Slide 1: Mechanism of EDG-7500
Mechanism of EDG-7500 September 22, 2026
Slide 2: Forward Looking Statement
Forward Looking Statement This presentation contains forward-looking statements as that term is defined in Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Statements in this presentation that are not purely historical are forward-looking statements.
Slide 3: Agenda Speakers
Agenda Speakers 01 Introduction to Edgewise Therapeutics’ Focused Cardiovascular Pipeline Dr. Kevin Koch 02 Chief Executive Officer EDG-7500 for HCM: Mechanism of Action 03 Near-term Program Milestones Dr. Alan Russell Chief Scientific Officer 04 Q&A Dr. Michael Ayers EDG-7500 Clinical Lead 3
Slide 4: Edgewise: Nine Years, Two Novel Targets and Three Clinical Programs
Edgewise: Nine Years, Two Novel Targets and Three Clinical Programs sevasemten sevasemten Positive P2 Becker P3 fully IND: P2 in P2 in in Becker & enrolled, readout First program sevasemten Becker DMD DMD Q4 2026 targeting muscular SERVIER dystrophies acquires 2017 sevasemten for 2.65B 2020 2021 202
Slide 5: Edgewise Cardiovascular Portfolio
Edgewise Cardiovascular Portfolio Regulatory Preclinical Phase 1 Phase 2 Phase 3 Submission EDG-7500 HCM EDG-15400 HFpEF EDG-003 HF EDG-7500 and EDG-15400, and EDG-003 are investigational therapies that have not been approved by any regulatory authority, and their safety and efficacy have not been e
Slide 6: Executive Summary
Executive Summary • EDG-7500 regulates the cardiac cycle through the Regulatory Light Chain (RLC) • Targeting the RLC results in diverse profiles, from CMI-like negative inotropes to precision modulators • EDG-7500 was selected to spare global systolic function and directly improve lusitropy • Precl
Slide 7: EDG-7500: A Unique Mechanism Leading to Clinical Differentiation in HCM
EDG-7500: A Unique Mechanism Leading to Clinical Differentiation in HCM
Slide 8: Four Questions That Have Defined the EDG-7500 Program
Four Questions That Have Defined the EDG-7500 Program 01 RELIEVING OBSTRUCTION 02 PRESERVING SYSTOLIC FUNCTION How might EDG-7500 reduce LVOT How might EDG-7500 modulate gradients without suppressing hypercontractility without contraction? suppressing LVEF? 03 IMPROVING DIASTOLIC FUNCTION 04 IMPROVI
Slide 9: Current HCM Therapies Leave Significant Unmet Need
Current HCM Therapies Leave Significant Unmet Need HCM is an inherited thickening of the heart muscle disease oHCM nHCM Current therapies relieve LVOT obstruction via negative inotropy LVOT obstruction Any diastolic benefit comes at direct systolic cost Diastolic dysfunction Abbreviations: LVOT, lef
Slide 10: HCM Pathology is Caused by Myosin Overactivation
HCM Pathology is Caused by Myosin Overactivation HEALTHY HCM Sarcomere Sarcomere • Hyperdynamic LVEF, hypertrophy Active myosin heads and obstruction Recruitable myosin heads • Diastolic dysfunction Inhibited myosin heads • Impaired cardiac reserve Abbreviations: HCM, hypertrophic cardiomyopathy; LV
Slide 11: CMIs Uniformly Inhibit Myosin Throughout the Cardiac Cycle
CMIs Uniformly Inhibit Myosin Throughout the Cardiac Cycle Systole The Cardiac Cycle Diastole squeeze / ejection relaxation / filling No recruitable myosin heads is a pseudonormal state Inhibited Active cycling myosin heads Force-generating KEY TAKEAWAY: Diastolic benefit comes at a systolic cost wi
Slide 12: Specific Phases of the Cardiac Cycle Drive Disease in HCM
Specific Phases of the Cardiac Cycle Drive Disease in HCM Systole The Cardiac Cycle Diastole squeeze / ejection relaxation / filling Early Mid Late Early Mid Late Diastolic Gradient Dysfunction in Initiation in Both oHCM and oHCM nHCM Abbreviations: HCM, hypertrophic cardiomyopathy; oHCM, obstructiv
Slide 13: The Ideal Therapeutic Profile Relieves Gradients, Preserves LVEF, Improves Diastolic Function
