Edgewise Therapeutics, Inc. · NASDAQ:EWTX
Edgewise Therapeutics — 27th International Annual Congress of the World Muscle Society 2022
98 slides from Edgewise Therapeutics's conference presentation, Oct 14, 2022
Slide 1: Targeting Fast Muscle Myosin: A Novel Approach to Protecting Muscle in the Dystrophinopathies
Targeting Fast Muscle Myosin: A Novel Approach to Protecting Muscle in the Dystrophinopathies Symposium at the 27th International Annual Congress of the World Muscle Society Halifax NS 14 October 2022 1
Slide 2: Disclosures
Disclosures • This presentation contains forward-looking statements that involve substantial risks and uncertainties of Edgewise Therapeutics, Inc. (“Edgewise” or the “Company”). All statements other than statements of historical facts contained in this presentation, including statements regarding o
Slide 3: Agenda and Presenters
Agenda 1. Preferential Fast Fiber Injury in Dystrophinopathies (Alan Russell) 2. Targeting Fast Myosin to Decouple Injury from Muscle Contraction in DMD and BMD (Alan Russell) 3. Mechanical Stress Induced Injury: Changes in Biomarkers of Dystrophic Muscle During Exercise in LGMD and BMD (John Vissin
Slide 4: Preferential Fast Fiber Injury in Dystrophinopathies
Preferential Fast Fiber Injury in Dystrophinopathies On behalf of H. Lee Sweeney, Ph.D. Alan Russell, Ph.D. Chief Scientific Officer Edgewise Therapeutics 4
Slide 5: Overview
Overview 1. Review of how skeletal muscle force control is achieved 2. Some insights into why human muscle fiber anatomy amplifies the impact of muscular dystrophy 3. Overview on why fast skeletal muscle fibers are more susceptible to injury 5
Slide 6: Innervation Controls Contraction of Groups of Fibers – The Motor Unit
Innervation Controls Contraction of Groups of Fibers – The Motor Unit • A single axon innervates a pool of fast or slow muscle fibers and is termed a Motor Unit • Each motor unit controls 10->1000 fibers • Motor units control fibers of the same type • Muscles of the hand and arm have approx. 113 mot
Slide 7: Skeletal Muscle is Comprised of Slow (type I) and Fast (type II) Fibers
Skeletal Muscle is Comprised of Slow (type I) and Fast (type II) Fibers Present as a mixed mosaic in all muscles Fast Slow Humans are Defined by their myosin motor protein ~ 50/50% fast/slow 7
Slide 8: Motor Unit Force Can be Varied by Altering Stimulation Frequency
Motor Unit Force Can be Varied by Altering Stimulation Frequency Electrical stimulation • The force-frequency relationship shows how the force produced by a motor unit varies with discharge rate. 8
Slide 9: Different Motor Units have Different Thresholds for Initiating Contraction
Different Motor Units have Different Thresholds for Initiating Contraction Motor Unit Recruitment • Different Motor Units have different thresholds for recruitment • As muscle effort increases, new motor units are recruited to add to the contractile fiber Motor Unit pool Recruitment Threshold • As a
Slide 10: Rate Coding and Recruitment Work Together to Control Muscle Power Output
Together, Rate Coding and Recruitment Work Together to Smoothly Control Muscle Power Output 25 Soleus Muscle • This clever system facilitates smooth motor control even Discharge rate (pps) Each line indicates the 20 force range over which a single motor unit could be under conditions of tracked extr
Slide 11: One Weakness of Human Muscle – Long Limbs = Long Fibers
One Weakness of Human Muscle – Long Limbs = Long Fibers • Mapping of muscle fibers in the human sartorius muscle Healthy volunteers • The longest muscle in the body (~60 cm) Human muscle fibers are • Each muscle fiber has one motor unit endplate >7x longer than those in • Not all fibers span the who
Slide 12: The Dystrophin Complex Helps Prevent Injury in Contracting Fibers
The Dystrophin Complex Helps Prevent Injury in Contracting Fibers Muscle fibers from different motor units contract indepedently Dystrophin connects contractile proteins to the membrane and surrounding matrix of fibers Long muscle fibers are more dependent upon dystrophin to help support fibers 12
