Edgewise reports positive top-line results from Phase II CIRRUS-HCM trial

Edgewise's EDG-7500 Shows Positive Phase II Results in HCM

Edgewise Therapeutics announced positive top-line data from Part D of its 12-week Phase II CIRRUS-HCM trial for EDG-7500, a cardiac sarcomere modulator, in patients with obstructive (oHCM) and non-obstructive (nHCM) hypertrophic cardiomyopathy. The trial demonstrated broad clinical responses across key haemodynamic and biomarker measures. In oHCM patients, significant reductions in left ventricular outflow tract gradient (LVOT-G) were observed, with 90% showing haemodynamic improvement and 74% achieving N-terminal pro-B-type natriuretic peptide (NT-proBNP) normalisation or a 50% drop. nHCM patients saw an average 65% NT-proBNP reduction, with 88% achieving normalisation or a 50% decrease. EDG-7500 was generally well tolerated, with adverse events mostly mild or moderate, and no notable impact on left ventricular ejection fraction.

• Efficacy in Obstructive HCM (oHCM): EDG-7500 demonstrated significant clinical benefits in oHCM patients, including substantial reductions in left ventricular outflow tract gradient (LVOT-G) at rest and after Valsalva. A notable 90% of patients achieved haemodynamic improvement, and approximately 74% either normalised their N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels or experienced at least a 50% reduction from baseline. Patients also showed an average 24-point increase in Kansas City Cardiomyopathy Questionnaire (KCCQ) score and 70% improved by at least one NYHA functional class.
• Efficacy in Non-Obstructive HCM (nHCM): For nHCM patients, EDG-7500 led to an average 65% reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, with 88% achieving normalisation or at least a 50% decrease. This cohort also experienced an average 13-point increase in Kansas City Cardiomyopathy Questionnaire (KCCQ) score, and 64% improved in NYHA functional class. Additionally, early diastolic mitral annular velocity (e’ lateral) increased by 37% and E/e’ improved by 6.1 points in a sub-study.
• Safety Profile and Future Development: The cardiac sarcomere modulator EDG-7500 was generally well tolerated among the cohort, with adverse events predominantly mild or moderate. Crucially, no notable changes in left ventricular ejection fraction (LVEF) were observed, and no cases of LVEF dipping below 50% occurred. Two new instances of atrial fibrillation (3.8%) were reported but not attributed to EDG-7500 by investigators. Based on these positive Phase II data, Edgewise Therapeutics plans to initiate a Phase III clinical program in the fourth quarter of 2026.

The Persistent Challenges in Hypertrophic Cardiomyopathy Management

Despite decades of clinical experience with hypertrophic cardiomyopathy (HCM), effective disease management remains elusive for a substantial proportion of patients. The heterogeneous nature of HCM presentation, combined with the limitations of conventional pharmacotherapy, continues to impose a significant clinical and economic burden on patients and healthcare systems alike.

• Inadequate symptom control with traditional pharmacotherapy: Beta-blockers and non-dihydropyridine calcium channel blockers — the historical cornerstones of HCM management — frequently provide insufficient symptomatic relief and are associated with notable side effects. These agents often fail to meaningfully reduce left ventricular outflow tract (LVOT) gradients, leaving a considerable proportion of patients with persistent functional impairment.

• High cardiovascular event burden despite treatment: Real-world data demonstrate that the majority of patients are already symptomatic at the time of obstructive HCM diagnosis. Following diagnosis, cardiovascular event rates remain markedly elevated, including atrial fibrillation/flutter (IR: 1.421 per person-year), heart failure (IR: 0.895 PPY), and dyspnea (IR: 0.797 PPY) — ranging from 3- to over 60-fold higher than matched controls. Hospitalization (0.454 PPY) and emergency room visit rates (0.611 PPY) further underscore the persistent unmet need despite pharmacotherapy escalation from 61.2% pre-diagnosis to 83.9% post-diagnosis.

• Procedural and surgical risks with invasive options: Septal reduction therapies, including surgical myectomy and alcohol septal ablation, have demonstrated hemodynamic benefit but carry inherent procedural risks, limiting their applicability — particularly in patients with significant comorbidities or those managed at lower-volume centers.

• Inconclusive evidence for dual chamber pacing: Randomized clinical trials, including the PIC and M-PATHY studies, have failed to establish conclusive long-term benefit from dual chamber pacing in hypertrophic obstructive cardiomyopathy (HOCM). The relationship between intraventricular gradient reduction and symptomatic improvement remains controversial, with a potentially significant placebo component. Current guidance mandates careful and selective patient screening before considering this modality.

• Constrained therapeutic window in emerging medical therapies: Novel cardiac myosin inhibitors, while representing a mechanistically targeted advance, are not without limitations. In the ODYSSEY-HCM trial, mavacamten did not achieve statistically significant improvement in co-primary clinical endpoints in non-obstructive HCM at 48 weeks, and treatment was associated with reversible reductions in ejection fraction requiring protocol-mandated dose interruptions — highlighting a narrow therapeutic window that demands rigorous echocardiographic monitoring and titration.

