Cyclerion Therapeutics, Inc. · NASDAQ:CYCN
Cyclerion Therapeutics — Corporate Update (January 2021)
37 slides from Cyclerion Therapeutics's corporate update, Jan 13, 2021
Slide 1: On a mission to develop treatments that restore cognitive function
January 2021 On a mission to develop treatments that restore cognitive function Exhibit 99.1
Slide 2: 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 management team that
Slide 3: On a mission to develop treatments that restore cognitive function
On a mission to develop treatments that restore cognitive function first-in-class: CY6463 crosses the blood-brain barrier to modulate a key node in a fundamental CNS signaling network broad potential: multidimensional pharmacology to impact a wide range of CNS diseases promising clinical profile: ra
Slide 4: Potential to impact a wide range of CNS diseases
Potential to impact a wide range of CNS diseases Current Focus Future Opportunities Neurodegenerative ADv Mitochondrial MELAS Neurodegenerative e.g., Alzheimer’s disease, frontotemporal dementia Neuro Psych e.g., schizophrenia Movement Disorders e.g., Parkinson’s disease, spinocerebellar ataxia sGC
Slide 5: CY6463 modulates a key node in a fundamental CNS signaling network
sGC GTP cGMP N O Arginine NOS PKG, PDE, ion channels + CY6463 Neuronal function Bioenergetics Vascular function Downstream targets (eg, CREB, BDNF) CY6463: first in class BBB-permeable, positive allosteric modulator of sGC amplifies endogenous NO-sGC-cGMP signaling Preclinical data and extensive aca
Slide 6: CY6463 biomarker-driven development strategy
Translational pharmacology study in healthy elderly (>65) (n=24) Exploratory Phase 2 studies CNS exposure CNS activity CNS disease biomarkers Phase 1 and translational pharmacology studies conducted at Centre for Human Drug Research, Leiden, NL CY6463 biomarker-driven development strategy completed
Slide 7: Rapid and persistent improvements in multiple biomarkers associated with cognitive impairment
CY6463 showed rapid and persistent improvements in multiple independent biomarkers associated with cognitive impairment Neuronal Function increased alpha and gamma power improved mismatch negativity (MMN) latency faster saccadic eye movement (SEM) reaction time rapid onset (<15 days) effect increase
Slide 8: CY6463 improved qEEG measures
CY6463 vs. baseline CY6463 improved qEEG measures Significant increase in EEG alpha power No effect of placebo Placebo vs. baseline CY6463 vs. placebo qEEG is quantitative electroencephalography, an objective method that measures electrical activity and brain wave patterns Significant increase in EE
Slide 9: CY6463 improved mismatch negativity (MMN) latency
CY6463 improved mismatch negativity (MMN) latency MMN MMN also known as N200 Latency is affected in aging and neurodegenerative diseases with cognitive impairment MMN measures reactions between a standard and deviant tone Significant decrease in MMN latencies for CY6463 vs untreated on day 15 (p<0.0
Slide 10: CY6463 improved saccadic reaction time
CY6463 improved saccadic reaction time * average of the post dose values on Day 15 0.02 0.00 -0.02 -0.04 Time (sec) p=0.0216 Significant decrease in saccadic reaction time Placebo CY6463 p=0.0216 Mean change from baseline on day 15 improvement Saccadic eye movement is an objective, functional measur
Slide 11: CY6463 improved neuroinflammatory biomarkers
CY6463 improved neuroinflammatory biomarkers A2M and C3 are associated with pathological aging and Alzheimer’s Disease Difference from placebo at Day 15 LS % Mean Difference from placebo at Day (95% CI) Alpha-2-macroglobulin (A2M) levels predict cognitive decline and development of AD; may lead to t
Slide 12: CY6463 biomarker-driven development strategy
Translational pharmacology study in healthy elderly (>65) (n=24) Exploratory Phase 2 studies CNS exposure CNS activity CNS disease biomarkers Phase 1 and translational pharmacology studies conducted at Centre for Human Drug Research, Leiden, NL CY6463 biomarker-driven development strategy completed
Slide 13: Biomarker-guided development strategy: ADv
Biomarker-guided development strategy: ADv Exploratory Phase 2 near-term impact on disease-specific biomarkers and cognition Larger, longer symptomatic trials focused on cognition Standard of care for patients with ADv Today Tomorrow Future Potential for disease modification and expansion into broad
Slide 14: ADv study expected to initiate in mid-2021
ADv study expected to initiate in mid-2021 evaluate safety, tolerability, and pharmacodynamic effects (EEG, MRI, neuroinflammatory biomarkers, cognition) once-daily CY6463 vs. placebo 12 weeks confirmed AD pathology (PET, CSF) 2+ cardiovascular risk factors mild-moderate subcortical small-vessel dis
Slide 15: 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-episodes Transformative therapy for patients with MELAS Today Tomorrow Future Potential for expansion into additiona
Slide 16: MELAS study underway; topline data expected mid-2021
MELAS study underway; topline data expected mid-2021 evaluate safety, tolerability, and pharmacodynamic effects (MRI, EEG, biomarkers) 29-day open label once-daily CY6463 up to 20 adults (targeting 12 completers) genetically confirmed mitochondrial disease with neurological features of MELAS elevate
Slide 17: Broadening clinical potential: NextGen sGC program