The Ideal Therapeutic Profile Relieves Gradients, Preserves LVEF, Improves Diastolic Function and Cardiac Reserve Systole The Cardiac Cycle Diastole squeeze / ejection relaxation / filling Early Mid Late Early Mid Late SLOW SPEED Contraction Relaxation Relieve gradient Improve diastolic pressures (o
Slide 14: Myosin Regulatory Light Chain (RLC) Fine-Tunes the Cardiac Cycle
Myosin Regulatory Light Chain (RLC) Fine-Tunes the Cardiac Cycle RLC 1 2 Two main Adjusting the stiffness of the lever arm to modify the Adjusting the position of functions efficiency of force development myosin heads relative to actin of the RLC and relaxation 14
Slide 15: EDG-7500 Alters Both Roles of the RLC to Adjust Contraction
EDG-7500 Alters Both Roles of the RLC to Adjust Contraction RLC 11 2 EDG-7500 EDG-7500 reduces the EDG-7500 moves myosin alters both stiffness of the lever arm heads towards actin functions of • Slowing early contraction, • Speeding of late systolic the RLC speeding relaxation contraction Emter et a
Slide 16: Not all RLC Modulators Behave Like EDG-7500
Not all RLC Modulators Behave Like EDG-7500 EDG-7499 and other RLCs EDG-7500 Spectrum of RLC Modulators CMI-Like Sarcomere Inhibitor1 Modulator • Our discovery process revealed extensive mechanistic diversity across RLC modulators • At the extreme are compounds that act like cardiac myosin inhibitor
Slide 17: EDG-7500 is Inactive When Myosin RLC is Removed
EDG-7500 is Inactive When Myosin RLC is Removed “Native Full-length Myosin” Full-length Myosin Full-length Myosin exchanged with containing RLC and ELC depleted of RLC human ventricle RLC Normalized ATPase Activity (%) Normalized ATPase Activity (%) Normalized ATPase Activity (%) 100 100 100 80 80 8
Slide 18: EDG-7500 Does Not Inhibit Myosin Enzymatic Activity
EDG-7500 Does Not Inhibit Myosin Enzymatic Activity 125 Full Length Myosin Myosin S1 S1 Subunit Subunit (RLC) Normalized ATPase Activity (%) 100 75 50 25 Full Length Myosin 0 0.01 0.1 1 10 100 [EDG-7500], μM Abbreviations: RLC, regulatory light chain
Slide 19: How might EDG-7500 reduce LVOT gradients without suppressing contraction?
How might EDG-7500 reduce LVOT gradients without suppressing contraction? 19
Slide 20: EDG-7500 Slows but Does Not Inactivate Myosin
EDG-7500 Slows but Does Not Inactivate Myosin In Vitro Motility Assay Measures the Sliding Velocity of Fluorescent Actin Filaments Propelled by Surface-Bound Myosin DMSO EDG-7500 CMI 1.25 EDG-7500 CMI Velocity Relative to DMSO 1.00 0.75 0.50 0.25 0.00 0.1 1 10 100 Compund (μ M) Video playback is at
Slide 21: EDG-7500 Slows Early Force Development
EDG-7500 Slows Early Force Development Rate of Force Development (Systole) 120 100 Activation Normalized Force (%Fmax) kACT Normalized (%Max) 100 80 80 60 60 40 40 Slower force development 20 20 0 0 0 50 100 0.01 0.1 1 10 100 1000 Time (s) EDG-7500 Concentration (µM) Abbreviations: kACT, normalized
Slide 22: EDG-7500 Slows Myosin Preferentially During Early Systole
EDG-7500 Slows Myosin Preferentially During Early Systole 100 Normalized ATPase Activity (%) 80 Big shift in inhibitory activity between high calcium (top) and 60 low calcium (bottom) EDG-7500 pCa 5.75 EDG-7500 pCa 7.0 40 0.01 0.1 1 10 100 [EDG-7500] (μM) Abbreviations: pCa, negative logarithm of th
Slide 23: EDG-7500 Administration Slowed Early Systolic Pressure in HCM
EDG-7500 Administration Slowed Early Systolic Pressure in HCM Systole The Cardiac Cycle Diastole squeeze / ejection relaxation / filling Early Mid Late Early Mid Late SLOW Contraction Pre-ET +17.3% Relieve Gradient (oHCM)1 1. Sherrid MV. Curr Cardiol Rev 2016; 12: 52-65 Abbreviations: oHCM, obstruc
Slide 24: How might EDG-7500 modulate hypercontractility without suppressing LVEF?