Positive Phase II Results for EDG-7500 in CIRRUS-HCM

The MAPLE-HCM trial (NCT05767346) evaluated aficamten versus metoprolol in a head-to-head, international, double-blind, randomized design enrolling 175 adults with symptomatic obstructive HCM over 24 weeks. Aficamten demonstrated significantly greater improvement in the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) compared with metoprolol (+7.8 points; 95% CI: 3.3–12.3; P < 0.001), with 38.6% of aficamten-treated patients versus 18.4% of metoprolol-treated patients achieving a clinically meaningful ≥20-point improvement (NNT = 4.9). Aficamten also produced a significant improvement in the Seattle Angina Questionnaire Physical Limitation scale (+10.1 points; 95% CI: 3.9–16.2; P = 0.001). The safety profile was acceptable, with no significant increase in treatment-emergent or serious adverse events across the cohort.

The ODYSSEY-HCM trial (NCT05582395) was a phase 3, randomized, double-blind, placebo-controlled study of mavacamten in 580 symptomatic adults with non-obstructive HCM (LVEF ≥60%), representing the largest HCM trial conducted to date. Despite 48 weeks of dose-titrated therapy, mavacamten did not achieve statistically significant improvement in either co-primary endpoint — peak oxygen uptake or KCCQ Clinical Summary Score. However, the drug demonstrated clear pharmacodynamic target engagement, with placebo-corrected reductions in maximal LV wall thickness (−2.1 mm), LV mass index (−3.8 g/m²), E/e′ (−1.3), and left atrial volume index in patients without atrial fibrillation (−2.6 mL/m²; P = 0.009). From a safety standpoint, LVEF reduction below 50% occurred in 21.5% of mavacamten-treated patients versus 1.7% on placebo, though these reductions were reversible upon drug interruption, underscoring a constrained therapeutic window in this non-obstructive cohort.

The EXPLORER-CN trial (NCT05174416) assessed mavacamten versus placebo in Chinese adults with symptomatic obstructive HCM over 30 weeks. Among 58 patients with available cardiac MRI data, mavacamten produced significant structural and functional improvements, including reductions in LV mass index (−30.8 g/m²; 95% CI: −41.5 to −20.1; P < 0.001), maximal LV wall thickness (−3.5 mm; P < 0.001), and maximal left atrial volume index (−18.3 mL/m²; P < 0.001), alongside a nominal reduction in the global mass of late gadolinium enhancement (−2.0 g; P = 0.007), suggesting attenuation of myocardial fibrosis burden. These findings were corroborated by a pooled meta-analysis of six RCTs (n = 1,081) across both mavacamten and aficamten, which demonstrated significant reductions in resting LVOT gradients (−70.22 mmHg), Valsalva LVOT gradients (−61.44 mmHg), NT-proBNP (−69.41 pg/mL), and cardiac troponin I (−42.66 ng/L), alongside a pooled relative risk of 2.21 for at least one NYHA functional class improvement — all with no significant increase in treatment-emergent adverse events, serious adverse events, or atrial fibrillation risk.

EDG-7500's Broad Promise: Differentiating in the HCM Landscape

The recent positive top-line data for EDG-7500 in its Phase II CIRRUS-HCM trial marks a compelling moment in the evolving treatment paradigm for hypertrophic cardiomyopathy (HCM). This cardiac sarcomere modulator demonstrated broad clinical responses across both obstructive (oHCM) and non-obstructive (nHCM) patient populations, a critical distinction in a field where targeted therapies for nHCM are less developed. The observed significant reductions in left ventricular outflow tract gradient (LVOT-G) in oHCM and substantial N-terminal pro-B-type natriuretic peptide (NT-proBNP) reductions in both groups underscore its potential to meaningfully improve cardiac function and patient outcomes.

This development is particularly noteworthy when viewed against the backdrop of existing and emerging HCM therapies. While traditional treatments like beta-blockers and disopyramide offer symptomatic relief, they are not disease-specific. The advent of cardiac myosin inhibitors, such as mavacamten and aficamten, has ushered in a new era of targeted therapy by directly addressing the underlying pathophysiology of sarcomere dysfunction. However, these agents have been associated with reductions in left ventricular ejection fraction (LVEF), necessitating careful monitoring and sometimes leading to treatment interruptions. EDG-7500's reported tolerability and, crucially, its lack of notable impact on LVEF, could provide a significant differentiator, potentially offering a more favorable safety profile for patients.

Looking ahead, the strategic implications are clear: EDG-7500 could carve out a strong position by offering a differentiated safety profile and addressing the unmet needs in nHCM. However, the journey from Phase II to widespread clinical adoption involves navigating several risks. Confirmation of these promising results in larger, longer-duration Phase III trials is paramount to establish sustained efficacy and long-term safety. Furthermore, as with other cardiac sarcomere modulators, potential pharmacokinetic variability or drug-drug interactions will need thorough investigation. Continuous monitoring for LVEF changes, despite initial positive findings, will also be essential to fully understand its long-term safety profile. If these hurdles are successfully cleared, EDG-7500 could significantly reshape the therapeutic landscape for HCM, offering a new, potentially safer, and broadly applicable treatment option.