Cyclerion Therapeutics, Inc. · NASDAQ:CYCN
Cyclerion Therapeutics — Corporate Update (April 2020)
35 slides from Cyclerion Therapeutics's corporate update, Apr 14, 2020
Slide 1: Creating breakthrough treatments by harnessing soluble guanylate cyclase (sGC)
Creating breakthrough treatments for patients with serious and orphan diseases by harnessing the power of soluble guanylate cyclase ( sGC ) April 10, 2020 Exhibit 99.1
Slide 2: Safe Harbor Statement
Safe Harbor Statement 2 This presentation contains forward - looking statements. Any statements contained in this presentation that are not historical fac ts may be deemed to be forward looking statements. Words such as “anticipate,” “believe,” “potential,” “expect,” “may,” “will,” “should,” “could,
Slide 3: Patient impact and value creation: 2020 catalysts across programs
Patient impact and value creation 2020 catalysts across programs Cyclerion: clinical stage startup developing sGC therapeutics for serious diseases • sGC : a clinically - validated fundamental mechanism • 2020 priorities • out - license praliciguat in cardiometabolic disease • clinical trial top - l
Slide 4: sGC: single target with potential to address multiple aspects of disease
sGC: single target with potential to address multiple aspects of disease Initial Breakthrough Emerging Insights Inflammation Neuronal Function Metabolism Fibrosis Metabolism Neuronal function Smooth muscle and vascular function Inflammation Graphic adapted from Buys et al. 2018. Discovery and develo
Slide 5: Nitric oxide (NO) signaling: clinically validated pathway
Nitric oxide (NO) signaling: clinically validated pathway • Multiple drugs created by targeting different steps in pathway • NO donors for angina (e.g., Nitropress ®, Imdur®, Corvasal ®, Corvaton ®) • PDE5 inhibitors for erectile dysfunction and pulmonary arterial hypertension (e.g., Viagra®, Cialis
Slide 6: A wholly owned pipeline of differentiated molecules
A wholly owned pipeline of differentiated molecules Liver - targeted Lung - targeted Preclinical Olinciguat Phase 2 proof - of - concept study in sickle cell disease ongoing (SCD) Topline data expected Q3 2020 Praliciguat Results support out - license for further development as a potential best - in
Slide 7: Experienced team and successful leadership
• distinctive track record of innovative drug discovery/development (e.g. -- CELEBREX ® , KALYDECO ® , LINZESS ® , LUNESTA ® , OPDIVO ® , ORKAMBI ® , YERVOY ® ) • successful sGC /cGMP drug hunters; deep knowledge of nitric oxide (NO) - cGMP pathway • broad experience in creating strong organizations
Slide 8: Praliciguat out-licensing discussions ongoing
Praliciguat out - licensing discussions ongoing • promising DN results: • UACR reductions on top of standard of care • reductions in blood pressure, HbA1c, total and LDL cholesterol • favorable safety profile, consistent with previous studies • attractive dosing and PK relative to others in class •
Slide 9: Olinciguat in sickle cell disease: potential for raising standard of care
Olinciguat in sickle cell disease (SCD): potential for raising standard of care across four therapeutic domains • upstream + downstream pharmacological intervention • impact potential in four clinical domains: anemia, daily symptoms , VOC, and organ protection -- not fully addressed by approved ther
Slide 10: Olinciguat: potential upstream and downstream interventions in SCD
Olinciguat: potential upstream and downstream interventions in SCD 10 sGC may restore deficient nitric oxide signaling Increased hemolysis leads to reduced nitric oxide state Upstream • increased HbF may lead to reduced proportion of sickled RBCs1 Downstream • improved blood flow • decreased vascula
Slide 11: Potential to raise standard of care across four therapeutic domains
Potential to raise standard of care across four therapeutic domains olinciguat improve daily symptoms reduce anemia reduce painful crises (VOC) preserve organ function • newly approved therapies each target a single clinical domain… • …olinciguat has the potential to improve four • daily symptoms an