Slide 13: Regional Stress of Long Muscles in BMD Leads to Uneven Fat Incorporation
Regional Stress of Long Muscles in BMD Leads to Uneven Fat Incorporation Greater fat fraction at the ends of the muscle fiber where stress is the greatest Eventually, the whole muscle is affected van de Velde et al., Neurology 2021;97:e513-e522 13
Slide 14: Fast Muscle Fibers are More Prone to Disruption in Response to Eccentric Exercise
Fast Muscle Fibers are More Prone to Disruption in Response to Eccentric Exercise in Unaffected Individuals More Disruption in Fast Muscle Fibers vs. Slow Muscle Fibers ✱ 20 Disrupted Muscle Fibers (%) 15 10 5 0 rs rs SLOW FAST be be Fi Fi • 30 mins controlled eccentric exercise st ow • Muscle biops
Slide 15: Skeletal Muscle Z-Discs Deform with Stress and have Different Architecture
Skeletal Muscle Z-Discs Deform with Stress and have Different Architecture Between Fast and Slow Fibers Relaxed Contracted Fast Slow JCB 57: 261-277, 1973 J Muscle Res Cell Motil (2009) 30:171–185 Fast Slow 15
Slide 16: Fast Fibers are also More Sensitive in DMD
Fast Fibers are also More Sensitive in DMD Black shading indicates eMHC- positive fibers Slow Fast Enrichment of muscle regeneration biomarkers in fast but not slow muscle fibers of Regeneration Marker young DMD kids Expressed mostly in fast but not slow fibers 16
Slide 17: Injury Biomarkers Tell the Same Story
Injury Biomarkers Tell the Same Story - Fast but not Slow Fiber Biomarkers are Elevated in BMD and DMD 43 out of 52 not measurable FAST FIBER PROTEIN SLOW FIBER PROTEIN Berthel et al., Muscle and Nerve. doi: 10.1002/mus.27222. Mar 2021 17
Slide 18: Summary
Summary • Contraction of skeletal muscle is a complex process that relies on a combination of rate coding and recruitment to control power output • The dystrophin complex stabilizes fiber contraction by providing support across surrounding fibers • When dystrophin is mutated, additional regional str
Slide 19: Targeting Fast Myosin to Decouple Injury from Muscle Contraction in DMD and BMD
Targeting Fast Myosin to Decouple Injury from Muscle Contraction in DMD and BMD Alan Russell, Ph.D. 19
Slide 20: Overview
Overview 1. Taking advantage of Fast Fiber Susceptibility and integrative flexibility for therapeutic benefit in dystrophinopathies 2. Preclinical data to support this hypothesis 20
Slide 21: A New Strategy to Rebalance Dystrophic Muscle
A New Strategy to Rebalance Dystrophic Muscle Selective inhibition of fast fiber contraction to prevent injury but at a level that doesn’t disrupt function 21
Slide 22: The Target – Fast Skeletal Muscle Myosin
The Target – Fast Skeletal Muscle Myosin Myosin Hydrolyzes ATP to bind actin and generate force 22
Slide 23: Development of a Potent, Selective Fast Skeletal Muscle Myosin Inhibitor, EDG-5506
Development of a Potent, Selective Fast Skeletal Muscle Myosin Inhibitor, EDG- 5506 Fast Skeletal Cardiac Muscle myofibril 125 Slow Skeletal 120 DMSO 0.1 µM EDG-5506 Skinned fast rabbit ATPase 0.6 µM EDG-5506 Normalized Tension (Percent) 100 1 µM EDG-5506 psoas fibers Normalized ATPase 100 10 µM EDG
Slide 24: EDG-5506 Stops Fiber Breakdown in Contracting DMD Muscle
EDG-5506 Stops Fiber Breakdown in Contracting DMD Muscle DMD muscle (mdx mouse) no treatment DMD muscle (mdx mouse) 0.3 uM EDG-5506 Contracting at 100% Contracting at 85% Claflin, Su and Brooks. U Michigan mdx mouse lumbrical muscle – 20, 1 second maximal isometric contractions (video sped up) 24
Slide 25: Protection Associated With Reduced Muscle Permeability
Protection Associated With Reduced Muscle Permeability In vivo Dye Uptake by Leaky Muscle Ex vivo Dye Uptake by Contracting Muscle Fibers Evans blue uptake in non-exercised mdx mice after 3 weeks of treatment ✱✱✱✱ 1 µM EDG-5506 5 µM EDG-5506 50 ✱✱✱✱ 40 (% muscle area) Procion uptake 30 20 10 0 Red =
Slide 26: EDG-5506 Reduces DMD Mouse CK After Exercise Testing
Summed Run Time (sec) W T ED W T 1 100 10000 10 1000 W G T -5 Ve ED 5ic 06 h W G le 1 T -5 5 m E 0 g W DG 6 3 /kg T - m E D 55 g/ G 06 kg 5 ns -5 50 m 6 g ✱✱✱✱ m 10 /kg dx m ED m d g/ m x k dx G - 5 Ve g Performance E 50 hi m DG 6 1 cle dx -5 50 mg m ED / dx G 6 3 kg - 5 m ED 5 g/ G 06 ns kg -5 5 50
