Cyclerion Therapeutics, Inc. · NASDAQ:CYCN
Cyclerion Therapeutics — Investor Presentation (July 2020)
37 slides from Cyclerion Therapeutics's investor presentation, Jul 9, 2020
Slide 1: Delivering impact in CNS diseases: Investor webinar
Delivering impact in CNS diseases Investor webinar July 9, 2020 V7
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: Cyclerion leaders and independent experts
Peter Hecht, PhD Chief Executive Officer Welcome to Cyclerion’s CNS discussion Marni J. Falk, M.D. University of Pennsylvania Professor of Human Genetics; The Children's Hospital of Philadelphia (CHOP), Director of the Mitochondrial Medicine Frontier Program Cheryl Gault Head of Strategy & Corporate
Slide 4: Pioneering therapeutics in SCD and CNS
Pioneering therapeutics in SCD and CNS Sickle Cell Disease (SCD) • upstream + downstream pharmacology • 70 patients enrolled; dosing completed • top line expected end Q3 2020 Central Nervous System (CNS) • potential to be next druggable neurotransmitter system • IW - 6463: oral, QD drug • first CNS
Slide 5: Cyclerion: delivering impact in CNS
Cyclerion: delivering impact in CNS Now is the time: value in CNS sGC and CNS: scientific and clinical basis for CNS therapies Translational pharmacology study: demonstrating CNS activity Clinical direction in CNS: important indications that yield early answers 1 2 3 4 5
Slide 6: Objectives for today
Objectives for today How Cyclerion can create value in CNS Discuss the broad therapeutic potential of sGC stimulators in CNS Describe the rich yield of data and its implications (data due late summer) Discuss our first indications: focused patient populations, biomarker - based development Now is th
Slide 7: Now is the time: value in CNS
Cyclerion: delivering impact in CNS Now is the time: value in CNS sGC and CNS: scientific and clinical basis for CNS therapies Translational pharmacology study: demonstrating CNS activity Clinical direction in CNS: important indications that yield early answers 1 2 3 4 • growing patient populations
Slide 8: Capturing potential in a high reward therapeutic area
Capturing potential in a high reward therapeutic area • rapidly growing patient population, lack of approved therapies, important unmet need • quickly evolving science: genetic insights and technologies • valued by investors and industry partners • Cyclerion is the innovator of sGC in the CNS Now is
Slide 9: Raising the odds of success
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 10: Biomarker-guided development in focused patient populations
IW - 6463 biomarker - guided development in focused patient populations P h1 (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 top lin
Slide 11: sGC and CNS: scientific and clinical basis for CNS therapies
sGC and CNS: scientific and clinical basis for CNS therapies Now is the time: value in CNS sGC and CNS: scientific and clinical basis for CNS therapies Translational pharmacology study: demonstrating CNS activity Clinical direction in CNS: important indications that yield early answers 1 2 3 4 • sGC
Slide 12: Drugs targeting the NO-sGC-cGMP 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: optimal tar
Slide 13: Role of NO-sGC-cGMP pathway in CNS disease
Growing appreciation of the role of NO - sGC - cGMP pathway in CNS disease sGC: a central regulator of brain physiology SMOOTH MUSCLE & VASCULAR FUNCTION METABOLISM CELLULAR BIOENERGETICS NEURONAL FUNCTION INFLAMMATION 13
Slide 14: sGC stimulators: potential next druggable neurotransmitter system
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®
Slide 15: From validated cardiometabolic diseases to CNS disease validation
15 NO - sGC - cGMP pathway: From validated cardiometabolic diseases to CNS disease validation Disease genetics network NO - sGC - cGMP pathway Human interactome x Network analysis reveals disease linkage Z - score CNS Diseases • Alzheimer’s disease • cognitive impairment • stroke • bipolar disorder
Slide 16: Preclinical effects in four domains of neurodegenerative disease
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 17: Attractive nonclinical profile supports clinical development
Attractive nonclinical profile supports clinical development • IW - 6463 demonstrates pharmacological activity across four distinct domains in multiple preclinical models • preclinical results support straightforward translation into the clinic • CNS exposure and target engagement demonstrated in mu
Slide 18: Translational pharmacology study: confirming CNS activity
