Cyclerion Therapeutics, Inc. · NASDAQ:CYCN
Cyclerion Therapeutics — Corporate Update (July 2020)
35 slides from Cyclerion Therapeutics's corporate update, Jul 9, 2020
Slide 1: Delivering impact in CNS diseases
Delivering impact in CNS diseases Investor webinar July 9, 2020
Slide 2: Safe Harbor Statement
Safe Harbor Statement 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: Two priority disease areas creating multiple potential ways to win in sickle cell and CNS
Two priority disease areas creating multiple potential ways to win in sickle cell and CNS • genetically and phenotypically defined populations with high unmet need • harness power, signaling precision of sGC • biomarker - guided fast - to - POC trials underway • supported by discovery platform • att
Slide 4: Clinical program snapshot
Clinical program snapshot 4 Ph1 (n=110 HV) SAD/MAD Ph 2a study: Alzheimer’s disease with vascular pathology (ADv) • safety/ tolerability in elderly subjects • PK • target and pathway engagement • pharmacodynamic biomarkers: CBF, cGMP December 2019 t op line expected late summer 2020 Ph1b translation
Slide 5: Sickle Cell: Olinciguat potential to raise the standard of care
Sickle Cell • potential for broad clinical utility in SCD • multi - dimensional mechanism that offers both upstream and downstream pharmacology • 70 patients enrolled; dosing completed • TL expected late Q3 2020 • Ph3 long - lead items underway: CMC, protocols, global ad board, regulatory plans • pl
Slide 6: Potential for broad clinical utility
• newly approved therapies each target a single clinical domain… • …olinciguat has the potential to improve four • daily symptoms and end - organ protection remain unaddressed, decreasing QoL and increasing mortality • further improvement in anemia and/or VOC possible with olinciguat alone or as add
Slide 7: Olinciguat: potential upstream and downstream interventions
OLINCIGUAT sGC stimulation may restore deficient nitric oxide signaling Increased hemolysis leads to reduced nitric oxide state Upstream • increased HbF may lead to reduced proportion of sickled RBCs 1 Downstream • improved blood flow • decreased vascular inflammation & cell adhesion • improved endo
Slide 8: Preclinical data support clinical investigation
1 2 3 4 * Decrease in progression of hemolytic anemia in Townes SCD mouse model Higher mRNA expression of the γ - globin subunit of fetal hemoglobin in cultured cells Olinciguat extended survival in TNF α challenge Berkeley SCD mouse model † Adhesion can occlude microcirculation and lead to painful
Slide 9: Lower expression of cellular adhesion molecules in preclinical model
1h predose olinciguat followed by treatment with TNF α in normal mice Lower expression of cellular adhesion molecules associated with olinciguat treatment in preclinical model † † in models of vascular inflammation, * p<0.05, ** p<0.001; **** p<0.0001 vs TNF α - vehicle 9
Slide 10: Progression of hemolytic anemia ameliorated in Townes mice
*p<0.05; ** p<0.01 Olinciguat vs Vehicle at Day 10 10 In a preclinical model of SCD, progression of hemolytic anemia was ameliorated in olinciguat treated Townes mice Red blood cell count Total hemoglobin Hematocrit
Slide 11: Olinciguat decreased biomarkers of inflammation, endothelial activation and renal injury
HbAAVeh Oli 0 100 200 300 400 s P - s e l e c t i n ( n g / m l ) HbSS *** * HbAAVeh Oli 0 50 100 150 200 s E - s e l e c t i n ( n g / m l ) HbSS *** * HbAAVeh Oli 0 2 4 6 8 10 12 I L - 6 p g / m L ** * HbSS HbAAVeh Oli 0 200 400 600 800 C y s t a t i n C ( n g / m l ) ** * HbSS HbAAVeh Oli 0.002 0
Slide 12: Olinciguat Phase 1: target engagement, PK, safety, QD dosing
Olinciguat Phase 1: target engagement, PK, safety, QD dosing Phase 1 design • 5 Ph1 studies including: - SAD - MAD - clinical pharmacology • 125 healthy volunteers • age range 18 - 57 • standard safety • PK • 8 dose levels tested • linear, predictable PK; consistent with QD dosing • determined well
Slide 13: Olinciguat phase 2 trial designed to support rapid advancement
Structure • 70 patients enrolled in all SCD genotypes, aged 16 – 70 • placebo controlled, double blind • 4 dose levels • 12 - week treatment Objectives • assess safety and tolerability • confirm PK profile in SCD patients • development of the CYCN fit - for - purpose patient - reported outcomes (ePR
Slide 14: Our strategy: target identifiable CNS patient populations
• targeting the untapped NO neurotransmitter pathway by sGC stimulation • initial two indications are characterized by strong biological rationale, targeted patient populations, enormous unmet patient need, lack of approved therapies, and biomarker - based development • MELAS - genetically defined r
Slide 15: Raising the odds of success: our approach
clear biological rationale geno/ phenotypically defined populations • pursue multiple indications in parallel • leverage biomarkers to drive development • implement nimble trials with leading edge investigators and imaging analytics • investigate a strategic R&D partnership to explore full potential
Slide 16: sGC stimulators: potential to be next druggable neurotransmitter system
Nitric oxide • IW - 6463 GABAergic • Valium® (1963) • Ambien® (1992) Dopaminergic • Levodopa (1970) • Risperdal® (1993) Cholinergic • Scopolamine (1979) • Aricept® (1996) Adrenergic/Serotonergic • Amitriptyline (1961) • Prozac® (1987) • Paxil® (1992) Successfully drugged neurotransmitter systems Glu
Slide 17: Preclinical benefits in four domains of neurodegenerative diseases
