Edgewise Therapeutics, Inc. · NASDAQ:EWTX
Edgewise Therapeutics — 28th International Annual Congress of the World Muscle Society 2023
59 slides from Edgewise Therapeutics's conference presentation, Oct 3, 2023
Slide 1: Becker Muscular Dystrophy Natural History and ARCH: Putting the Data into Context
Becker Muscular Dystrophy Natural History and ARCH, an Open Label Study in Becker: Putting the Data into Context Symposium at the 28th International Annual Congress of the World Muscle Society Charleston, SC October 3, 2023 1
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation contains forward-looking statements that involve substantial risks and interim, preliminary, topline or expected results; Edgewise’s ability to enroll patients in its uncertainties of Edgewise Therapeutics, Inc. (“Edgewise” or the “Company”). All statemen
Slide 3: Program Overview
Program Overview • Joanne M Donovan, MD, PhD, Chair, Chief Medical Officer, Edgewise Introduction • Erik Niks, MD, PhD, Pediatric and adult Neurologist, Leiden University Medical Center The Natural History of Becker Muscular Dystrophy • Sam Collins, MD, PhD, Vice President, Clinical Development, Edg
Slide 4: Key Takeaways
Key Takeaways • Becker muscular dystrophy is a serious dystrophinopathy. Once function begins to decline, individuals continue to irreversibly lose muscle and their disease progresses. • Stabilizing function or even reducing the slope of decline is an important goal in Becker muscular dystrophy. 4 4
Slide 5: The Natural History of Becker Muscular Dystrophy
The Natural History of Becker Muscular Dystrophy Erik Niks, MD, PhD Pediatric and Adult Neurologist Leiden University Medical Center 5
Slide 6: Becker Muscular Dystrophy Natural History
Becker Muscular Dystrophy Natural History Erik Niks – pediatric & adult neurologist
Slide 7: Disclosures
Disclosures Participant in advisory boards for Edgewise, Italfarmaco, Sarepta, Epirium, Regenxbio and Janssen Principal investigator at LUMC for clinical trials from Edgewise, Italfarmaco, Sarepta, Fibrogen, NS Pharma, Reveragen, Santhera, BioMarin, ML Bio, Janssen, ArgenX and Alexion Grants from Pf
Slide 8: Becker Muscular Dystrophy
Becker Muscular Dystrophy 14 male patients Onset 12-25 years Slowly progressive Hypertrophic calves Waisting of quadriceps 8 Becker et al. Archiv für Psychiatrie und Zeitschrift Neurologie 1955
Slide 9: Becker Muscular Dystrophy
Becker Muscular Dystrophy 14 male patients Onset 12-25 years Slowly progressive Hypertrophic calves Waisting of quadriceps Clinical variation 9 Becker et al. Archiv für Psychiatrie und Zeitschrift Neurologie 1955
Slide 10: Becker and Duchenne share the gene and protein
Becker and Duchenne share the gene and protein 10
Slide 11: Dystrophin links sarcolemma and cytoskeleton
Dystrophin links sarcolemma and cytoskeleton dystrophin actin 11
Slide 12: 79 exons of the DMD gene
79 exons of the DMD gene nNOS 12 Adapted from Duan et al. Nat Rev Dis Primers 2021
Slide 13: Duchenne - out of frame deletions
Duchenne - out of frame deletions X nNOS 13 Adapted from Duan et al. Nat Rev Dis Primers 2021
Slide 14: Becker – in frame deletions
Becker – in frame deletions nNOS 14 Adapted from Duan et al. Nat Rev Dis Primers 2021
Slide 15: Muscle biopsy
Muscle biopsy The picture can't be displayed. Normal Becker Duchenne 15 Beekman et al. PLoS One. 2018
Slide 16: Clinical symptoms
Clinical symptoms Proximal and paraspinal weakness Acquire jumping and hopping Ambulant beyond 16 yrs (no steroids) Muscle pain and cramps Muscle hypertrophy -> atrophy Cardiomyopathy 16
Slide 17: North Star Ambulatory Assessment
North Star Ambulatory Assessment 17 items Score of 0-2 per item Unable - With assistance - Independent Maximum of 34 points 10-meter walk/run test Primary endpoint in DMD and BMD trials MCID and use for external controls in DMD 17
Slide 18: BMD Natural History study - Italy
BMD Natural History study - Italy N = 69 Age 6-69 Follow-up 12 months Mutations Del 45-x (28) Del 48 (10) Del x-51 (10) Other (21) NSAA at baseline 25.3 ± 10.8 Mean change at 12m -0.9 ± 1.6 (p<0.001) 18 Bello et al. Sci Rep 2016
Slide 19: BMD Natural History study - Netherlands