Eliciting different patterns of CNS engagement* Broadening clinical potential: NextGen sGC program *Positive fMRI BOLD activation pattern in healthy rats Increasing CNS/plasma exposure Yellow = hippocampal complex and cortical areas associated with memory Red = anterior cerebellum Dark blue = midbra
Slide 18: Advancing a growing pipeline for targeted patient populations
* Mitochondrial Encephalomyopathy, Lactic acidosis, and Stroke-like episodes Ph 2a study: Alzheimer’s disease with vascular pathology (ADv) Ph 2a study: MELAS* with CNS symptoms CNS exposure CNS activity CNS disease activity Ph1 SAD/MAD/FE Ph1b translational pharmacology study Advancing a growing pi
Slide 19: 2021: executing on our priorities
2021: executing on our priorities * Preliminary, unaudited unrestricted cash, cash equivalents and restricted cash balance as of December 31, 2020 ADv Ph2 study start mid-2021 MELAS Ph2 study topline data mid-2021 additional indication investigation NextGen development candidate praliciguat out-lice
Slide 20: On a mission to develop treatments that restore cognitive function
On a mission to develop treatments that restore cognitive function first-in-class: CY6463 crosses the blood-brain barrier to modulate a key node in a fundamental CNS signaling network broad potential: multidimensional pharmacology to impact a wide range of CNS diseases promising clinical profile: ra
Slide 21: Appendix
Appendix
Slide 22: Consistent alpha power effects across repeat sessions
DAY 1 baseline DAY 15 change from baseline Magnitude of improvement represents decline after 2 years aging CY6463’s consistent alpha power effects across repeat sessions indicate stable and robust signal CY6463 relative to placebo CY6463 Placebo Pre- dose 1 Pre- dose 2 Pre-dose last dose 2 hr post-d
Slide 23: CY6463 increased alpha power with high responder rate
1. Includes all subjects. For CY6463 and pbo each: n=12 for period 1, n=6 for period 2 CY6463 increased alpha power with high responder rate (>70%) Consistent individual treatment responses Posterior Closed-Eye Alpha (8-12 Hz) Power 17% treatment effect over placebo Similar increase in anterior alph
Slide 24: Improvement trend in gamma power associated with CY6463 treatment
Improvement trend in gamma power associated with CY6463 treatment Placebo CY6463 Placebo CY6463 200 150 100 50 0 -50 -100 Anterior (p = 0.081) Posterior (p = 0.1163) Change from baseline (%) Change in Closed-Eye Gamma (25-45 Hz) Power
Slide 25: Beneficial effects in preclinical studies across multiple domains
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 26: Improved neuronal function: restored hippocampal long-term potentiation
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) Hippocampal slices from symptomatic Huntington’s Disease (R6/2) mice incubated with CY6463 for 25-30 minutes before LTP indu
Slide 27: Increased qEEG gamma power; no effect seen with PDE9 inhibitor
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) Improve Cerebral Blood Flow Enhance Cellular Bioenergetics Reduce Neuro- inflammation Improve Neuronal Function
Slide 28: 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 CY6463 may offer opportunity to enhance attention and cognitive performance alone and on top of standard of care *p<0.05 vs Veh # p<0.05 CY6463 vs CY6463 +Donepezi
Slide 29: 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 Cerebral Blood Flow Enha
Slide 30: Improved cognitive function in pharmacologically impaired rats
CY6463 improved cognitive function in pharmacologically impaired rats **p<0.01 vs. VEH + MK801 rats ***p<0.001 vs. VEH + MK801 rats Male rats administered vehicle, galantamine (positive control) or CY6463, followed by MK-801 or vehicle Improve Cerebral Blood Flow Enhance Cellular Bioenergetics Reduc
Slide 31: Improved neuronal function: enhanced hippocampal spine density
Aged Control CY6463 improved neuronal function Enhanced hippocampal spine density in aged animals treated with CY6463 3-month old (young) or 16-month old (aged) healthy mice at study initiation Aged mice treated for 4 months with 1 mg/kg CY6463 *p<0.05, **p<0.01 vs. Aged Restoration of spine density
Slide 32: Reduced neuroinflammation
CY6463 reduced neuroinflammation Decreased markers of LPS-induced neuroinflammation in vitro *p<0.05, **p<0.01, ***p<0.001 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
Slide 33: Enhanced cellular bioenergetics
CY6463 enhanced cellular bioenergetics Increased ATP and restored decreased gene expression in cells from patients with mitochondrial diseases *p<0.05, **p<0.01, ***p<0.001 vs. vehicle-treated wells GM13740 Leigh Syndrome patient cells obtained from the Coriell Institute were treated for 24h before
Slide 34: Improved cerebral blood flow
CY6463 improved cerebral blood flow Increased blood flow in areas associated with memory and arousal by fMRI BOLD imaging Healthy awake male rats treated with 0.3 mg/kg iv; image quantification 20-30 minutes post-dose reticular activating system thalamus cortical transition areas ventral hippocampus
Slide 35: 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 signalling in the mammalian brain: role in synaptic plasticity
Slide 36: 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;24:405–12Kleppisch T, Feil R. cGMP signa
Slide 37: On a mission to develop treatments that restore cognitive function
On a mission to develop treatments that restore cognitive function
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