The ODYSSEY-HCM and MAPLE-HCM studies: the role of cardiac myosin inhibitors in hypertrophic cardiomyopathy (obstructive and non-obstructive)

Abstract

Hypertrophic cardiomyopathy (HCM) is an inherited heart disease characterized by unexplained left ventricular hypertrophy with or without outflow tract obstruction. Conventional therapies may relieve symptoms associated with left ventricular outflow tract (LVOT) obstruction; however, they do not act directly on the contractile cell, and refractory patients may require septal reduction therapy. Allosteric cardiac myosin inhibitors (CMIs) represent a novel therapeutic approach directly targeting sarcomeric hypercontractility. Mavacamten and aficamten have demonstrated significant clinical and haemodynamic benefits in obstructive HCM (oHCM). The MAPLE-HCM trial revealed that aficamten significantly improved peak oxygen uptake, NYHA functional class, quality of life, and reduced LVOT gradients compared with metoprolol, with a favourable safety profile. Encouraged by these findings, CMIs have been investigated in non-obstructive HCM (nHCM). The ODYSSEY-HCM trial evaluated mavacamten in patients with symptomatic nHCM. While the primary endpoints of exercise capacity and patient-reported health status were not met, secondary analyses showed favourable effects on NT-proBNP, high-sensitivity troponin I, left ventricular diastolic function, and hypertrophy parameters. In conclusion, CMIs offer substantial benefits in oHCM, improving symptoms and cardiac haemodynamics. In nHCM, despite limited impact on functional capacity, CMIs demonstrate biological activity and favourable cardiac remodelling, supporting further research into their potential role in modulating disease pathophysiology.

Hypertrophic cardiomyopathy (HCM) is a common inherited myocardial disease that affects roughly 1 in 200 to 500 adults, characterized by left ventricular (LV) hypertrophy that is unexplained by other causes and hyperdynamic systolic function with or without dynamic LV outflow tract (LVOT) obstruction.^1,2

Patients affected by hypertrophic cardiomyopathy (HCM) may experience symptoms such as shortness of breath on exertion, chest discomfort, or episodes of syncope. They also have an elevated risk of developing atrial fibrillation (AF), heart failure, and sudden cardiac death. Conventional treatments—such as β-blockers, non-dihydropyridine calcium channel blockers, and disopyramide—help to relieve symptoms associated with LVOT gradient, mainly by lowering heart rate or myocardial contractility; however, these therapies do not reverse left ventricular hypertrophy nor modify the underlying course of the disease. Patients still symptomatic despite medical therapy may require septal reduction therapy (SRT) via surgical myectomy or alcohol septal ablation.^3,4

The emergence of allosteric cardiac myosin inhibitors (CMIs) marks a significant therapeutic advancement, specifically addressing the hypercontractility that underlies the pathophysiology of hypertrophic cardiomyopathy (HCM). Mavacamten became the first CMI approved in 2022 for the treatment of adults with symptomatic obstructive HCM (oHCM), followed by ongoing clinical evaluation of a second compound, aficamten. CMIs act directly on the cardiac sarcomere, diminishing excessive actin–myosin cross-bridge interactions, thereby alleviating hypercontractility, lowering left ventricular outflow tract (LVOT) pressure gradients, and enhancing diastolic performance.

Early clinical investigations showed that treatment with CMIs led to marked improvements in both symptoms and haemodynamic parameters in patients with obstructive HCM (oHCM).⁵

The MAPLE-HCM trial (Aficamten or Metoprolol Monotherapy for Obstructive Hypertrophic Cardiomyopathy) was a multicentre, double-blind, randomized, double-dummy clinical study designed to compare the efficacy and safety of aficamten with metoprolol in patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM).⁶ The trial enrolled 175 adult participants who were randomly assigned in a 1:1 ratio to receive either aficamten (5–20 mg once daily) or metoprolol (50–200 mg once daily) for a duration of 24 weeks.