BMD Natural History study - Netherlands N = 36 Age 18-67 Annual FU - 3 years Yearly functional assessments MRI optional (1st and 3rd visit) Mutations Del 45-47 (11) Involving nNOS (21) NSAA main decline in 10-32 19 Schrama and Koeks et al. In preparation
Slide 20: Responsiveness of functional tests at 1 and 3-year FU
Responsiveness of functional tests at 1 and 3-year FU Standardized Response Mean (SRM) Sample size (SS) calculation based on 50% treatment effect in 1:1 randomisation Mean change at SRM SS Mean change at SRM SS N at Mean (SD) at 1- year follow-up 1 year 1 year 3-year follow-up 3 year 3 year baseline
Slide 21: MRI as biomarker in BMD
MRI as biomarker in BMD Increased fat fraction Differs between muscles Differs within muscles Axial and longitudinal plane 21 Hooijmans et al. NMR in Biomed 2020 & van de Velde et al. Neurology 2021
Slide 22: MRI as biomarker in BMD
MRI as biomarker in BMD Fat fraction using Dixon N = 24 at baseline, N = 20 after 2 years Manual delineation of 19 muscles: • 23 slices of 10 mm with 5 mm gap • Middle slice based on anatomical landmarks • Values for 3 center slices and whole muscle • Values per muscle and for 6 groups Fat Water • F
Slide 23: Increase in FF over 24 months
Increase in FF over 24 months Median whole muscle FF increased between 0.2% and 2.6% 23 Van de Velde and Hooijmans et al. Neurology 2021
Slide 24: Functional change over 24 months
Functional change over 24 months 24 Van de Velde and Hooijmans et al. Neurology 2021
Slide 25: Stepwise analysis
Stepwise analysis Sensitivity to detect change (standardized response mean) Correlation with baseline function (NSAA, 6MWT, TMRv) Reproducibility 25 Van de Velde and Hooijmans et al. Neurology 2021
Slide 26: Whole thigh FF most sensitive and reproducible
Whole thigh FF most sensitive and reproducible 26 Van de Velde and Hooijmans et al. Neurology 2021
Slide 27: Cognition in BMD
Cognition in BMD y Y. eta Original Article Journal of Child Neurology Voluime 23 Ni 2 cro 19 Minh 2019 | tnt 11 otter 2019 | cr 19 Ox 2019 fae Ss eae . . 0.1 Bonet’ CLINICAL RESEARCH ARTICLE PME Witey Cognitive and Psychological Profile of ON inapicn — samencwaveme hosted at Males With Becker Muscul
Slide 28: Natural history - ongoing studies
Natural history - ongoing studies CINRG US, Canada, UK, Italy GRASP - Defining Endpoints in BMD US, Europe NorthStar Assessment for LGMD (NSAD) MRI ImagingNMD US BIND (Brain Involvement iN Dystrophinopathies) UK, Italy, Spain, Denmark, France, Netherlands 28
Slide 29: Summary
Summary BMD and DMD are both part of a spectrum High clinical variability and slow progression Complex genotype-phenotype correlations Changes in motor function > 12 months Decline in baseline NSAA 10-32 MRI is a promising biomarker Bridging the gap in NH data 29
Slide 30: Targeting Fast Myosin in Becker and Duchenne Muscular Dystrophy
Targeting Fast Myosin in Becker and Duchenne Muscular Dystrophy Sam Collins, MD, PhD Vice President, Clinical Development 30
Slide 31: The Dystroglycan Complex Helps Prevent Injury in Contracting Fibers
The Dystroglycan Complex Helps Prevent Injury in Contracting Fibers Muscle fibers from different motor units contract independently Dystrophin connects contractile proteins to the membrane and surrounding matrix of fibers Long muscle fibers are more dependent upon dystrophin to help support fibers 3
Slide 32: Fast Muscle Fibers Are More Susceptible to Damage in Response to Eccentric Exercise
Fast Muscle Fibers Are More Susceptible to Damage in Response to Eccentric Exercise in Unaffected Individuals More Damage 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 biopsy
Slide 33: Injury Biomarkers Tell the Same Story
Injury Biomarkers Tell the Same Story: Fast but not Slow Fiber Biomarkers are Elevated in Becker and Duchenne Fast Skeletal Muscle Troponin I † Slow Skeletal Muscle Troponin I Creatine Kinase (TNNI2) (TNNI1) ✱✱✱✱ ns ✱✱✱✱ ns ✱✱✱✱ 100000 1000 100 ns ns ns ✱✱✱✱ Fast Troponin I (ng/mL) Slow Troponin (ng
Slide 34: A New Strategy to Rebalance Dystrophic Muscle
A New Strategy to Rebalance Dystrophic Muscle Protecting muscle is predicted to preserve function 34
Slide 35: EDG-5506 Stops Fast Fiber Breakdown in Contracting mdx Muscles
EDG-5506 Stops Fast Fiber Breakdown in Contracting mdx Muscles Dystrophic muscle (mdx mouse) no treatment Dystrophic 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 (