Slide 27: EDG-5506 Decreases CK and Increases Activity in DMD Dogs
EDG-5506 Decreases CK and Increases Activity in DMD Dogs Decreased injury biomarker Increased activity measured (plasma CK) with an activity monitor Before After dosing w/ Before dosing After dosing w/ dosing EDG-5506 EDG-5506 27 27
Slide 28: Summary
Summary • Allosteric inhibitors of fast skeletal muscle myosin are capable of selective inhibition of force in fast fibers • Modest inhibition of myosin is sufficient for complete protection against contraction-caused calcium entry and destruction in dystrophic muscle • Protective doses of selective
Slide 29: Muscle Injury in Muscular Dystrophies
Muscle Injury in Muscular Dystrophies John Vissing, M.D., Ph.D. Director, Copenhagen Neuromuscular Center at the National Hospital, Rigshospitalet 29
Slide 30: Eccentric Exercise Causes Muscular Injury in Healthy Volunteers
Eccentric Exercise Causes Muscular Injury in Healthy Volunteers Reduced strength Increased soreness • Eccentric exercise of the forearm flexors Reduced range Increased • Two sets of 35 maximal of motion CK contractions • 5 min rest between sets Source: Figure adapted Clarkson et al, Med Sci. Sports
Slide 31: Muscle Injury is Associated with Fast but not Slow Muscle Biomarkers
Muscle Injury is Associated with Fast but not Slow Muscle Biomarkers Source: Figure adapted Chapman et al, J Science and Med in Sport, 16: 82-85, 2013 31
Slide 32: Injury Biomarkers Elevated with Exercise in Becker Muscular Dystrophy
Similar to Health Individuals, Injury Biomarkers are Elevated with Exercise in Becker Muscular Dystrophy and McArdle Disease 20 mins, 95% VO2 Max bike exercise followed by 40 leg presses at 80% 1-RM max Source: Figure adapted Dahlqvist al, Muscle Nerve 49: 261–266, 2014 32
Slide 33: Study Aims: Better Understanding Muscle Injury Biomarkers in Myopathies
Study Aims: Better Understanding Muscle Injury Biomarkers in Myopathies Circulating proteins Mechanical Stress- Induced Damage Are there differences between damage to fast vs. slow fibers with exercise in muscular dystrophies? Are elevated protein levels in plasma directly caused by exercise-induced
Slide 34: Methodology: Exercise Challenge and SOMAscan Analysis
Methodology: Exercise Challenge and SOMAscan Analysis SOMAScan Blood Plasma Modified aptamer-based assay for ~7000 circulating proteins 10 min Assessment rest Exercise Protocol Post-Exercise Observation VO2max Test Cycle 5x 4 min @ 95% VO2max Quadricep 1- rep max ID Strength 0 hr 2 hr 4 hr 24 hr 4x,
Slide 35: Understanding the Universality of the Muscle Injury Signature
Understanding the Universality of the Muscle Injury Signature Myofibril proteins Mechanical Stress- Induced Damage Dystrophin Membrane Repair Mutation Dystroglycan (LGMDR12) (BMD) Glycosylation (LGMDR9) 35
Slide 36: Participants and Demographics
Participants and Demographics 36
Slide 37: Proteomics Approach - SOMAscan Aptamer Technology
Proteomics Approach - SOMAscan Aptamer Technology Enables Relative Measurement of 7000 Proteins for a Single Blood Sample ‘Slow Off-rate Modified Apatamer Scan’ Proteins are identified in a complex solution by aptamer- linked precipitation Protein data is reported as relative to a normalizer, not an
Slide 38: Identification of a Shared Pre-exercise Baseline Signature
Identification of a Shared Pre-exercise Baseline Signature Nonmuscle Tissues Muscle Tissues 32 common elevated proteins 1 common decreased protein (Ecto-ADP-Ribosyltransferase) 38
Slide 39: Exercise Dynamics of Baseline Signature Proteins
Protein Concentration Change Relatative to Healthy Baseline -2 0 2 4 6 8 F KL BP 2 M HL YB 41 P AD C2 S TN S1 M NT YB 3 P D C1 U PD EN 1 O 3 M A C YB 3 AC PH T TN N2 PD T N LI 2 M TN 3 M N U I2 ST TH N1 Responsive AP C 4 K AP GP M O D C BE 1 KB C |C 2 M KM YO M M2 YL H PF SP B C MY 6 H C L3 H D C 10
Slide 40: Validation of the Universal Baseline Signature Using BMD Data
