Aficamten outperforms metoprolol in obstructive HCM

Two phase III trials presented at ESC 2025 have provided new insights into the role of myosin inhibitors in hypertrophic cardiomyopathy (HCM), with one trial demonstrating superiority over standard care in obstructive HCM and another failing to meet its primary endpoints in nonobstructive HCM.

The MAPLE-HCM trial showed that the cardiac myosin inhibitor aficamten was superior to the beta-blocker metoprolol as a first-line treatment for symptomatic obstructive HCM. Conversely, the ODYSSEY-HCM trial did not demonstrate a statistically significant benefit for the myosin inhibitor mavacamten over placebo in patients with nonobstructive HCM. This illustrates how these novel drugs perform quite differently in patients with obstructive vs nonobstructive disease.

Aficamten wins

MAPLE-HCM was a double-blind, double-dummy trial that enrolled 175 adults with symptomatic obstructive HCM (mean age 58 years, 58.3 percent men, mean LVOT 47 mm Hg at rest and 74 mm Hg after the Valsalva manoeuvre). They were randomly assigned to receive either aficamten (starting at 5 mg, titrated to 20 mg daily) or metoprolol (starting at 50 mg, titrated to 200 mg daily) for 24 weeks. [N Engl J Med 2025;393:949-960]

The primary endpoint was the change from baseline in peak oxygen uptake (pVO₂). Key secondary endpoints included improvement in New York Heart Association (NYHA) functional class, change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), and change in left ventricular outflow tract (LVOT) gradient after the Valsalva manoeuvre.

At 24 weeks, the aficamten group demonstrated a mean increase in pVO₂ of 1.1 mL/kg/min, whereas the metoprolol group showed a decrease of 1.2 mL/kg/min. The least-squares mean difference between the groups was 2.3 mL/kg/min (95 percent confidence interval [CI], 1.5–3.1; p<0.001), favouring aficamten.

Aficamten monotherapy was superior to metoprolol monotherapy in improving pVO₂ and haemodynamics and decreasing symptoms, reported the investigators.

Additionally, patients in the aficamten group showed significantly greater improvements in NYHA class, health status as measured by the KCCQ-CSS, LVOT gradient, N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, and left atrial volume index than patients given metoprolol. There was no difference in left ventricular mass index. Serious adverse events occurred in 8 percent of the aficamten group and 7 percent of the metoprolol group.

The results from MAPLE-HCM offer the first direct evidence that a cardiac myosin inhibitor is superior to a beta-blocker, the long-established first-line therapy for obstructive HCM.

Lead investigator Dr Pablo Garcia-Pavia from Hospital Universitario Puerta de Hierro de Majadahonda, Madrid, Spain, said the findings “challenge current guidelines,” adding that the evidence “warrants a change in practice, if aficamten receives regulatory approval.” The drug is currently under review by the US FDA.

“Aficamten targets the underlying pathophysiology of hypertrophic cardiomyopathy by reducing hypercontractility,” he explained. “The drug has already demonstrated benefit when added to standard care. This time, in MAPLE-HCM, we have shown aficamten as a new, first-line monotherapy of choice for obstructive disease.”

Mavacamten disappoints

Meanwhile, the ODYSSEY-HCM trial, which evaluated mavacamten in nonobstructive HCM, did not reach statistical significance for its co-primary endpoints of change in pVO₂ (p=0.07) and KCCQ score (p=0.06).

Mavacamten was US FDA-approved in April 2022 for obstructive disease based on data from the EXPLORER-HCM trial [Lancet 2020; 396:759-769], but it performed less favourably in nonobstructive disease.

“There is a serious unmet need for effective therapies in symptomatic nonobstructive HCM,” commented ODYSSEY-HCM investigator Dr Milind Desai from the Cleveland Clinic, Ohio, US, at an ESC press conference. “We have made a lot of strides in obstructive HCM, but this remains somewhat of an uncharted territory.”

He explained that in obstructive HCM, dynamic LVOT obstruction causes many of the symptoms, whereas nonobstructive HCM is much more heterogeneous. “If you take the outflow tract out of the equation, is there enough that we can modulate to help symptoms in nonobstructive HCM?”

Although phase II data leading up to ODYSSEY-HCM showed promise for mavacamten, phase III data were disappointing.

Investigators enrolled 580 patients (mean age 56 years, 46 percent women) with symptomatic nonobstructive HCM. They were randomly assigned to mavacamten (starting at 5 mg/day and adjusted to a maximum of 15 mg/day based on left ventricular ejection fraction (LVEF) or placebo (with sham dose adjustment) for 48 weeks. [N Engl J Med 2025;393:961-972]

Changes from baseline to 48 weeks in peak oxygen uptake and health status, as measured by the KCCQ-CCS, are the primary endpoints. For peak oxygen uptake, the least-squares mean change was 0.52 mL/kg/min with mavacamten and 0.05 mL/kg/min with placebo, resulting in a between-group difference of 0.47 mL/kg/min (p= 0.07).

For KCCQ-CS, the least-squares mean change was 13.1 points with mavacamten and 10.4 points with placebo, with a between-group difference of 2.7 points (p=0.06). Additionally, patients in the mavacamten group were more likely to experience reductions in LVEF and interruptions to the trial regimen.

Desaid reported that prespecified subanalyses indicated that younger patients, those with less advanced and shorter disease duration, and those with less diastolic dysfunction showed trends favouring mavacamten, as did those on beta-blockers.

Serious adverse events that resulted in treatment interruption were more common in the mavacamten than the placebo group (14.6 percent vs 5.2 percent), as were adverse events that resulted in permanent discontinuation of treatment (5.2 percent vs 2.8 percent). These included congestive heart failure in 6.6 percent and atrial tachyarrhythmias in 4.2 percent among patients on mavacamten.

LVEF <50 percent was observed in 21.5 percent of patients assigned to mavacamten and 1.7 percent of those assigned to placebo, with LVEF <30 percent noted in 2.4 percent of the treatment group. However, LVEF returned to ≥50 percent for all but three patients after the trial regimen was interrupted.

Nonetheless, Desai remains hopeful that ongoing research in imaging, biomarkers, and a future detailed responder analysis could potentially identify a subgroup of patients who would benefit from mavacamten.

Takeaways

The findings from MAPLE-HCM suggest a potential shift in the treatment paradigm for obstructive HCM, positioning aficamten as a first-line therapeutic option. As for ODYSSEY-HCM, the results highlight the ongoing challenge of finding effective treatments for the more heterogeneous nonobstructive subtype of the disease.

Study discussant Dr Carolyn Ho from Brigham and Women’s Hospital in Boston, Massachusetts, US commented that MAPLE-HCM and ODYSSEY-HCM make the case for why conducting studies that “challenge the status quo and test our hypotheses” is important.

She added that MAPLE-HCM, which suggests beta-blockers may not provide meaningful benefit in obstructive HCM, should inspire the field to “be cautious when standard of care evolves out of practice rather than evidence.”

Regarding nonobstructive HCM, Ho explained that the putative mechanisms driving symptoms are “diastolic abnormalities and inefficient energetics.” Nonobstructive HCM is more complex and heterogeneous than obstructive HCM. Therefore, it will be crucial to investigate whether it is possible to identify physiologically relevant subgroups of nonobstructive HCM that could benefit from cardiac myosin inhibitors, she asserted.