The primary endpoint was the change from baseline in peak oxygen uptake (pVO₂) measured by cardiopulmonary exercise testing at week 24, reflecting improvement in exercise capacity. Aficamten demonstrated a statistically and clinically significant increase in pVO₂ compared with metoprolol (least-squares mean difference of approximately +2.3 mL/kg/min; P < 0.001). Patients treated with aficamten showed a mean improvement of +1.1 mL/kg/min, whereas those receiving metoprolol experienced a decline of −1.2 mL/kg/min.

Secondary endpoints further supported the superiority of aficamten. A greater proportion of patients in the aficamten group exhibited at least a one-class improvement in New York Heart Association (NYHA) functional status. Additionally, aficamten led to significant improvements in quality of life, as assessed by the Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (KCCQ-CSS), with a mean increase of approximately +15.8 points compared with +8.7 points in the metoprolol group.

Echocardiographic parameters revealed that aficamten markedly reduced left ventricular outflow tract (LVOT) gradients both at rest and with the Valsalva manoeuvre. Moreover, treatment with aficamten was associated with decreases in NT-proBNP levels, left atrial volume index, and other indicators of diastolic and filling pressure improvement. No significant difference was observed in left ventricular mass index between the two treatment arms.

Regarding safety, adverse events occurred with comparable frequency in both groups, and the incidence of serious adverse events was low (8.0% in the aficamten arm vs. 6.9% in the metoprolol arm). A transient and asymptomatic reduction in left ventricular ejection fraction to less than 50% occurred in 1 patient (1%) in the aficamten group and none of the patients in the metoprolol group. Adverse events resulting in early treatment withdrawal occurred in one patient (1%) in the aficamten group who died suddenly after a brief viral illness, and in three patients (3%) in the metoprolol group. Two patients had 1-day interruptions of treatment owing to an adverse event (pericarditis and atrial fibrillation in a patient who received aficamten and simultaneous dizziness, shortness of breath, and fatigue in a patient who received metoprolol). A transient and asymptomatic reduction in left ventricular ejection fraction to less than 50% occurred in 1 patient (1%) in the aficamten group and none of the patients in the metoprolol group.

In summary, the MAPLE-HCM trial demonstrated that aficamten monotherapy provides superior clinical and functional benefits compared with metoprolol in patients with symptomatic oHCM (see Table 1 for a brief summary of the main characteristics of the study).

Table 1.

Summary of the key characteristics of the MAPLE-HCM and ODYSSEY-HCM trials, including study design, primary and key secondary endpoints and main results.

Study	Population/Design	Primary Endpoint	Key Secondary Endpoints	Main Results
MAPLE-HCM trial	Adults with obstructive HCM (NYHA II–III); aficamten vs. metoprolol; 24 weeks, randomized, double-blind, active-controlled.	Change in peak VO2 at 24 weeks.	Change in LVOT gradient (Valsalva), in KCCQ-CSS, improvement in NYHA class, change in NT-proBNP, LAVi, LVMi	↑ peak VO2 +1.1 vs. −1.2 mL/kg/min (Δ 2.3; P < 0.0001) in aficamten group; improvement in NYHA class and KCCQ-CSS in aficamten group, marked LVOT gradient, LAVi and NT-proBNP reduction in aficamten group
ODYSSEY-HCM trial	Adults with non-obstructive HCM (NYHA II–III); mavacamten vs. placebo; 48 weeks, randomized, double-blind, placebo-controlled.	Change in KCCQ-CSS and peak VO2 at 48 weeks.	Change in the slope of VE/VCO2, change in NT-proBNP, improvement of NYHA class, change in HCMSQ shortness-of-breath score	Primary endpoints not met: no significant benefit in pVO2 or KCCQ. Although some secondary endpoints show favorable trends, they did not meet the requirement for further statistical testing.

HCM, hypertrophic cardiomyopathy; HCMSQ, Hypertrophic Cardiomyopathy Symptom Questionnaire; KCCQ-CSS, Kansas City Clinical Questionnaire clinical summary score; LAVi, left atrial volume index; LVOT, left ventricular outflow tract; NT-proBNP, N-terminal pro–B-type natriuretic peptide; NYHA, New York Heart Association; pVO2, peak oxygen uptake; VE/VCO2, ventilation divided by carbon dioxide production.