Validation of the Universal Baseline Signature Using BMD Data Baseline 33-protein Signature Baseline Signature Comparison Copenhagen BMD Exercise Newcastle Tissue Dataset (N=9) Bank Dataset (N=55) 80 60 Copenhagen Newcastle Age (yrs) 40 Larger age range Similar pattern of elevation and 20 in Newcast
Slide 41: Exercise Responsive and Nonresponsive Proteins Show Opposing Age Correlations
Exercise Responsive and Nonresponsive Proteins Show Opposing Age Correlations Exercise Responsive BMD-Specific Elevated Proteins (CKM) with age Increases ✱✱✱✱ 0.5 Correlation with Age (Pearson Coefficient) 0.0 30 - 50% of responsive and nonresponsive proteins exhibit Exercise Nonresponsive with age
Slide 42: Conclusions and Future Questions
Conclusions and Future Questions We have identified and validated a common signature of biomarkers that are elevated in several muscular dystrophies Further annotation of these biomarkers by examination of change with exercise is possible Exercise responsive and nonresponsive markers exhibit opposit
Slide 43: Acknowledgments
Acknowledgments Exercise trial participants and Muscular dystrophy patients Neuromuscular Center, University of Copenhagen Mads Stemmerik, Nanna Andersen, Sophie V. Skriver MRC Centre Biobank for Rare and Neuromuscular Diseases Dan Cox, Volker Straub, Donors of plasma Edgewise Therapeutics Ben Barth
Slide 44: Clinical Course of Dystrophinopathies with a Focus on Becker Muscular Dystrophy
Clinical Course of Dystrophinopathies with a Focus on Becker Muscular Dystrophy Craig McDonald, M.D. 10/14/2022 44
Slide 45: Defining Becker Muscular Dystrophy
Defining Becker Muscular Dystrophy • Desire to classify, especially in light of new therapeutics emerging • Tremendous Variability – due to amount and quality of dystrophin From PPMD and Community Draft Guidance for Industry: Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystro
Slide 46: Loss of Ambulation in Duchenne Muscular Dystrophy
Loss of Ambulation in Duchenne Muscular Dystrophy CM McDonald, et al. Lancet. 2018;391:451-461. 46
Slide 47: Defining Becker Muscular Dystrophy by Age at Loss of Ambulation
Defining Becker Muscular Dystrophy Defining by age at loss of ambulation, which varies broadly DMD: Era before steroids: Current Current Age 10 (Range 7-13) era: era: Age 16 Age 18 No On Steroids Steroid 47
Slide 48: Defining Becker Muscular Dystrophy: Clinical Trial Criteria
Defining Becker Muscular Dystrophy: Clinical Trial Criteria Edgewise: Adults (aged ≥ 18 years) with a documented dystrophin mutation and phenotype consistent with BMD, and history of being ambulatory beyond 16 years of age without steroids OR history of being ambulatory beyond 18 years of age with s
Slide 49: Becker Muscular Dystrophy Arises from In-Frame Mutation of Dystrophin
Classical Definition - Becker Muscular Dystrophy Arises from In-Frame Mutation of the Dystrophin Protein • In-frame mutation of the dystrophin gene results in a truncated form of the protein • Incidence: >1 in 18,450 male live births • the global prevalence of BMD estimated at 1.6 per 100,000 people
Slide 50: Effects of Very Low Dystrophin Levels on Disease Phenotype
Investigating the Effects of Very Low Dystrophin Levels on Muscular Dystrophy Disease Phenotype Study objective: —Determine whether a low residual quantity of dystrophin protein is associated with delayed clinical milestones in patients with DMD mutations 50
Slide 51: Retrospective Cohort Study of Very Low Dystrophin Levels
A Retrospective Multicentric Cohort Study of Very Low Dystrophin Levels in the UMD-DMD France Database UMD-DMD French Database (n=3880) Clinical Outcomes Genetic diagnostic (n=2542) (Laboratory of Molecular Genetics, Cochin University Hospital) • Age at first symptoms and loss of ambulation Assessed
Slide 52: Patient Mutations and Disease Severity Varied by Dystrophin Quantity
Patient Mutations and Disease Severity Varied by Dystrophin Quantity Group A: No Dystrophin Group B: >0% and <5% Group C: ≥5% (n=42) of normal dystrophin (n=34) of normal dystrophin (n=14) 0% had IMD 10% had IMD 3% had IMD Rate of DMD and BMD Disease 74% 2% had BMD 18% 61% had BMD 0% 57% had BMD dif
Slide 53: Impact of Residual Dystrophin on Time to LoA