Translational pharmacology study: confirming CNS activity Now is the time: value in CNS sGC and CNS: scientific and clinical basis for CNS therapies Translational pharmacology study: demonstrating CNS activity Clinical direction in CNS: important indications that yield early answers 1 2 3 4 • ration
Slide 19: 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 20: 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 21: Translational study design: pharmacodynamic biomarkers and safety
Translational study design: pharmacodynamic biomarkers and safety 21 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
Slide 22: 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 23: Clinical direction in CNS: indications that yield early answers
Clinical direction in CNS: important indications that yield early answers Now is the time: value in CNS sGC and CNS: scientific and clinical basis for CNS therapies Translational pharmacology study: demonstrating CNS activity Clinical direction in CNS: important indications that yield early answers
Slide 24: MELAS: multi-system manifestations
Central Nervous system Strokes, Stroke - like Episodes (SLEs), Ataxia (Imbalance), Epilepsy (Seizures), Migraine, Headaches, Cognitive Impairment, Learning Disability, Dementia, Mood disorders Skeletal muscle Muscle weakness, myopathy, exercise intolerance Mitochondrial Encephalomyopathy , Lactic Ac
Slide 25: Primary mitochondrial disease patient population
~80% experience cerebellar ataxia, sensorineural hearing loss, ophthalmologic problems, neuropathies Almost all patients present with neurologic symptoms such as stroke and developmental disabilities Almost all patients exhibit neurological manifestations, including hypotonia, epilepsy, ataxia, etc.
Slide 26: Potential therapeutic benefit in MELAS pathophysiology
Potential therapeutic benefit of IW - 6463 Impaired mitochondrial energy production IW - 6463: potentially impacts MELAS pathophysiology at multiple points Impact of L - Arginine/citrulline treatment Mutation leading to decreased protein synthesis Decreased citrulline & arginine synthesis Mitochondr
Slide 27: MELAS: supportive data for NO-sGC-cGMP pathway
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 28: 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 adults (targeting 12 completers) Sites • centers of excelle
Slide 29: Vascular pathology in dementia: clinical perspective
• AD & vascular dementia - two most common dementias • pure forms exist, but vascular pathology widely prevalent in AD • mixed dementia = broad area of overlap • subcortical small vessel disease (SVD) in a significant portion • mixed dementia patients more rapidly progressive disease, higher symptom
Slide 30: Vascular pathology: a key contributor to dementia
Vascular pathology: a key contributor to dementia Adapted from Faraco and Iadecola (2013) Hypertension 62:810 • risk factors and common comorbidities : DM, HTN, HL, Smoking, CAD • ApoE risk partly mediated by endothelial dysfunction and BBB breakdown • brain ischemic changes present in dementia, inc
Slide 31: AD with vascular pathology: focused mixed dementia subset
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 32: 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 33: Committed to building CNS as a core therapeutic area
Current Immediate Execution • pioneer understanding of powerful pharmacology • IW - 6463 MELAS study • IW - 6463 ADv study • explore partnership Long - term Portfolio Growth • commercialization • diversified portfolio • robust series of clinical catalysts • partnership(s) 33 Mid - term Portfolio Adv
Slide 34: Thank you for joining
Thank you for joining • powerful platform for potential CNS therapies • adaptive, risk - reducing, development approach • seasoned drug development leaders with specialized scientific advisors • multiple ways to win: SCD and CNS • ownership base of long - term investors and employees 34
Slide 35: Questions
Questions 35
Slide 36: Delivering impact in CNS diseases: Investor webinar
Delivering impact in CNS diseases Investor webinar July 9, 2020 V7
Slide 37: Citations
Citations Page Topic Citation 25 MELAS epidemiolgy Sources: 1. J Neurol. 2016; 263: 179 – 191; US population estimated at 327.2 million;2. Brain. 2003; 126(5): 1231 – 1240; 3. NIH Genetics Home Reference; 4. NCBI GeneReviews; 5. Neurotherapeutics. 2013 Apr; 10(2): 186 – 198 26 MELAS MOA El - Hattab,
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