How might EDG-7500 modulate hypercontractility without suppressing LVEF? 24
Slide 25: EDG-7500 Alters Both Roles of the RLC to Adjust Contraction
EDG-7500 Alters Both Roles of the RLC to Adjust Contraction RLC 11 2 EDG-7500 EDG-7500 reduces the EDG-7500 moves myosin alters both stiffness of the lever arm heads towards actin functions of • Slowing early contraction, • Speeding of late systolic the RLC speeding relaxation contraction Abbreviati
Slide 26: EDG-7500 Shifts Myosin Closer to Actin
EDG-7500 Shifts Myosin Closer to Actin 0.5 Sarcomere Rest (higher number close to actin) 0.4 Myosin Head Movement 0.3 I1,1/I1,0 Sarcomere Rest + EDG-7500 0.2 0.1 0.0 Control Sarcomere EDG-7500 Sarcomere Active myosin heads Recruitable myosin heads Inhibited myosin heads Rest Rest+EDG-7500 WT Control
Slide 27: In Late Systole, EDG-7500 Speeds Force Development
In Late Systole, EDG-7500 Speeds Force Development Fiber bundle 125 fully activated Fiber bundle fully activated 100 Tension (%Max) Tension redevelopment accelerates with EDG-7500 Rapidly shorten myosin heads disengage 50 Rapidly lengthen Fiber rapidly shortened then DMSO myosin heads re- re-lengthe
Slide 28: Clinically, EDG-7500 Has Not Affected LVEF
Clinically, EDG-7500 Has Not Affected LVEF Systole The Cardiac Cycle Diastole Early Mid Late Early Mid Late EDG-7500 SLOWS SPEEDS Healthy volunteers received doses of placebo or 5-300 mg in the SAD and placebo or 25-100 mg in the MAD CIRRUS Part A participants received single doses of 50 mg, 100 mg
Slide 29: How might EDG-7500 improve relaxation?
How might EDG-7500 improve relaxation? 29
Slide 30: EDG-7500 Preferentially Speeds Relaxation in Cardiac Fibers
EDG-7500 Preferentially Speeds Relaxation in Cardiac Fibers 120 120 kREL(fast) Normalized (%Max) Normalized Force (%Fmax) 100 115 80 110 Rate of Relaxation Faster 60 relaxation 105 (Diastolic) 40 100 20 0 95 52 54 56 58 0.01 0.1 1 10 100 1000 Time (s) EDG-7500 Concentration (µM) EDG-7500 4X more pot
Slide 31: EDG-7500 Improves Left Ventricular Relaxation Without Systolic Cost in Pig Model of nHCM
EDG-7500 Improves Left Ventricular Relaxation Without Systolic Cost in Pig Model of nHCM LVEF LVEDP EDPVR End Diastolic Pressure-Volume Realtionship 80 45 6 LV End Diastolic Pressure (mmHg) 70 40 5 Ejection Fraction (%) 60 35 30 4 50 (mmHg/mL) 25 40 3 20 30 15 2 20 10 1 10 5 0 0 0 WT Control R403Q +
Slide 32: Administration of EDG-7500 Led to Increases in e' Lateral Suggesting Positive Lusitropic Effects
Administration of EDG-7500 Led to Increases in e’ Lateral Suggesting Positive Lusitropic Effects oHCM / nHCM: Rapid Improvements in Mean e’ Lateral Observed (means ±SE) oHCM ~20% Improvement in e’ lateral nHCM ~37% Improvement in e’ lateral 30 50 25 40 % Change from Baseline % Change from Baseline 2
Slide 33: Lusitropic Benefits Observed Even at Lower Exposures
Lusitropic Benefits Observed Even at Lower Exposures CIRRUS-HCM Part B (oHCM) - Low Dose (25mg) Cohort 40 NT-proBNP LVOT-G (rest) 20 % Change from Baseline 0 -20 Early Diastolic -28% -40 Improvements Peak Gradient -41% Effects -60 Day 1 Wk1 Wk2 Study Visit Abbreviations: oHCM, obstructive hypertroph
Slide 34: Why might EDG-7500 translate into meaningful improvements in symptoms and functional capacity?