Impact of Residual Dystrophin on Time to LoA Loss of Ambulation (Group A, B, C) Loss of Ambulation (Group B’, B”) Group A: 0% A: No dystrophin Group B: 0-5% B: <5% dystrophin Group B’: 0-0.5% Group B”: 0.5-5% C: ≥5% dystrophin Group C: ≥5% Number at risk Number at risk A 41 41 19 1 0 0 0 B’ 25 25 23
Slide 54: Impact of Residual Dystrophin on Survival, Cardiac and Respiratory Function
Impact of Residual Dystrophin on Survival, and Cardiac and Respiratory Function A: No dystrophin B: <5% dystrophin C: ≥5% dystrophin VC <50% LVEF <55% Survival Median age Median age Median age Group A: 15.0 years Group A: 15.4 years Group A: 28.7 years Group B: Undefined Group B: 23.7 years Group B:
Slide 55: Becker Muscular Dystrophy Manifests with Progressive, Debilitating Weakness
Becker Muscular Dystrophy Manifests with Progressive, Debilitating Weakness • BMD is extremely heterogenous • Symptom onset from 5 to 60 years old, typically between ages 8 to 13 —90% >20 yr old patients have symptoms of weakness • Walking problems usually noticed around age 15/16, with loss of ambu
Slide 56: Discordance of Cardiomyopathy and Skeletal Myopathy
Discordance of Cardiomyopathy and Skeletal Myopathy Key Considerations: • There may be a discordance with skeletal myopathy and cardiomyopathy • Highly functional BMD patients in young adulthood may present with severe cardiomyopathy • Severe cardiomyopathy leading to destination VAD and/or cardiac
Slide 57: Use of Assistive Devices for Mobility is Common in Becker Adults
Use of Assistive Devices for Mobility is Common in Becker Adults 2 to 18 years Adult I can get around on my own but I sometimes need 14% 15% help from a mobility device. I use a wheelchair or other mobility device and 8% 34% rarely or never walk. I usually or always walk on my own without help or 74
Slide 58: One Year Longitudinal Changes in BMD
One Year Longitudinal Changes in BMD 6MWD NSAA (“del 45-x”) (“del x-51”) Conclusions: del 45–47, del 34–51, • patients with “del x-51” or “del 48” mutations have mild 45–48, 45–51, or asymptomatic BMD, 45–49, and 48–51, and • “del 45-x” and “other” mutations cause comparatively 45–55 50–51 severe we
Slide 59: Proportion of Patients Continuing to Walk
Proportion of patients continuing to walk Proportion of patients continuing to run (Usually 10 meter run/walk of approx. < 3 sec) 59 Bello et al. Scientific Reports (2016) 6:32439
Slide 60: Ambulatory Function Shows a Steady Decline Once Compromised
Ambulatory Function Shows a Steady Decline Once Function Becomes Compromised 34 30 • Luca Bello’s BMD Natural History Study, 25 the most comprehensive study of its kind to date, demonstrates that NSAA 20 decline is consistent in BMD patients NSAA Score who are already progressing 15 • BMD individual
Slide 61: Leiden Natural History Data
Leiden Natural History Data Van de Velde et al, 2021, Neurology 61
Slide 62: Findings: Correlations of Outcome Values at Baseline
Findings: Correlations of Outcome Values at Baseline (minors: left panel; adults: right panel) Dang et al, 2022 ICNMD presentation 62
Slide 63: Findings: Who Became Non-ambulatory?
Findings: Who Became Non-ambulatory? Dang et al, 2022 ICNMD presentation 63
Slide 64: Baseline Factor Likely Predictive of Disease Progression
Baseline Factor Likely Predictive of Disease Progression Age 10 meter R/W 5 sec Dang et al, 2022 ICNMD presentation 64
Slide 65: Weakness Develops as a Result of Localized Muscle Loss
Weakness Develops as a Result of Localized Muscle Loss Mean 10 yrs, 50% ambulant • Focal muscle loss in the thighs, shoulders and arms • Focal loss results in greater fat accumulation in select muscles compared to Duchenne for a given functional status Mean 41 yrs, ambulant • Thigh fat correlates wi
Slide 66: Total Steps per Day
Total Steps per Day Adult NMD (BMD n = 12) 6000 5000 * Total Steps per Day 4000 * * 3000 2000 1000 0 Control BMD CMT FSH MMD LG
Slide 67: Steps at High Activity Level per Day
Steps at High Activity Level (>30 steps/min) 2500 Steps at High Activity Level per Day 2000 1500 1000 500 0 Control BMD CMT FSH MMD LG All NMD groups are significantly different from control group.
