Edgewise Therapeutics (EWTX) Study Update summary

Background and Rationale

• EDG-7500 is a novel oral cardiac sarcomere modulator developed to treat both obstructive and non-obstructive hypertrophic cardiomyopathy (HCM) and other diastolic dysfunction diseases, aiming to avoid ejection fraction reduction seen with cardiac myosin inhibitors.

• HCM is a prevalent genetic cardiovascular disease affecting 1 in 500 people, with up to 85% undiagnosed, significant morbidity, and limited current treatment options.

• Existing therapies, including cardiac myosin inhibitors, have efficacy and safety limitations, often requiring intensive monitoring due to risk of reduced ejection fraction and heart failure.

Preclinical and Phase 1 Results

• Preclinical models showed EDG-7500 reduced cardiac outflow gradients and improved diastolic relaxation without affecting ejection fraction.

• Phase 1 SAD/MAD studies enrolled 72 healthy subjects, testing doses from 5 to 300 mg, with no serious adverse events and no LVEF drop below 50%.

• Pharmacokinetics showed a half-life of ~30 hours, linear and dose-proportional exposure, and steady state in ~4 days, supporting once-daily dosing.

• No correlation between EDG-7500 plasma levels and LVEF reduction, supporting a differentiated safety profile.

Phase 2 CIRRUS-HCM Part A (Single Dose in oHCM)

• Eleven obstructive HCM patients received a single dose (50, 100, or 200 mg); seven met efficacy criteria.

• EDG-7500 was well tolerated, with no LVEF drop below 50% and only mild, unrelated adverse events.

• Resting LVOT gradient was reduced by 67% and Valsalva LVOT gradient by 55% in the 100/200 mg cohorts, with several patients achieving clinically significant gradient relief.

• NT-proBNP, a heart failure biomarker, was robustly reduced (mean 31% at 100 mg, 64% at 200 mg), indicating improved diastolic function.

• No correlation between drug concentration and LVEF change; all LVEF changes within normal measurement variability.