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EDG-7500 was well-tolerated in healthy patients in Phase 1 while achieving gradient relief without LVEF reductions in the Phase 2 CIRRUS-HCM trial.
EDG-7500 appeared tolerable and effective in new topline data from a Phase 1 trial in healthy subjects and the single-dose arm of the Phase 2 CIRRUS-HCM trial in patients with obstructive hypertrophic cardiomyopathy (HCM).1
Announced by Edgewise Therapeutics on September 19, 2024, EDG-7500 is a novel oral, selective, cardiac sarcomere modulator designed to reduce early contraction velocity and address impaired cardiac relaxation correlated with HCM.
In this data release, EDG-7500 remained well-tolerated without meaningful change in left ventricular ejection fraction (LVEF) in the Phase 1 population while showing notable left ventricular outflow tract (LVOT) gradient reductions without meaningful change in LVEF in topline data from CIRRUS-HCM.
“We believe our innovative approach, where we have observed gradient relief without reductions in LVEF, has the potential to be a valuable advancement in the treatment of obstructive HCM,” said Kevin Koch, PhD, president and chief executive officer at Edgewise.1
The placebo-controlled Phase 1 single ascending dose (SAD) trial enrolled 48 healthy subjects, who received single doses of EDG-7500, ranging from 5 to 300 mg.2 In the multiple ascending dose (MAD) trial arm, 24 healthy patients received 25 to 100 mg EDG-7500 doses once daily for 14 days. Across both the dose arms, EDG-7500 demonstrated tolerability, without clinically meaningful trends in vital signs, clinical chemistry, hematology, or electrocardiograms.1
These data showed no meaningful trend in LVEF for all patients across a range of EDG-7500 exposures. In MAD, a half-life of nearly 30 hours was identified, with steady state achieved approximately 4 days after the start of daily dosing. Dose proportional increases in exposure were observed across the SAD and MAD trials.
CIRRUS-HCM is a three-part, multi-center, open-label Phase 2 trial enrolling approximately 55 patients with HCM at nearly 20 clinical sites in the US.3 Its primary objective in Part A was to measure the safety and tolerability of a single oral dose of EDG-7500—Parts B and C are planned to assess multiple doses over 28 days in patients with obstructive or non-obstructive HCM.
In Part A, patients with obstructive HCM received a single dose of 50, 100, or 200 mg of EDG-7500. In patients receiving the 100 and 200 mg EDG-7500 doses, a 67% mean reduction in resting LVOT-G and a 55% mean reduction in provokable (Valsalva) LVOT-G were identified, respectively.1
Further analysis revealed LVOT gradients <30 mmHg at rest and <50 mmgHg with Valsalva were seen in 60% of patients receiving 100 or 200 mg EDG-7500. Gradient reductions were achieved without a meaningful change in LVEF, according to Edgewise.
Notably, a single dose of EDG-7500 displayed a 64% reduction in NT-proBNP, an important marker of heart failure, in the 200 mg cohort. Edgewise indicated this reduction showed the potential for this novel mechanism to treat diastolic dysfunction, including non-obstructive HCM.
Both the Phase 1 and CIRRUS-HCM trials demonstrated no LVEF reduction to below 50% across a wide range of exposure to EDG-7500.
“There continues to be an unmet need for patients with obstructive and non-obstructive HCM and we are excited to be part of the ongoing CIRRUS-HCM trial evaluating a novel treatment,” said investigator Anjali T. Owens, MD, medical director, the Center for Inherited Cardiac Disease and associate professor of medicine at the University of Pennsylvania.1
In the release, Edgewise announced their expectations to report initial 28-day data in the first quarter of 2025.
“Based on the strength of clinical and preclinical data-to-date, we have initiated the 28-day part of CIRRUS-HCM in patients with obstructive and non-obstructive HCM,” said Marc Semigran, MD, chief development officer at Edgewise.1 “Importantly, we plan to continue the evaluation of tolerability, pharmacokinetics, and effects on LVOT-G, LVEF, biomarkers, and measures of feel and function in these patients.”
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