Slide 1: Targeting the Mechanism of Hypertrophic Cardiomyopathy
Targeting the Mechanism of Hypertrophic Cardiomyopathy Session: Progress in Designing Hypertrophic Cardiomyopathy Trials Marc J. Semigran MD Chief Development Officer Edgewise Therapeutics
Slide 2: Disclosure & Disclaimer
Disclosure & Disclaimer Dr. Semigran is a full-time employee of Edgewise Therapeutics 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 historica
Slide 3: Advancing EDG-7500, a First-In-Class Sarcomere Modulator for HCM
Advancing EDG-7500, a First-In-Class Sarcomere Modulator for Hypertrophic Cardiomyopathy (HCM) • Edgewise Therapeutics' robust discovery platform is yielding novel compounds targeting important unmet needs of patients suffering from disorders of cardiac and skeletal muscle. • EDG-7500 is first-in-cl
Slide 4: LVOT Obstruction Results from Abnormalities in Early Systolic Blood Flow & Mitral Structure
LVOT Obstruction Results from Abnormalities in Early Systolic Blood Flow & Mitral Structure Normal Flow in Healthy Individuals Systolic Anterior Motion in HCM AO LA LV Adapted from Ro R, et al. J Am Coll Cardiol. 2014;64:1984-1995
Slide 5: Systolic Function: EDG-7500 Reduces +dP/dtmax and Prolongs Pre Ejection Period in Healthy Canines
Systolic Function: EDG-7500 Reduces +dP/dtmax during Isovolumic Contraction and Prolongs Pre Ejection Period in Healthy Canines; Stroke Volume is Preserved ✱✱ 10 PRE 2,100 EDG-7500 (0.3 mg/kg) ✱ STROKE VOLUME Pre Ejection Period (% cycle) 1,800 dP/dtmax (mmHg/s) 8 LVP (mmHg) 1,500 6 -8% +9% 1,200 90
Slide 6: Diastolic Function: EDG-7500 Increases Left Ventricular Compliance in Healthy Canines
Diastolic Function: EDG-7500 Increases Left Ventricular Compliance in Healthy Canines End Diastolic Pressure (mmHg) End Diastolc Volume (RVU) 25 ns 12 PRE EDG-7500 ✱✱ 20 8 LVP (mmHg) 15 +7% 4 -10% 10 0 LVV (RVU) PRE POST PRE POST ** p < 0.01 N=4 0.3 mg/kg 0.3 mg/kg Measurements made after iv EDG-750
Slide 7: EDG-7500 Relieves LVOT Gradient Without Changing Fractional Shortening in Cats with Genetic oHCM
EDG-7500 Relieves LVOT Gradient Without Changing Fractional Shortening in Cats with Genetic oHCM ✱ 80 20 ns -2% PGLVOT (mmHg) A31P MyBP-C Mutation Cat LV FS (%) 60 Model of oHCM (n=6). 15 Measurements made after Clinically significant 40 single fixed dose oral EDG- 10 pressure gradient in cats 7500
Slide 8: Abnormal LV Relaxation, Filling Pressure, & Diastolic Compliance Acutely Improve with EDG-7500
Abnormal LV Relaxation, Filling Pressure, & Diastolic Compliance Acutely Improve with EDG-7500 MYH7 R403Q Minipig Genetic Model of nHCM (n=6) ✱✱ PRE EDG 40 ✱✱ 0 60 8 ✱ dP/dtmin (mmHg/s) Eed (mmHg/mL) EDP (mmHg) 30 6 tau (ms) -500 40 20 4 -1000 20 10 2 WT -1500 0 0 0 * PRE EDG PRE EDG PRE EDG R403Q R
Slide 9: Summary
Summary • Knowledge of muscle biology and the pathophysiologic mechanisms of HCM has informed design of a small molecule that directly targets both early-systolic and diastolic myocardial function with modest effects on overall systolic performance as measured by ejection-phase indices. • EDG-7500 h