Why might EDG-7500 translate into meaningful improvements in symptoms and functional capacity? 34
Slide 35: With Exercise, Cardiac Output Increases
With Exercise, Cardiac Output Increases Exercise Increased Demand Normal Cardiac Reserve Requires: Heart Rate Contractility/Stroke Volume Increased Output Resting Output with Exercise KEY TAKEAWAY: Preservation of recruitable myosin pool is central to maintaining a normal cardiac reserve 35
Slide 36: Increasing Cardiac Output Relies Heavily on Myosin Availability
Increasing Cardiac Output Relies Heavily on Myosin Availability Rapid Re-Engagement During Exercise Reduced Ability to Engage EDG-7500 in HCM Models CMI in HCM1 Active myosin heads Recruitable myosin heads Inhibited myosin heads 1Anderson RL, et. al., PNAS, 2018 Abbreviations: HCM, hypertrophic card
Slide 37: EDG-7500 Restores Cardiac Reserve in Two Animal Models
EDG-7500 Restores Cardiac Reserve in Two Animal Models Normal Rat nHCM Pig (MYH7R403Q) 70 Control 30.0 10.0 EDG-7500 60 Fractional Shortening (%) CMI ΔStroke Volume (mL) 27.5 7.5 Stroke Volume (mL) 50 5.0 40 25.0 30 2.5 -40% 22.5 20 0.0 20.0 10 -2.5 WT Control R403Q R403Q 0 Baseline Dobutamine Place
Slide 38: With Administration of EDG-7500, KCCQ Improvements are Consistent with Increased Cardiac Reserve
With Administration of EDG-7500, KCCQ Improvements are Consistent with Increased Cardiac Reserve oHCM: Mean KCCQ-OSS (N=20) nHCM: Mean KCCQ-OSS (N=33) 90 80 75 80 +24 KCCQ-OSS KCCQ-OSS 70 70 Improvement at +13 Week 12 vs baseline 65 60 Improvement at 60 Week 12 vs baseline 50 55 Baseline Wk4 Wk8 Wk1
Slide 39: EDG-7500's Unique MoA Consistent with Observations in Clinic
EDG-7500’s Unique MoA Consistent with Observations in Clinic EDG-7500 Mechanistic Translatability Clinical Observations 01 RELIEVING OBSTRUCTION • Slowed rate of contraction (fiber bundles) • Slowing rate of pressure development DECREASES in LVOT-G (rest and Valsalva) 02 PRESERVING SYSTOLIC FUNCTION
Slide 40: A New Era of Direct Positive Lusitropes at Edgewise
A New Era of Direct Positive Lusitropes at Edgewise 2026 - Future 2015 - 2025 Direct Lusitropic Agents 1982 Indirect ● The world’s first direct lusitropic agents ● Selective SERCA 1897 activators showed Lusitropy some lusitropic action ● EDG-7500, EDG-15400 but yielded no ● Directly improving the pr
Slide 41: Edgewise Pipeline is Rich in Anticipated Near-Term, Value-Creating Catalysts
Edgewise Pipeline is Rich in Anticipated Near-Term, Value-Creating Catalysts H2 2026 H1 2027 H2 2027 EOP2 FDA Feedback; EDG-7500 48-Week Phase 3 Design OL oHCM & nHCM Data HCM EDG-7500 P3 Initiation oHCM & nHCM Cardiac EDG-15400 P2 Initiation EDG-15400 P2 Data HFpEF in HFpEF in HFpEF EDG-003 HF Cand
Slide 42: = Edgewise
= Edgewise <L & O