33: Appendices
Appendices Preclinical, Phase 1 and translational pharmacology studies, references
Slide 34: Preclinical Data
aw 7 = cyclerion “Us PRECLINICAL DATA
Slide 35: CY6463 demonstrated beneficial effects in preclinical studies
CY6463 demonstrated beneficial effects in preclinical studies across multiple domains associated with cognitive disease Cerebral Blood Flow Increased blood flow in areas associated with memory and arousal by fMRI BOLD imaging IMPROVED Cellular Bioenergetics Increased ATP and restored gene expression
Slide 36: 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 fEPSP Amplitude Time (min) 10 30 50 70 1.0 5 2.0 2.5 Improve Neuronal Function Reduce Neuroinflammation Enhance
Slide 37: 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 Improve Neuronal Function Reduce Neuroinflammation Enhance Cellular Bioenerge
Slide 38: 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 Improve Neuronal Function Reduce Neuroinflammation Enhance Cellular Bioenergetics Improve Cerebral Blood Flow *p<0.05 vs Veh # p<0.05 CY6463 vs CY6463 +Donepezil H
Slide 39: 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 *p<0.05 vs. Aged vehicle-treated Improve Neuronal Function Reduce
Slide 40: CY6463 improved cognitive function in pharmacologically impaired rats
CY6463 improved cognitive function in pharmacologically impaired rats Improve Neuronal Function Reduce Neuroinflammation Enhance Cellular Bioenergetics Improve Cerebral Blood Flow Rat Novel Object Recognition *p<0.05 vs. VEH + MK-801 rats CY6463 acts downstream of NMDA receptor to reverse deficit in
Slide 41: CY6463 improved neuronal function: spine density
Mushroom spine density Restoration of spine density has potential to provide neuroprotective effects 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 CY
Slide 42: CY6463 reduced neuroinflammation
CY6463 reduced neuroinflammation Inhibited in vitro LPS-induction of biomarkers of neuroinflammation *p<0.05 vs. control LPS-treated wells CY6463 (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 incuba
Slide 43: CY6463 enhanced cellular bioenergetics
CY6463 enhanced cellular bioenergetics Increased ATP and restored decreased gene expression in cells from patients with mitochondrial diseases *p<0.05 vs. vehicle-treated wells GM13740 Leigh Syndrome patient cells obtained from the Coriell Institute were treated for 24h before ATP quantification TFA
Slide 44: CY6463 improved cerebral blood flow
CY6463 improved cerebral blood flow Increased blood flow in areas associated with memory and arousal by fMRI BOLD imaging Peripherally restricted sGC stimulator CNS-penetrant sGC stimulator CY6463 Improve Neuronal Function Reduce Neuroinflammation Enhance Cellular Bioenergetics Improve Cerebral Bloo
Slide 45: Phase 1 Study Results
aw 7 = cyclerion “Us PHASE 1 STUDY RESULTS
Slide 46: 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 Jan. 2020) 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, consistent
Slide 47: Translational Pharmacology Study Results
Translational Pharmacology Study Results
Slide 48: 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 49: 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 moving recorded with eyes open and cl
Slide 50: 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 51: Consistent alpha power effects across repeat sessions
CY6463’s consistent alpha power effects across repeat sessions indicate stable and robust signal Footer DAY 1 baseline DAY 15 change from baseline CY6463 relative to placebo CY6463 Placebo Pre- dose 1 Pre- dose 2 Pre-dose last dose 2 hr post-dose 3 hr post-dose 6 hr post-dose Magnitude of improvemen
Slide 52: 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 power Day 15 change from baseline in mean closed-eye alpha (8-12 Hz) Power Consistent individual treatment responses Posterior Closed-
Slide 53: 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 54: Biomarker overview: event-related potential (ERP)
Biomarker overview: event-related potential (ERP) Trial: 500 tones 80% standard, 20% deviant Deviant Standard ERP oddball paradigm Subjects wear EEG cap and headphones, hear tones with instruction to press a button upon deviant tones P300 N200 N200 Stable component of ERP waveform Stimulus identific
Slide 55: 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 pronounced in older subjects
Slide 56: CY6463 improved N200 latency, driven by response in older subjects
65 to 69y n=10 ≥70 y n=14 p=0.016 CY6463 improved N200 latency, driven by response in older subjects Greater decrease in ≥70y vs <70y Day 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, magnitud
Slide 57: 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 58: 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 59: 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 60: Relevant reference publications
Relevant reference publications
Slide 61: Relevant reference publications (1 of 2)
Relevant reference publications (1 of 2) NO-sGC-cGMP signaling in the CNS Garthwaite, John. “Nitric oxide as a multimodal brain transmitter.” Brain and neuroscience advances vol. 2 2398212818810683. 4 Dec. 2018 Kleppisch T, Feil R. cGMP signaling in the mammalian brain: role in synaptic plasticity a
Slide 62: Relevant reference publications (2 of 2)
Relevant reference publications (2 of 2) Event-related potential (ERP): MMN, N200 and P300 Bennys 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;
Slide 63: AW) Wy,
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