Edgewise Therapeutics has reported promising top-line results from its Phase 2 CIRRUS-HCM trial evaluating EDG-7500, a novel oral cardiac sarcomere modulator designed specifically for hypertrophic cardiomyopathy (HCM). The four-week study demonstrated significant clinical benefits in both obstructive and nonobstructive forms of the disease, potentially offering advantages over existing treatments.
The multi-part trial assessed EDG-7500's safety and efficacy in 29 participants across two cohorts – 17 with obstructive HCM and 12 with nonobstructive HCM. Patients received once-daily doses of either 50mg or 100mg for four weeks.
Significant Reductions in Cardiac Obstruction
In participants with obstructive HCM, EDG-7500 showed dose-dependent reductions in left ventricular outflow tract gradient (LVOT-G), a key measure of cardiac obstruction. The 100mg dose demonstrated particularly impressive results, with mean reductions from baseline of 71% in resting gradients and 58% in provokable gradients.
Crucially, these improvements occurred without meaningful changes in left ventricular ejection fraction (LVEF), addressing a significant safety concern associated with current myosin inhibitor therapies. No participants experienced LVEF values below 50% at any measurement point during the trial.
Improvements in Heart Failure Biomarkers and Symptoms
Treatment with 100mg EDG-7500 led to a substantial 62% mean reduction in NT-proBNP, an important biomarker of heart failure, in obstructive HCM patients. Similar benefits were observed in nonobstructive HCM, with a 42% mean decrease in NT-proBNP at the 100mg dose.
Patient-reported outcomes also showed marked improvement. The Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) increased by a mean of 23 points in obstructive HCM patients and 17 points in nonobstructive HCM patients at the 100mg dose – substantial improvements in quality of life after just four weeks of treatment.
Functional capacity improvements were equally impressive, with 78% of obstructive HCM participants improving by one NYHA Class, and 67% improving to NYHA Class I, indicating minimal symptoms.
Mechanism of Action Differentiates from Existing Therapies
EDG-7500 represents a novel approach to treating HCM. Unlike cardiac myosin inhibitors such as Bristol Myers Squibb's Camzyos (mavacamten), EDG-7500 is designed as a selective cardiac sarcomere modulator that slows early contraction velocity and addresses impaired cardiac relaxation without significantly impacting systolic function.
"These results suggest EDG-7500 may offer a differentiated profile compared to current myosin inhibitors," said Edgewise in their announcement. "The compound's mechanism appears to provide the benefits of gradient reduction while maintaining cardiac function."
Safety Profile and Adverse Events
The safety profile of EDG-7500 appears generally favorable, with most adverse events reported as mild to moderate. The most common side effects included dizziness, upper respiratory tract infection, and atrial fibrillation.
Two participants experienced serious adverse events of atrial fibrillation requiring cardioversion. The company noted that the rates of atrial fibrillation were comparable to those reported in other Phase 2 clinical trials of cardiac myosin inhibitors for HCM. One participant discontinued treatment due to moderate dizziness.
Addressing an Unmet Need in HCM Treatment
HCM affects approximately 1 in 500 people worldwide and is characterized by thickening of the heart muscle, particularly the left ventricle. The condition can lead to obstruction of blood flow, impaired relaxation of the heart, and in some cases, life-threatening arrhythmias.
Current treatment options for HCM include beta-blockers, calcium channel blockers, and more recently, cardiac myosin inhibitors like Camzyos. However, concerns about ejection fraction reduction with myosin inhibitors have limited their use in some patients.
EDG-7500's ability to reduce obstruction without significantly impacting ejection fraction could potentially address this limitation, offering a valuable treatment option for HCM patients who cannot tolerate or are not ideal candidates for existing therapies.
Next Steps in Development
Following these encouraging Phase 2 results, Edgewise Therapeutics is expected to advance EDG-7500 into larger and longer-duration clinical trials. The company has not yet announced specific timelines for potential Phase 3 studies.
The data from the CIRRUS-HCM trial suggests that EDG-7500 could eventually compete with Bristol Myers Squibb's Camzyos in the HCM treatment landscape, potentially offering a more favorable safety profile while maintaining similar efficacy in reducing cardiac obstruction and improving symptoms.