Slide 12: Preclinical data support clinical investigation
Preclinical data support clinical investigation 1 2 3 Anemia Inflammation Fetal Hemoglobin Lower levels of vascular inflammatory markers and improved vascular function in mouse models of inflammation † Decrease in progression of hemolytic anemia in Townes SCD mouse model Higher mRNA expression of th
Slide 13: Olinciguat phase 2 trial designed to support rapid advancement
STRUCTURE OBJECTIVES INSIGHTS FOR PHASE 3 DESIGN Topline results expected Q3 2020 • 70 patients enrolled in all SCD genotypes, aged 16 – 70 • placebo controlled, double blind • 4 dose levels • 12 - week treatment • assess safety and tolerability • confirm PK profile in SCD patients • development of
Slide 14: IW-6463 in CNS: advancing development for neurodegenerative diseases
IW - 6463 in CNS: advancing development for potential treatment of serious neurodegenerative diseases TLD data expected mid 2020 Ph 1 showed safety, target engagement, CNS exposure 14 3 Preclinical evidence: stimulation of nitric oxide - cGMP pathway improves determinants of brain health Potential f
Slide 15: IW-6463 potential to restore nitric oxide-cGMP signaling
IW - 6463 potential to restore nitric oxide - cGMP signaling Nitric oxide insufficiency leads to • neuroinflammation and neurodegeneration • impaired cerebral blood flow Improved brain health • decreased neuroinflammation • increase cerebral blood flow • neuroprotection and enhanced cognition 15 Fig
Slide 16: IW-6463 preclinical results support potential broad utility in CNS disease
IW - 6463 preclinical results support potential broad utility in CNS disease 16 Note: data provided in this slide is based on preclinical models, *p<0.05 vs LPS + DETA Control Maze performance in aged rats Inflammatory cytokine in rat brain 3D microtissues Cerebral blood flow Cognition Neuro - infla
Slide 17: Positive phase 1 IW-6463 results support further development
Positive phase 1 IW - 6463 results support further development Insights • CNS drug presence at levels expected to be pharmacologically active • QD dosing, linear and predictable PK • may be taken with or without food • evidence of target engagement (blood pressure) • well - tolerated at all dose lev
Slide 18: Translational design: IW-6463 pharmacology across domains
18 Translational design: IW - 6463 pharmacology across 4 domains Assessing • safety • pharmacokinetics • target engagement Neuronal Function Neuro - inflammation Cellular Bioenergetics Cerebral Blood Flow 24 healthy elderly subjects IW - 6463 QD placebo IW - 6463 QD placebo washout 15 days 15 days T
Slide 19: Clinical direction: accelerate and de-risk into high value CNS indications
Clinical direction: accelerate and de - risk into high value CNS indications IW - 6463 ph1 SAD/MAD/FI additional clinical studies in neurodegenerative disorders safety, tolerability, PK, biomarkers: CBF, cGMP 19 2019 2020 2021 completed December 2019 Top - line expected mid 2020 translational pharma
Slide 20: Patient impact and value creation: 2020 catalysts across programs
Patient impact and value creation 2020 catalysts across programs Cyclerion: clinical stage startup developing sGC therapeutics for serious diseases • sGC : a clinically - validated fundamental mechanism • 2020 priorities • out - license praliciguat in cardiometabolic disease • clinical trial top - l
Slide 21: Creating breakthrough treatments by harnessing soluble guanylate cyclase (sGC)
Creating breakthrough treatments for patients with serious and orphan diseases by harnessing the power of soluble guanylate cyclase ( sGC ) April 10, 2020
Slide 22: Appendix
Appendix 22
Slide 23: NO-sGC-cGMP signaling
NO - sGC - cGMP signaling 23 NOS=nitric oxide synthase; cGMP=cyclic guanosine monophosphate; PDE=phosphodiesterase; GTP=guanosine triphosphate; GMP=guanosine monophosphate Reviewed in: Sandner et al. (2018) Soluble Guanylate Cyclase Stimulators and Activators. In: . Handbook of Experimental Pharmaco
Slide 24: sGC stimulators are positive allosteric modulators enhancing NO-sGC-cGMP signaling
