Key result
EDG-7500 normalizes LV filling pressure and prevents cardiac remodeling while preserving systolic function in preclinical HCM.
Why the study?
Small molecules modulating myosin ATPase via the regulatory light chain show diverse effects on relaxation and contraction, and the diastolic-selective profile of EDG-7500 and its therapeutic potential in HCM require characterization.
Absolute Event Rate: 52% vs 57%
EDG-7500 is a novel diastolic-selective cardiac sarcomere modulator that improves ventricular relaxation and prevents remodeling without balancing systolic impairment in preclinical models of hypertrophic cardiomyopathy.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“cardiac myosin inhibitors such as Camzyos and aficamten may be on-off switches for myosin, while EDG-7500, which is a cardiac sarcomere modulator, is more about controlling the rate of interaction. With the company's more controlled approach, there may be fewer side effects”
“It is a complex condition, with a highly variable presentation, from both a clinical and a genetic standpoint. The phenotypes range from [asymptomatic] carriers of a pathogenic, or likely pathogenic, DNA variant without any hypertrophy, to extreme left ventricular hypertrophy, and patients presenting primarily with heart failure. So that's the big challenge: it's one disease with one name, but it comes with many different faces.”
“We know of mavacamten and aficamten, there is also MYK-224 from Bristol Myers Squibb and then there is also a cardiac myosin inhibitor or modulator that EdgeWise Therapeutics is working on.”
Hypothesis-generating for diastolic-selective HCM therapy; leaves open translation from swine models to clinical trials.
Small molecules that modulate myofibril ATPase activity via the myosin regulatory light chain (RLC) display a broad spectrum of activity in their ability to enhance relaxation and slow contraction. EDG-7500 exhibits features consistent with a 'diastolic-selective' cardiac sarcomere modulator (d-CSM), and its ability to treat HCM was explored in engineered human tissue (EHT), human HCM cardiac strips, and an R403Q mutation swine model. In fibers, EDG-7500 preferentially inhibited myofibril ATPase activity and force at diastolic calcium levels, retained length-dependent force activation, accelerated relaxation, and exhibited a shallow, self-limiting inhibitory-exposure response to LV fractional shortening. Compared to CMIs, EDG-7500 moved myosin heads towards the thin filament and accelerated relaxation without decreasing force in mutated EHTs (R403Q). In human HCM cardiac strips, EDG-7500 did not alter myosin SRX state, but decreased Ca2+-sensitivity of force independent of mutation. In R403Q swine, chronic EDG-7500 normalized LV filling pressure and prevented pathological cardiac remodeling while preserving normal systolic function and cardiac reserve. EDG-7500 differentiates itself from CMIs by uniquely targeting both phases of the cardiac cycle, improving ventricular relaxation while preserving systolic function. This suggests optimal diastolic efficacy can be reached without balancing systolic impairment.
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Emter et al. (2026) studied Hypertrophic cardiomyopathy (MYH7 R403Q mutation model) (n=31). EDG-7500 vs. Placebo was evaluated on Diastolic filling time as a percentage of the cardiac cycle. In a preclinical swine model of hypertrophic cardiomyopathy, chronic EDG-7500 normalized left ventricular filling pressure and prevented pathological cardiac remodeling while preserving normal systolic function.
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