Slide 68: Exercise Training in BMD
Exercise Training in BMD Sveen et al; Brain, 2008 • 11 gene + BMD patients age 18-55; 7 nl controls • 12 weeks of 65% VO2 max aerobic exercise on bicycle ergometer; 30 min; 5x per week (50 sessions) — 6 pts continued protocol for 12 months at 3x/week • Muscle biopsies done pre/post-exercise in 6 • C
Slide 69: Exercise in BMD
Exercise in BMD Sveen et al, 2008 VO2 max P<0.005 • VO2 max up by 47 + 11% C — 16% in normals • W max work up 80+ 19% • Strength up by 13-40% • Most “showed improvement” in QOL W max • No change in HR, CK, histology, P<0.005 central nuclei C • Improvements maintained at one year in six patients • “O
Slide 70: Conclusions
Conclusions • Low levels of dystrophin result in intermediate dystrophinopathy and Becker muscular dystrophy with ambulation past the age of 16 (without steroids and > 18 (with steroids) • Variability, frame-shift rule does not always apply and patients with “del x-51” or “del 48” mutations have mil
Slide 71: Clinical Development of EDG-5506 in Duchenne and Becker Muscular Dystrophy
Clinical Development of EDG-5506 in Duchenne and Becker Muscular Dystrophy Joanne Donovan, M.D., Ph.D. Chief Medical Officer Edgewise Therapeutics 71
Slide 72: BMD and DMD Represent Severe Dystrophinopathies
BMD and Duchenne Muscular Dystrophy (DMD) Represent Severe Dystrophinopathies Spectrum of Severity Across Dystrophinopathies Functional Dystrophin Normal Levels No Dystrophin BMD DMD Severe No Damage Intensity of Muscle Damage BMD and DMD represent a continuum of the same disease; Edgewise’s approac
Slide 73: Schematic of Clinical Development of EDG-5506 to Date
Schematic of Clinical Development of EDG-5506 to Date Phase 1 in Healthy Adults and Adults with Becker Muscular Dystrophy Open-label Study in Becker Muscular Dystrophy Phase 2 in Adults and Phase 2 in Children with Adolescents with Becker Duchenne Muscular Muscular Dystrophy Dystrophy 73
Slide 74: EDG-5506 Represents a Novel, Potentially Disease-Modifying MOA
EDG-5506 Represents a Novel, Potentially Disease-Modifying MOA for DMD and BMD The Core Problem in Dystrophinopathies EDG-5506 • Increased muscle injury biomarkers in plasma Reduced muscle Daily mechanical stress on muscle • Replacement of muscle by fat and fibrosis function fibers results in muscle
Slide 75: EDG-5506 Phase 1 Study in Healthy Volunteers and BMD Participants
EDG-5506 Phase 1 Study Conducted in Healthy Volunteers and Participants with Becker Muscular Dystrophy Ambulatory Subjects with Becker Muscular Healthy Volunteers Dystrophy (BMD) • Single Ascending Doses: up to 135 mg, • Multiple Doses: 20 mg/day, administered as solid administered as liquid formula
Slide 76: Overview of Healthy Volunteers Phase 1a SAD/MAD
Overview of Healthy Volunteers (HVs) Phase 1a SAD/MAD with EDG-5506 EDG-5506 was generally well tolerated with no serious adverse events observed. Most common AEs were somnolence and dizziness, which were generally mild and transient Plasma PK showed good oral absorption with or without food, and an
Slide 77: Participants in the BMD Phase 1b Had Significant Baseline Functional Impairment
Participants in the BMD Phase 1b Had Significant Baseline Functional Impairment Characteristic BMD Participants (N=7) Age Normative Values Age 33.8 years Functional Measures (median) 10-meter walk/run 8.3 sec < 4 sec Rise from floor 20 sec < 3 sec Serum Creatinine (mean, mg/dL) 0.58 0.92 - 1.16 Seru
Slide 78: EDG-5506 Concentrates in Healthy and Dystrophic Muscle
EDG-5506 Concentrates in Healthy and Dystrophic Muscle, Demonstrating Delivery of Drug to the Target, Fast Myosin Daily Dose Muscle (ng/g)* Healthy Adults 5 mg* 980 Liquid Healthy Adults 10 mg* 2,740 Formulation Healthy Adults 20 mg 4,360 Healthy Adults 20 mg 6,140 Solid Dosage Form Healthy Adults 4
Slide 79: A Proteomic Signature for BMD was Identified