sGC stimulators are positive allosteric modulators that enhance NO - sGC - cGMP signaling 24
Slide 25: sGC stimulators act synergistically with NO
sGC stimulators act synergistically with NO 25 In vitro (HEK293 cells) -11 -10 -9 -8 -7 -6 -5 -4 0 200 400 600 800 log [stimulator] c G M P ( n M ) EC 50 ~ 100 nM EC 50 ~ 3 µM Stimulator + NO donor PBS NO donor Stim Stim + NO donor 0 10 20 30 c G M P ( n M ) * *** **** In vivo (rat liver/retrodialys
Slide 26: Preclinical data for praliciguat support potential utility in diabetic nephropathy
26 † Dahl salt - sensitive rat model of hypertension and ZSF1 rat model of DN, 1. * p<0.05, *** p<0.001; **** p<0.0001 vs High - salt co ntrol in Dahl salt - sensitive rat model; 2.*** p<0.001; **** p<0.0001 vs TGF β - vehicle in human renal proximal tubule epithelial cells in cell culture 1 2 1 • p
Slide 27: Phase 2 showed promising improvement in UACR
Phase 2 showed promising improvement in UACR (90 % CIs by dose & timepoint) LS mean (90% CI) change UACR in (mg/g) ( mITT ) 1 % UACR change from baseline 1. mITT : modified intent - to - treat population n=133 excludes data from site 00A where data inconsistencies were observed in both the tre atmen
Slide 28: Lower expression of cellular adhesion molecules with olinciguat in preclinical model
1h predose olinciguat followed by treatment with TNF α in normal mice Reducing vascular inflammation via blockade of specific adhesion receptors is a clinically validated approach to reducing painful crises (e.g. crizanlizumab ) Lower expression of cellular adhesion molecules associated with olincig
Slide 29: Hemolytic anemia progression ameliorated in olinciguat-treated mice
In a preclinical model of SCD, progression of hemolytic anemia was ameliorated in olinciguat treated mice *p<0.05; ** p<0.01 Olinciguat vs Vehicle at Day 10 29 OLINCIGUAT
Slide 30: Greater fetal hemoglobin gamma-globin expression with olinciguat
Treatment of K562 cells with vehicle or olinciguat for 7 days in cell culture Increasing fetal hemoglobin is a clinically validated approach to the treatment of sickle cell disease (i.e. hydroxyurea)* * In patients with SCD, higher HbF levels are associated with reduced rates of VOC, decreased frequ
Slide 31: Increased blood flow to brain areas in rats treated with IW-6463
Reticular activating system thalamus cortical transition areas ventral hippocampus sGC stimulator : Peripherally Restricted IW - 6463: CNS - penetrant - Increased blood flow to areas associated with memory and arousal in normal rats by fMRI BOLD imaging - Note: data provided in this slide is based o
Slide 32: Anti-inflammatory neuroprotective effects in mice treated with IW-6463
Note: data based on IW - 6463 pretreatment in preclinical models, *p<0.05 vs LPS + DETA Control IW - 6463 sGC NO cGMP GTP PKG pCREB Neuroinflammation Anti - inflammatory neuroprotective effects in mice treated with IW - 6463 - Increased cGMP and pCREB in rat brain 3D microtissues - - Decreased infla
Slide 33: Neuroprotective effects in mice treated with IW-6463
Neuroprotective effects in mice treated with IW - 6463 33 - Synaptic spine density in aged mice at same level observed in young mice - Note: data provided in this slide is based on preclinical models IW - 6463 Cerebral Blood Flow Neuroinflammation Neuroprotection Cognitive Function *p<0.05 vs. contr
Slide 34: Improved cognitive function in rats treated with IW-6463
Improved cognitive function in rats treated with IW - 6463 34 - Positive effect on cognitive function in multiple animal models, including both aged and pharmacologically impaired rats - Note: data provided in this slide is based on preclinical models Thigmotaxis : tendency to stay close to walls wh
Slide 35: Cortical brain activity greater in rats treated with IW-6463
Cortical brain activity greater in rats treated with IW - 6463 - Opportunity for Early Clinical Proof of Pharmacologic Effects – - Pharmacological effects of IW - 6463 can be assessed clinically using translational non - invasive methods including EEG, MRS, ASL , and fMRI BOLD - Note: data provided
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