Slide 36: ARCH Open-Label Study Design in Becker Patients
ARCH Open-Label Study Design in Becker Patients • An open-label, single-center study of EDG-5506 to assess the safety and pharmacokinetics of EDG-5506 in adults with Becker • Primary objective: Safety and tolerability at 12 months, now extended to 24 months • Key inclusion criteria − Ambulatory male
Slide 37: Baseline Characteristics: Becker Participants Had Significant Functional Impairment
Baseline Characteristics: Becker Participants Had Significant Functional Impairment and Decreased Muscle Mass Becker Participants Age Normative Characteristic (N=12) Values Unlike clinical trials Age (SD) 32.8 (8.1) years for children with Functional Measures (median) Duchenne, the 10-meter walk/run
Slide 38: EDG-5506 Was Well Tolerated at All Doses
EDG-5506 Was Well Tolerated at All Doses; No Dose Reductions, No Treatment Discontinuations and No SAEs Number of Participants Reporting an AE 10 mg EDG-5506 15 mg EDG-5506 20 mg EDG-5506 Total Treatment Emergent AE 2 months of dosing 4 months of dosing 6 months of dosing 12 months Dizziness 2 (17%)
Slide 39: Muscle Damage in Muscular Dystrophies Leads to Leak of Injury Biomarkers
Muscle Damage in Muscular Dystrophies Leads to Leak of Injury Biomarkers, including CK, TNNI2 and Myoglobin Activity-Induced Muscle Injury in Muscular Dystrophies Contraction induced muscle damage Fast fibers are subsequently injured leading to release of muscle causes excessive degeneration injury
Slide 40: EDG-5506 Led to a Sustained Decrease in Biomarkers of Muscle Damage
EDG-5506 Led to a Sustained Decrease in Biomarkers of Muscle Damage After 12 Months of Dosing 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/L) 30 1,000 -37%
Slide 41: NSAA Shows Stabilization and Trend Toward Improvement
NSAA Shows Stabilization and Trend Toward Improvement – Mean +0.4 Improvement Relative to Predicted -1.2 Point Decline from NHx Individual NSAA Responses at 12 Months – NSAA Change 75% Remained the Same or Improved 10 mg 15 mg 20 mg 3 3 Individual subjects in ARCH 2 2 Change in NSAA Change in NSAA 1
Slide 42: No Decline from Baseline On Meter Time Test Velocity
No Decline from Baseline On 100 Meter Time Test Velocity; No Significant Impact on Grip Strength 100-Meter Timed Test Velocity Maximum Grip Strength 1.5 10 mg 15 mg 20 mg 30 10 mg 15 mg 20 mg 100 Meter Velocity (m/sec) 1.0 20 Strength (Kg) 0.5 10 0.0 0 0 2 4 6 8 12 0 1 2 4 6 8 12 Duration of Treatme
Slide 43: Self-Reported Pain Scores Trended Better after 12 Months
Pain is a Significant Hallmark of Becker and Self-Reported Pain Scores Trended Better after 12 Months with EDG-5506 5 Becker Individuals Report Diffuse Pain, Focus on Spine And Calves Self-Reported Pain Score (0-10) 4 3 • While the ARCH study is not placebo 2 controlled, a positive trend in self- re
Slide 44: Outcomes of the ARCH Study
Outcomes of the ARCH Study Pivotal Dose Safety Biomarkers Function Identified Demonstration of Maximal biomarker rapid, sustained Stabilization of response even at and significant functional 10 mg dose Well-tolerated at all decreases in assessments with doses multiple trends toward PK/PD sup
Slide 45: Putting the Data into Context
Putting the Data into Context Barry Byrne, MD, PhD Director, UF Health Center for Advanced Therapeutics and Powell Gene Therapy Center University of Florida 45
Slide 46: Becker and Duchenne Muscular Dystrophy are Related Dystrophinopathies
Becker and Duchenne Muscular Dystrophy are Related Dystrophinopathies Spectrum Across Dystrophinopathies Functional Dystrophin No Dystrophin Unaffected Levels Becker Duchenne Severe No Pathological Injury Intensity of Muscle Damage The combination of dystrophin functionality and background genetics
Slide 47: NSAA: A Well-Established and Validated Measure of Global Function
NSAA: A Well-Established and Validated Measure of Global Function that is Clinically Meaningful in a Real-World Context • Composite evaluation of motor function across 17 test items with • Each activity scored on whether it can be completed: increasing difficulty − Normally (2 points) − With an adju
Slide 48: What Does a Nominal NSAA Mean to an Individual with Becker?
