Edgewise Therapeutics (EWTX) Study update summary

Historical context and pipeline evolution

• Initial focus was on rare muscle disorders, leading to the development and sale of sevasemten, which provided significant funding for cardiovascular programs.

• Cardiovascular pipeline originated from high-throughput screening, identifying molecules with potent cardiac tissue effects; over 7,000 RLC candidates were screened to find those with positive lusitropic effects and no systolic liabilities.

• The cardiovascular portfolio includes EDG-7500 (HCM), EDG-15400 (HFPEF), and EDG-003 (HF), all in various stages of clinical development.

• EDG-7500 is advancing to phase III by year-end or in the second half of 2026, with additional candidates like EDG-15400 and EDG-003 in earlier stages.

• Regulatory feedback and phase III trial initiation are expected in the near term, with key data readouts planned through 2027.

Mechanism of action and differentiation

• EDG-7500 targets the regulatory light chain (RLC) of myosin, modulating lever arm stiffness and myosin-actin proximity to improve both contraction and relaxation phases.

• Unlike traditional cardiac myosin inhibitors (CMIs), EDG-7500 slows early systolic pressure but preserves ejection fraction by enabling a catch-up in mid-to-late systole and accelerates early diastolic relaxation.

• The compound maintains myosin availability, supporting cardiac reserve and functional capacity during exercise.

• Mechanistic diversity within RLC modulators was highlighted, with EDG-7500 showing a diastolic bias compared to more inhibitory analogs.

• The mechanism is agnostic to baseline RLC phosphorylation and HCM phenotype, supporting broad patient benefit.

Preclinical and clinical findings

• Preclinical studies in pig and rat models demonstrated preserved systolic function, improved diastolic relaxation, and enhanced ventricular compliance.

• Clinical data showed a 37% increase in e' (early diastolic mitral valve movement), reduced LVOT gradients, preserved LVEF, and significant improvements in KCCQ scores.

• Early clinical effects include reductions in NT-proBNP at low doses before gradient relief, suggesting direct diastolic improvement.

• The 12-week Phase 2 CIRRUS-HCM trial showed EDG-7500 was generally safe and well tolerated, with no significant changes in left ventricular ejection fraction.

• Early clinical observations in symptomatic HCM patients were consistent with preclinical findings.