Edgewise Therapeutics (EWTX) Study Update summary

Study background and rationale

• EDG-7500 is a novel oral cardiac sarcomere modulator developed to treat hypertrophic cardiomyopathy (HCM) and other diastolic dysfunction diseases, aiming to address both obstructive and non-obstructive forms.

• The molecule was engineered to modulate actin-myosin cross-bridge interactions, improving diastolic function without reducing ejection fraction.

• HCM affects 1 in 500 people, with up to 85% undiagnosed; current therapies have efficacy and safety limitations, especially for non-obstructive HCM.

• Existing treatments, including cardiac myosin inhibitors, often require intensive monitoring due to risk of reduced ejection fraction and heart failure.

• The CIRRUS-HCM trial was designed to assess safety, tolerability, pharmacokinetics, and pharmacodynamics in HCM patients.

Preclinical and phase 1 results

• Preclinical studies showed EDG-7500 reduces LVOT gradient and improves diastolic function without significant reduction in systolic performance.

• Phase 1 in healthy volunteers (n=72) demonstrated EDG-7500 was well tolerated across single and multiple ascending doses (5–300 mg), with no serious adverse events or significant changes in vital signs, labs, or ECGs.

• No subjects experienced LVEF <50% at any dose; pharmacokinetics supported once-daily dosing with a mean half-life of ~30 hours and steady state achieved in ~4 days.

• Unlike other cardiac myosin inhibitors, EDG-7500 did not cause dose-dependent reductions in LVEF.

• Adverse event rates were low and similar between placebo and active groups; all events were mild except one moderate ECG tab site irritation.

Phase 2 CIRRUS-HCM Part A (single dose in oHCM)

• In CIRRUS-HCM Part A, 11 obstructive HCM patients received a single dose (50, 100, or 200 mg) of EDG-7500; 7 met efficacy criteria.

• EDG-7500 was well tolerated with no LVEF <50% or drug-related serious adverse events; adverse events were mild and unrelated.

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

• No correlation between plasma concentration and LVEF change; NT-proBNP, a marker of diastolic function, decreased dose-dependently by up to 64% at 200 mg.

• 60% of patients receiving 100 or 200 mg achieved resting LVOT-G <30 mmHg and provokable LVOT-G <50 mmHg.