Aficamten Bests Metoprolol in Cytokinetics' Trial for Obstructive Hypertrophic Cardiomyopathy

The specialty cardiovascular biopharmaceutical company Cytokinetics has presented primary results at the European Society of Cardiology Congress 2025 in Madrid, simultaneously publishing those results in the New England Journal of Medicine, of a Phase III trial (MAPLE-HCM) that demonstrated the superiority of aficamten to metoprolol for the treatment of patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) (1).

In a press release, Cytokinetics said 175 patients were enrolled in the MAPLE-HCM clinical trial; those patients were randomized on a 1:1 basis to receive either aficamten or metoprolol as monotherapy (1). Compared to a previous Phase III trial (SEQUOIA-HCM), the MAPLE-HCM trial included patients with less severe oHCM, such as those without obstruction at rest, and with higher predicted peak oxygen uptake.

According to Cytokinetics, aficamten is a small-molecule cardiac myosin inhibitor, designed to reduce active actin-myosin cross-bridges during each cardiac cycle and consequently suppress myocardial hypercontractility (1). Metoprolol, the current standard of care, is classified as a beta blocker.

Aficamten is currently under regulatory review in the United States, with FDA reviewing a new drug application with a Prescription Drug User Fee Act target action date of Dec. 26, 2025.

How did experts respond to study results?

“This important study has the potential to inform our approach to treating obstructive HCM, as MAPLE-HCM provides the field its first look at a cardiac myosin inhibitor compared directly to a beta blocker,” Pablo Garcia-Pavia, MD, PhD, Head of the Inherited Cardiac Diseases and Heart Failure Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro and full professor, Centro Nacional de Investigaciones Cardiovasculares in Madrid, said in Cytokinetics’ press release (1). “In showing that aficamten is superior to metoprolol on all clinically relevant efficacy endpoints, these results call into question the reliance on beta blockers as the initial treatment modality for obstructive HCM that has prevailed for over 60 years.”

“These results demonstrate that aficamten meaningfully improves exercise capacity in patients with obstructive HCM while treatment with metoprolol resulted in a meaningful reduction in exercise capacity,” said Fady I. Malik, MD, PhD, Cytokinetics executive vice-president of Research & Development, in the release (1). “The clinical difference in the two treatments is reinforced by the effect of aficamten on the secondary endpoints. Compared to first-line standard-of-care metoprolol, treatment with aficamten had a larger effect on measures of symptoms, functional class, and LVOT [left ventricular outflow tract] gradients. Importantly, these effects were achieved in a broader patient population with oHCM than previously studied in SEQUOIA-HCM, inclusive of patients in MAPLE-HCM with less severe disease as measured by objective metrics of disease burden.”

Labeling challenges for metoprolol?

In the first installment of an ongoing three-part exclusive series on PharmTech.com, Paul L. Pluta, RPh, PhD, uses certain metoprolol preparations as examples for how personnel involved in pharmaceutical compounding must be aware of inconsistent, confusing, or non-standard labeling that does not follow FDA formatting (2).

“For example, metoprolol tartrate (Lopressor) is an immediate-release beta blocker that is dosed twice daily; metoprolol succinate (Toprol XL) is an extended-release metoprolol preparation formulated for once-daily dosage,” Pluta explains in the article (2). “Secondary labeling on metoprolol succinate products references metoprolol tartrate to aid in transitioning patient dosage.”

Part two of that three-part series can be found at this link; part three is coming soon.

References

1. Cytokinetics. Cytokinetics Announces Primary Results from MAPLE-HCM Presented at the European Society of Cardiology Congress 2025 and Published in The New England Journal of Medicine. Press Release. Aug. 30, 2025.
2. Pluta, P. L.; Thakar, N. B.; and Chaiyaperm, V. Pharmaceutical Compounding Calculations, Part One–Non-Salts, Salts, and Policy-Exception Salts. PharmTech.com, April 18, 2025.