Using SOMAscan 7,000 Analyte Set, A Proteomic Signature for BMD was Identified Baseline BMD vs. Healthy Biomarker Fingerprint Analysis PROTEINS LOWER IN BMD PROTEINS HIGHER IN BMD • Baseline plasma samples (n=7) were compared to samples from healthy volunteers (n=25) • Proteins filtered by magnitude
Slide 80: Majority of BMD Signature Proteins are Lowered by EDG-5506
The Majority of BMD Signature Proteins are Lowered by EDG-5506 BMD Biomarkers Change From Baseline After 14 Days ✱✱✱✱ • BMD proteomic fingerprint unchanged in 3 ns ✱✱✱ control group following EDG-5506 treatment (Log2 Relative to Respective Baseline) 2 Plasma Concentration 1 • BMD participants treate
Slide 81: Biomarkers Most Elevated in BMD are Decreased Most with EDG-5506
Biomarkers Most Elevated in BMD are Decreased Most with EDG-5506 Change with 14 Days EDG-5506 Treatment Baseline BMD vs Placebo EDG-5506 Healthy (n=2) (n=5) Consistent response across Log2 Difference treated individuals with DD greatest decrease in the most elevated biomarkers Source: Data on file 8
Slide 82: Elevated Biomarkers Decrease Most Following EDG-5506
Elevated Biomarkers Decrease Most Following EDG-5506 2 • Close association of elevated BMD biomarkers with EDG-5506 response Decreased by EDG-5506 at 14 days treatment (Log2) 1 reveals a significant relationship to biomarker lowering 0 • Overall, this suggests a broad -1 -2 normalization of the BMD
Slide 83: Consistent and Progressive EDG-5506 Effect on Exercise Responsive Markers
Consistent and Progressive EDG-5506 Effect on Exercise Responsive Markers EDG-5506 (N=5) • In adults with BMD SOMAscan ✱✱✱✱ samples from an exercise study were 3 (Log2 Relative to Pre-Dose Baseline) used to define a proteomic signature 2 ✱✱✱✱ that was elevated compared to Plasma Concentration ✱✱✱✱ c
Slide 84: One Year Open Label Study Design
One Year Open Label Study Design • An open-label, single-center study of EDG-5506 to assess the safety and pharmacokinetics (PK) of EDG-5506 in adults with Becker muscular dystrophy (BMD) —12 patients enrolled, ambulatory with BMD, including all from Phase 1 study Screening After 6 months all EDG-55
Slide 85: Participants in the BMD Open-Label Study Had Significant Baseline Impairment
Participants in the BMD Open-Label Study Had Significant Baseline Functional Impairment R ange of N S A A and N S A D BMD Participants Age Normative Characteristic (N=12) Values 54 Age 32.8 (8.1) years r2= 0.9595 Functional Measures (median) 40 10-meter walk/run 8.4 sec < 4 sec NSAD Rise from floor
Slide 86: Functional Measures Correlate with Measures of Muscle Mass
Functional Measures Correlate with Measures of Muscle Mass 100 m walk/run vs. NSAD 100 m walk/run vs. creatinine % Lean Body Mass vs. NSAD 200 0.8 80 DXA Lean Body Mass (percent) 100 m walk/run time (secs) 150 0.6 70 Creatinine (ng/ml) 100 0.4 60 50 0.2 50 0 0.0 40 0 10 20 30 40 50 60 0 50 100 150 2
Slide 87: EDG-5506 Well Tolerated After Four Months of Dosing at 15 mg
EDG-5506 Continued to be Well Tolerated After Four Months of Dosing with the 15 mg Dose; Six Months Total Dosing 2-month (%); 4-month period (%); Total Treatment Emergent AEs 10 mg EDG-5506 15 mg EDG-5506 6 months Dizziness 2 (17%) 1 (8%) 3 (25%) Somnolence 2 (17%) 1 (8%) 3 (25%) Headache - 3 (25%)
Slide 88: Target Plasma PK Achieved; Patients Showed Continued Activity
Target Plasma PK Achieved After Increasing Dose to 15 mg/day; BMD Patients Showed Continued Activity After 6 Months of Dosing 150 EDG-5506 Plasma PK Patient Step Count 5,000 Legend Mean AUC24 (ng/ml): 2,293 1,454 2,299 2,400 • Exposure with 15 mg dose 4,000 reached the target exposures observed with
Slide 89: Sustained Decrease in CK and Suppression of TNNI2
EDG-5506 Led to a Sustained Decrease in CK and Profound Suppression of TNNI2 Demonstrating Target Engagement Creatine Kinase Fast Skeletal Muscle Troponin I (TNNI2) 3,000 2,000 150 50 ✱✱✱ ✱✱✱ 40 1,500 TNNI2 Concentration (ng/ml) TNNI2 Concentration (ng/ml) 2,000 100 CK Activity (U/L) CK Activity (U/
Slide 90: SOMAscan Signature of Long-Term Response Emerging with Treatment?
