Aficamten Monotherapy Superior to Metoprolol Monotherapy for Obstructive Hypertrophic Cardiomyopathy
Key findings
- Beta-blockers have long been a first-line treatment for patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM), a practice based largely on expert opinion
- The MAPLE-HCM trial, an international, double-blind, double-dummy, randomized trial, compared monotherapy with aficamten, a next-in-class cardiac myosin inhibitor, and metoprolol monotherapy in patients with symptomatic obstructive HCM
- Aficamten monotherapy was superior to metoprolol monotherapy based on improved peak oxygen uptake after 24 weeks of treatment, the primary endpoint
- Aficamten monotherapy was also associated with significantly greater improvements in symptoms, left ventricular outflow tract gradient, N-terminal pro–B-type natriuretic peptide level, and left atrial volume index
For almost 60 years, beta-blockers have been a first-line treatment for patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM). This practice is based largely on expert opinion, as only a few small, single-center trials have been published in support.
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Aficamten, a next-in-class cardiac myosin inhibitor, has an FDA breakthrough therapy designation for the treatment of obstructive HCM. A new drug application is pending, with a decision expected in December 2025, based on the results of the phase 3 SEQUOIA-HCM trial. Treatment with aficamten for 24 weeks significantly improved exercise capacity compared with placebo.
Cytokinetics, the manufacturer of aficamten, also funded the MAPLE-HCM trial, which compared aficamten monotherapy with metoprolol monotherapy in patients with symptomatic obstructive HCM. Michael A. Fifer, MD, former director and emeritus of the Hypertrophic Cardiomyopathy Program at the Corrigan Minehan Heart Center at Massachusetts General Hospital, and colleagues found that aficamten was superior based on improved peak oxygen uptake after 24 weeks of treatment, the primary endpoint, and five of six secondary measures.
Their report appears in The New England Journal of Medicine.
Methods
The 175 participants in MAPLE-HCM (mean age 58, 58% male, 20% non-white) were enrolled between June 20, 2023, and August 9, 2024, at 71 sites in North America, Brazil, Europe, Israel, and China. They were randomly assigned 1:1 in a double-blind fashion to receive aficamten plus placebo, or metoprolol plus placebo.
76% of participants underwent washout of a beta-blocker, calcium-channel blocker, or both at least 7 days before screening. 30% had a new HCM diagnosis or had not received treatment in the past year.
The starting dose, aficamten 5 mg or metoprolol 50 mg, could be escalated to a maximum dose of 20 mg or 200 mg, respectively. At the end of treatment, 76% of patients treated with aficamten were receiving 15 or 20 mg/day, and 63% treated with metoprolol were receiving 150 or 200 mg/day.
Primary Endpoint
The mean change in peak oxygen uptake by week 24 was 1.1 mL/kg/min in the aficamten group and −1.2 mL/kg/min in the metoprolol group (P<0.001). The treatment effect appeared to be consistent across 12 prespecified subgroups, including patients who had a new diagnosis or had not recently received treatment, those with longstanding HCM, and those with a known pathogenic sarcomere variant.
Secondary Endpoints
Aficamten was significantly superior (P<0.01) to metoprolol on all secondary endpoints except left ventricular mass index.
At week 24:
- Improvement of at least one New York Heart Association (NYHA) functional class level: 51% of the aficamten group vs. 26% of the metoprolol group
- Change on the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS): 15.8 vs. 8.7 points
- Proportional change in N-terminal pro–B-type natriuretic peptide (NT-proBNP) level: 0.3 vs. 1.4 pg/mL
- Change in left ventricular outflow tract gradient after the Valsalva maneuver: −40.7 vs. −3.8 mm Hg
- Change in left atrial volume index: −3.8 vs. 2.8
- Change in left ventricular mass index: −6.9 vs. −3.8
Safety
Adverse events (AE) were similar in the two groups:
- Any serious AE: 8% of the aficamten group and 7% of the metoprolol group
- Any AE leading to early withdrawal of treatment: 1% and 3%
- Any AE leading to temporary treatment interruption: 1% and 1%
- Any AE leading to dose reduction: 1% and 5%
One patient in the aficamten group died suddenly after a brief viral illness. In the metoprolol group, the AEs that required early withdrawal were ischemic stroke, hypotension, and dizziness leading to a fall and fracture.
Preparing for Potential FDA Approval
These results may influence the choice of therapies for patients with symptomatic obstructive HCM. They also give insight into the effects of metoprolol in this population. The beta-blocker did not improve the objective measures of peak oxygen uptake, left ventricular outflow tract gradient, NT-proBNP level, or left atrial volume index, despite improvements in NYHA functional class and KCCQ-CSS.
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