IW - 6463 demonstrates in preclinical studies beneficial effects in four important domains of neurodegenerative diseases Cellular Bioenergetics Increased ATP and restored gene expression in cells from patients with mitochondrial diseases Cerebral Blood Flow Increased blood flow in areas associated w
Slide 18: Preclinical results support potential broad use in CNS treatment
IW - 6463 preclinical results support potential broad use in CNS treatment Cellular Bioenergetics Cerebral Blood Flow Neuro - inflammation Neuronal Function ENHANCE IMPROVE REDUCE IMPROVE Inflammatory cytokine in rat brain 3D microtissues V e h i c l e A M P K a c t i v a t o r F C C P ( 1 0M ) I W
Slide 19: Translational approach from discovery to approval and beyond
Translational approach from discovery to approval and beyond • indication selection • patient selection • biomarker enrichment • endpoint selection • trial design • regulatory approach top line data late summer 2020 Establish PD biomarkers preclinically Effects across four domains of neurodegenerati
Slide 20: Biomarker-driven early clinical development strategy
Translational pharmacology study in elderly (ongoing) • safety • pharmacokinetics • target engagement • pharmacodynamic biomarkers Phase 1 (completed) • safety • pharmacokinetics • pharmacodynamics • target engagement • dose selection for next study Parallel exploratory Phase 2 studies • focused pat
Slide 21: Phase 1: CNS exposure, target engagement, PK, and safety
IW - 6463 Phase 1: CNS exposure, target engagement, PK, and safety Study design • three stages: - SAD - MAD - food interaction • 110 healthy volunteers • age range 18 - 63 • standard safety • PK (blood & CSF) • wide dose range tested • identified safe and well - tolerated dose levels with steady - s
Slide 22: Translational study design: pharmacodynamic biomarkers and safety
Cellular Bioenergetics • brain metabolism via magnetic resonance spectroscopy (MRS) Cerebral Blood Flow • MRI arterial spin labeling (ASL ) Neuro - inflammation • cytokines, adhesion molecules Neuronal Function • qEEG • measures of cognition and behavior ( NeuroCart ®) ENHANCE IMPROVE REDUCE IMPROVE
Slide 23: MELAS: supportive data for NO-sGC-cGMP pathway involvement
MELAS: Strong supportive data for NO - sGC - cGMP pathway involvement Clinical precedence for NO - sGC - cGMP pathway • L - Arginine (NO precursor) recommended for acute and chronic treatment Pathophysiology • CNS metabolic dysfunction, elevated lactate, decreased NO • CNS vascular pathology - impai
Slide 24: Ph 2a open-label study in patients with MELAS
Ph 2a: open - label study of IW - 6463 in patients with MELAS Enrichment strategy • genetically defined MELAS with neurological features and elevated plasma lactate (disease biomarker) Treatment • once - daily IW - 6463 • 29 days • up to 20 patients (targeting 12 completers) Sites • centers of excel
Slide 25: Alzheimer's with vascular pathology: disease rationale
Alzheimer’s Vascular mixed dementia Pathophysiology NO dysregulation, endothelial cell loss, impaired blood flow, vascular leakage, inflammation, neuronal dysfunction, and neuronal loss are major contributing factors to rapid disease progression Standard of care No approved therapies to treat vascul
Slide 26: Ph 2a study in ADv: emerging design
Treatment • once - daily IW - 6463 Enrichment strategy • confirmed AD pathology (PET, CSF) • 3+ cardiovascular risk factors • mild - moderate subcortical small - vessel disease on MRI • mini Mental State Exam score (16 - 26) Objectives • establish safety and pharmacodynamic effects of IW - 6463 in a
Slide 27: Building our company: the science, the pipeline and the team
• sGC stimulators: powerful intervention in a genetically and clinically validated pathway • a wholly owned pipeline of differentiated molecules • exploring partnerships across programs; praliciguat out - licensing scope expanded • experienced leadership team with a distinctive track record of innov
Slide 28: sGC stimulators: ideal intervention in a validated pathway
• multiple successful drugs target the NO - sGC - cGMP pathway for the treatment of CV diseases NO donors, PDE5 inhibitors, sGC stimulators • NO - sGC - cGMP pathway plays central role in CNS diseases Network analysis delivers z - scores for CNS diseases similar to validated CV diseases • sGC: optim
Slide 29: Broad impact in the NO-sGC-cGMP pathway
SMOOTH MUSCLE & VASCULAR FUNCTION METABOLISM CELLULAR BIOENERGETICS NEURONAL FUNCTION INFLAMMATION 29 Broad impact in the NO - sGC - cGMP pathway
Slide 30: sGC stimulators are positive allosteric modulators
30 sGC stimulators are positive allosteric modulators that enhance NO - sGC - cGMP signaling
Slide 31: 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 late Q3 2020 Praliciguat Results support out - license for further development IW - 6463 Phase 1 completed, with good CNS exposure, once - daily oral
Slide 32: Praliciguat out-licensing discussions ongoing with expanded scope
• 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 • VICTORIA results further validate cardiometaboli
Slide 33: 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 34: Delivering impact in CNS diseases
Delivering impact in CNS diseases Investor webinar July 9, 2020
Slide 35: SCD and CNS: creating breakthrough treatments
AZ = = cyclerion “Ai\\ SCD and CNS: creating breakthrough treatments harnessing the power of soluble guanylate cyclase (sGC) Corporate Overview July 9, 2020
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