Aficamten Beats Metoprolol on Exercise Capacity in Phase 3 Head-to-Head Trial for Obstructive HCM

In 175 patients randomized over 24 weeks, the FDA-approved cardiac myosin inhibitor aficamten (Myqorzo) improved peak oxygen uptake by 1.1 mL/kg/min while metoprolol reduced it by 1.2 mL/kg/min — a 2.3 mL/kg/min treatment difference that drove superiority across five of six pre-specified secondary endpoints; left ventricular mass index did not differ significantly.

A Phase 3 head-to-head trial has found that aficamten (Myqorzo), an oral selective cardiac myosin inhibitor, outperformed the beta-blocker metoprolol on exercise capacity, symptoms, and hemodynamics in adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Primary results from the MAPLE-HCM trial (NCT05767346), sponsored by Cytokinetics, were presented at the European Society of Cardiology Congress in Madrid on August 30, 2025, and simultaneously published in The New England Journal of Medicine (DOI: 10.1056/NEJMoa2504654). Results were posted to ClinicalTrials.gov this week.

Trial Design

MAPLE-HCM enrolled 175 adults with symptomatic oHCM who had a resting left ventricular outflow tract (LVOT) gradient ≥30 mm Hg or a Valsalva-provoked gradient ≥50 mm Hg. Participants were randomized 1:1 — 88 to aficamten and 87 to metoprolol — as monotherapy for 24 weeks in a double-blind, active-comparator design. The primary endpoint was change in peak oxygen uptake (peak VO₂) from baseline to week 24, measured by cardiopulmonary exercise testing.

Primary Endpoint

At 24 weeks, aficamten-treated patients gained a mean of +1.1 mL/kg/min in peak VO₂ (95% CI, 0.5 to 1.7), while the metoprolol group experienced a mean decline of −1.2 mL/kg/min (95% CI, −1.7 to −0.8). The least-squares mean between-group difference was 2.3 mL/kg/min (95% CI, 1.5 to 3.1; P < 0.001), establishing aficamten’s superiority on the primary endpoint.

“Aficamten — as monotherapy and as first-line therapy — demonstrated greater improvements in exercise capacity and symptoms than beta-blockers.” — Dr. Pablo García-Pavia, MAPLE-HCM principal investigator, ESC Congress 2025

Secondary Endpoints and Biomarkers

Aficamten achieved superiority across five of six pre-specified secondary endpoints. NYHA functional class improved by one or more grades in 51% of aficamten patients versus 26% in the metoprolol group (P < 0.001). The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) improved by a least-squares mean difference of 6.9 points in favor of aficamten (P < 0.01). Resting LVOT gradient fell by −30 mm Hg (P < 0.0001) and Valsalva LVOT gradient by −35 mm Hg (P < 0.0001). NT-proBNP declined 73% from baseline in the aficamten group while rising 42% in the metoprolol group, a treatment-effect difference of −81% (P < 0.001). Left atrial volume index improved by 7.0 mL/m² (P < 0.0001) with aficamten. Left ventricular mass index — the sixth pre-specified secondary endpoint — did not differ significantly between treatment groups.

Safety

Overall rates of treatment-emergent adverse events were similar: 73.9% in the aficamten group and 75.9% in the metoprolol group. Serious adverse events occurred in 8% versus 7%. Dose down-titration was required in 4 aficamten patients (4.5%) versus 26 metoprolol patients (29.9%). The primary protocol-specified trigger for aficamten dose reduction was LVEF falling below 50%; the specific reasons for each of the four reductions were not fully detailed in available sources at time of publication.

Aficamten carries a boxed warning for heart failure due to systolic dysfunction. In the United States, the drug is dispensed exclusively through the MYQORZO REMS program, which requires prescriber certification and echocardiographic monitoring before and during treatment. Patients cannot obtain aficamten outside this program; those interested in treatment should speak with a cardiologist who can evaluate whether the drug is appropriate and initiate REMS enrollment.

Correction, June 10, 2026: The original dek and body of this article stated that aficamten achieved superiority across “every” (dek) and “all key” (body) pre-specified secondary endpoints. Post-publication fact-check confirmed via the NEJM primary paper (DOI: 10.1056/NEJMoa2504654) that left ventricular mass index — a pre-specified secondary endpoint — did not differ significantly between the aficamten and metoprolol groups. Both the dek and the secondary-endpoints paragraph have been updated to reflect the accurate result: superiority across five of six pre-specified secondary endpoints.

Regulatory Context

The FDA approved aficamten (Myqorzo) on December 19, 2025, for adults with symptomatic oHCM to improve functional capacity and symptoms. Aficamten is an approved medicine, not an investigational drug. The EMA’s CHMP issued a positive opinion recommending EU marketing authorization on December 12, 2025; the European Commission’s formal marketing authorization followed in February 2026. MAPLE-HCM, alongside the earlier SEQUOIA-HCM trial, was central to both regulatory submissions.

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