SOMAscan Signature of Long-Term Response Emerging with Treatment? 2.0 Normalized Protein Concentration 1.5 1.0 0.5 0.0 s s s s l th e tro th th th th lin on on on on on on se M M M M M C Ba 1 y 2 3 4 6 lth D BM ea H • Previous studies focused on rapidly-changing biomarkers of muscle injury with EDG-
Slide 91: Natural History of BMD Provides Context for Interpreting NSAA Changes
The Natural History of BMD Provides Helpful Context for Interpreting Changes in NSAA in Response to EDG-5506 34 30 • Luca Bello’s BMD Natural History Study, the most comprehensive study of its kind to date, demonstrates that NSAA 25 decline is consistent in BMD patients who are already progressing 2
Slide 92: NSAA and NSAD Durable Improvements Relative to Natural History
NSAA and NSAD Durable Improvements Observed Over 6 Months of EDG-5506 Relative to Natural History NSAA change NSAD change 3 3 2 2 Change in NSAA Change in NSAD 1 1 0 0 Natural History -1 Average -1 -2 -2 0 2 4 6 0 2 4 6 Month of Treatment Month of Treatment NSAA Represents an Integrated Measure of F
Slide 93: Diffuse Pain in Becker Muscular Dystrophy
Diffuse Pain in Becker Muscular Dystrophy • Self-reported pain over the previous 3 months in Duchenne and Becker muscular dystrophy (DMD N=15, Age 24+/-6 yrs; BMD N=18, Age 42+/-14 yrs) • 10/18 BMD ambulant • BMD individuals report more diffuse pain, focus on spine and calves PLoS ONE 14(2): e021243
Slide 94: Self-Reported Pain Scores Trended Better Following EDG-5506 Dosing
Self-Reported Pain Scores Also Trended Better Following 6 Months of EDG-5506 Dosing 5 • While the ARCH study is not placebo controlled, a Self-Reported Pain Score (0-10) 4 positive trend in self-reported pain scores was 3 observed after 6 months of EDG-5506 dosing 2 • Additionally, other patient-rep
Slide 95: Ongoing and Upcoming Clinical Studies with EDG-5506
Ongoing and Upcoming Clinical Studies with EDG-5506 Status Phase 1 OL Study (BMD) (NCT05160415) Steady-state PK, biomarker response and longer-term safety Fully Enrolled Natural History Study in BMD (NCT05257473) Observational natural history study in BMD adults and adolescents Enrolling Conducted b
Slide 96: Phase 2 Study in Adults and Adolescents with Becker
Phase 2 Study in Adults and Adolescents with Becker • Population: —Age 12 to 50 years old, inclusive —Confirmed mutation in dystrophin gene with characteristic Becker phenotype —Ambulatory —Not on corticosteroids • Design: 12-month placebo-controlled • Endpoints: —Biomarker (CK) at 12 months —Safety
Slide 97: Phase 2 Dose-Ranging Study in Boys with Duchenne
Phase 2 Dose-Ranging Study in Boys with Duchenne • Planned to start in Q4 2022 • Population: —4 to 9 years old, inclusive —Confirmed mutation in dystrophin gene with characteristic phenotype —Ambulatory —On stable dose of corticosteroids; can be on approved exon-skipping rx • Design: 3-month placebo
Slide 98: Acknowledgements: Study Participants and their families
Acknowledgements: Study Participants and their families Rare Disease Research Atlanta GA Principal Investigator: Han Phan, MD Site Personnel: Emily Murray Alvin Nguyen Darwin Nguyen H 98
Edgewise Therapeutics — 27th International Annual Congress of the World Muscle Society 2022 on 6ix