Given the promising results of CMIs in oHCM, their potential role has also been explored in the non-obstructive HCM (nHCM), with the rationale that these drugs may favourably modulate the disease's underlying pathophysiology. The ODYSSEY-HCM trial (Mavacamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy) was a Phase 3, international, multicentre study designed to evaluate the efficacy and safety of mavacamten in patients with symptomatic non-obstructive HCM.⁷ The trial enrolled 580 adults who had NYHA class II or III symptoms, a preserved left ventricular ejection fraction, and no significant obstruction in the left ventricular outflow tract either at rest or with provocation. Participants were randomly assigned to receive either mavacamten or placebo and were followed for 48 weeks.

The primary goal of the study was to assess improvements in exercise capacity, measured by peak oxygen uptake (pVO₂), and patient-reported health status, assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ). At the end of the study period, the change in peak oxygen uptake in the mavacamten group was slightly greater than in the placebo group, but the difference did not reach statistical significance. Similarly, the improvement in KCCQ scores was numerically greater in the mavacamten group, yet this difference also failed to achieve statistical significance.

Despite these neutral primary results, two separate secondary exploratory analyses were performed, showing that mavacamten was associated with favourable effects on certain secondary measures. Cardiac biomarkers such as NT-proBNP and high-sensitivity troponin I showed significant improvement compared with placebo⁸ Also, echocardiographic analyses indicated modest improvements in left ventricular diastolic function and reductions in left ventricular hypertrophy parameters.⁹ However, these changes did not translate into measurable improvements in functional capacity or symptom relief for patients.

At the end of the study, the proportion of patients who discontinued the trial regimen owing to a left ventricular ejection fraction below 50% was higher in the mavacamten group than in the placebo group (21.5% vs. 1.7%) and an ejection fraction of 30% or lower occurred in 7 patients (2.4%) in the mavacamten group and in none of the patients receiving placebo. In this study, mavacamten dosing was titrated on the basis of serial ejection fraction assessments, in contrast to studies of obstructive disease, in which the dose was escalated when left ventricular outflow tract obstruction persisted. Notably, in the ODYSSEY-HCM trial, this more aggressive dose-adjustment strategy resulted in a higher proportion of patients (49.1%) receiving the upper dosing range (10 mg or 15 mg), compared with previous trials in obstructive HCM.

The overall incidence of adverse events during the trial period was similar between patients receiving mavacamten and those receiving placebo. Serious adverse events involving congestive heart failure and atrial tachyarrhythmias (fibrillation or flutter) occurred in 19 patients (6.6%) and 12 patients (4.2%), respectively, in the mavacamten group and in 5 patients (1.7%) and 10 patients (3.4%), respectively, in the placebo group.

In conclusion, the ODYSSEY-HCM trial demonstrated that mavacamten, although biologically active and capable of improving certain cardiac parameters, did not provide significant clinical benefit in terms of exercise capacity or symptom relief for patients with nonobstructive hypertrophic cardiomyopathy (see Table 1 for a brief summary of the main characteristics of the study).

In summary, cardiac myosin inhibitors, both mavacamten and aficamten, offer a significant advancement in the management of symptomatic obstructive HCM, even when compared with conventional therapies, such as beta blockers in the MAPLE trial, providing meaningful improvements in haemodynamics and functional capacity. In nHCM, despite limited impact on functional capacity, CMIs demonstrate biological activity and favourable cardiac remodelling, supporting further research into their potential role in modulating disease pathophysiology.

Funding

None.

Data availability

No new data were generated or analysed in support of this research.

Disclaimer

This paper was originally published in the Italian language as ‘Gli studi Odyssey–HCM e MAPLE–HCM: ruolo dei modulatori della miosina nella cardiomiopatia ipertrofica (ostruttiva e non)’, in the Volume degli Atti del Congresso “Conoscere e Cuare il Cuore 2026”, published by Centro per la Lotta contro l'Infarto for distribution at the CCC Conference. This paper was translated by Dr. Mario Albertucci, representative of the CLI Foundation, and republished with permission.