EDG-7500 Achieves Positive Phase 2 Results in Obstructive HCM

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.”

References

1. _{Edgewise therapeutics announces positive top-line data from phase 1 trial in healthy subjects and phase 2 cirrus-HCM trial in patients with obstructive hypertrophic cardiomyopathy (HCM). Edgewise Therapeutics. September 19, 2024. Accessed September 19, 2024. https://investors.edgewisetx.com/news/news-details/2024/Edgewise-Therapeutics-Announces-Positive-Top-Line-Data-from-Phase-1-Trial-in-Healthy-Subjects-and-Phase-2-CIRRUS-HCM-Trial-in-Patients-with-Obstructive-Hypertrophic-Cardiomyopathy-HCM/}
2. _{A Study of EDG-7500 in Healthy Adults. Clinicaltrials.gov. July 16, 2024. Accessed September 19, 2024. https://clinicaltrials.gov/study/NCT06011317.}
3. _{A Study of EDG-7500 in Adults with Hypertrophic Cardiomyopathy (CIRRUS-HCM). Clinicaltrials.gov. September 19, 2024. Accessed September 19, 2024. https://clinicaltrials.gov/study/NCT06347159.}