What Does a Nominal NSAA Mean to an Individual with Becker? • Data: NSAA scores in 39 ambulatory adults enrolled in Edgewise studies —Grouped by baseline scores: ≥30, 20-29, 10-19, <10 • Methods: —At different NSAA scores, what functions are completely lost? —What functions require some degree of co
Slide 49: Natural History: Once Declining, Decrease of ~1.2 NSAA Points/Year
Natural History: Once Declining, Decrease of ~1.2 NSAA Points/Year Group 1 Score: ≥30 Group 2 Score: 20 − 29 Group 3 Score: 10 − 19 Group 4 ~5 years Score: 0 − 9 ~8 years ~8 years 34 30 20 10 0 NSAA Score 49
Slide 50: Group 1: Baseline NSAA 30–34
Compensating % of Patients Loss of Function 100% 20% 40% 60% 80% 0% 3. 1. S S ta ta Can complete all functions Q1 nd nd up 2. 4. W S 11 f ro a Q2 ta . G m lk nd e c 5. o n ts h a t i Q3 S ta on o s r nd e itt i Q11 6. on leg ng C - l i m o n e ri g h Q4 Group 1: Baseline NSAA 30 – 34 8. b b leg t 7.
Slide 51: Group 2: Baseline NSAA 20–29
Group 2: Baseline NSAA 20 – 29 Can complete most functions but need to compensate because of weakness — Reflects progressive loss of muscle, progressive weakness Climb/Descend Rise from Stand on Stand up Box Step Floor Heels Compensating from Chair Hop Loss of Function 10 meter Walk/Run 100% 80% % o
Slide 52: Group 3: Baseline NSAA 10–19
Group 3: Baseline NSAA 11 – 20 Unable to complete most functions and need to compensate for almost all functions — Reflects progressive loss of muscle, progressive weakness Rise from Stand on Stand up Floor Heels from Chair Climb/Descend 10 meter Compensating Jump Walk/Run Hop Box Step Loss of Funct
Slide 53: Group 4: Baseline NSAA 0–9
Compensating % of Patients Loss of Function 100% 20% 40% 60% 80% 0% 3. 1. S S ta ta Q1 nd nd up 2. 4. W S 11 f r a Q2 Stand Walk ta . G om lk 5. nd e c Q3 o n ts h a S t i ta on o s r nd e itt i Q11 6. on leg ng C - Group 4: Baseline NSAA 0 – 9 l i m o n e ri g h Q4 8. b b leg t 7. C ox -l D l i m s
Slide 54: Key Takeaways
Key Takeaways • Becker muscular dystrophy is a serious dystrophinopathy. Once function begins to decline, individuals continue to irreversibly lose muscle and their disease progresses. • Stabilizing function or even reducing the slope of decline is an important goal in Becker muscular dystrophy. 54
Slide 55: Next Steps
Next Steps Joanne Donovan, MD, PhD Chief Medical Officer Edgewise Therapeutics 55
Slide 56: A Pivotal Study in Becker
A Pivotal Study in Becker A global 18-month trial to evaluate the safety and efficacy of EDG-5506 in individuals living with Becker Population: Male, ages 18-50 Visit Schedule Genetic diagnosis of Becker Ambulatory with NSAA 5-32 Study Visits Primary endpoint: (month): NSAA Additional endpoi
Slide 57: Questions?
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Slide 58: United States
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Slide 59: 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 59
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