MINNEAPOLIS — Readouts of data on an experimental drug for hypertrophic cardiomyopathies showed the agent appeared safe and effective in long-term treatment and can significantly improve exercise capacity.

New evidence from the FOREST-HCM trial of the investigational myosin inhibitor aficamten (Cytokinetics) showed early and durable improvements in symptoms of heart failure and improved health status up to 96 weeks in people with nonobstructive hypertrophic cardiomyopathy.

Another study of aficamten, a prespecified analysis of the MAPLE-HCM trial, found the agent superior to metoprolol for improving physiologic adaptation exercise among people with the obstructive form of the condition.

Researchers presented the data from both trials at the Heart Failure Society of America (HFSA) 2025 Annual Scientific Meeting (abstracts LB-4 and LB-6).

“I think these two studies really advance our knowledge and care of our patients. They also allow us to look at hypertrophic cardiomyopathies in the two phenotypes we see in clinical practice, obstructive and nonobstructive,” said James Fang, MD, chief of cardiovascular medicine at the University of Utah School of Medicine, Salt Lake City, who was not involved in the research.

FOREST-HCM

The 96-week assessment of the extended open-label FOREST-HCM trial builds on previously reported interim findings. The current results in 34 patients with symptomatic nonobstructive hypertrophic cardiomyopathy at baseline demonstrated aficamten was well-tolerated during extended treatment. Investigators reported early and sustained reductions in cardiac biomarkers for wall stress and subclinical myocardial injury, for example.

Effective treatments for the condition are needed, experts said.

“Obstructive HCM is a chronic condition that affects patients’ quality of life and exercise tolerance, in addition to being progressive in nature,” Ahmad Masri, MD, associate professor of medicine and director of the Hypertrophic Cardiomyopathy Center at Oregon Health & Science University in Portland, Oregon, told Medscape Medical News.

“Aficamten continues to perform well in nonobstructive hypertrophic cardiomyopathy over almost 2 years of treatment without any permanent discontinuations,” added Masri, who presented the findings at the meeting.

The agent was well-tolerated, with more than 80% of patients receiving the highest available doses — 15 mg or 20 mg — according to the researchers. Aficamten improved symptoms, indicated by change in New York Heart Association class, in 80% of patients, including 74% who became asymptomatic. The agent improved patient-reported symptoms, with an 11-point increase on the Kansas City Cardiomyopathy Questionnaire compared to baseline.

Investigators also reported a 5% reduction in left-ventricular ejection fraction (LVEF). Four patients experienced an episode of LVEF below 50%; two of these were asymptomatic and managed with down titration, and the other two were in the setting of atrial fibrillation or treatment for it, Masri said.

MAPLE-HCM Results

The MAPLE-HCM trial addresses treatment of obstructive hypertrophic cardiomyopathy. “Currently, based mainly on expert opinion, beta blockers such as metoprolol are first-line therapy for treatment of obstructive hypertrophic cardiomyopathy,” co-investigator Gregory Lewis, MD, section head for heart failure at the Mass General Brigham Heart and Vascular Institute, Boston, told Medscape Medical News.

This prespecified analysis of MAPLE-HCM showed aficamten was superior to metoprolol for improving submaximal, peak, and recovery measures of exercise. At the same time, metoprolol “appeared to be detrimental to patients as measured by multiple metrics of response to exercise,” the investigators noted.

“Our take-home message is the aficamten and metoprolol have divergent effects on exercise responses, with aficamten improving submaximum and maximum exercise capacity, workload achievable, exercise duration, cardiac power, ventilatory efficiency, and speed of VO₂ recovery in comparison to metoprolol,” said Lewis, who is also director of the Mass General Cardiopulmonary Exercise Testing Laboratory (CPET).

“Taken together, this data supports aficamten use as first-line therapy for patients with obstructive HCM and exercise intolerance.” 

Contrast to Previous Findings

Fang questioned why FOREST-HCM showed positive outcomes, whereas another study, ODYSSEY-HCM, failed to show an improvement with mavacamten, another myosin inhibitor, relative to placebo. 

In FOREST-HCM, “clearly, the drug is having an effect,” Fang added, including decreases in brain natriuretic peptide and troponin. “So how do you explain or reconcile these two studies?” The question remains unanswered, but the study populations did differ at baseline: participants in ODYSSEY-HCM included a higher percentage of men, participants were sicker participants, and had less familial cardiomyopathy.

Limitations of FOREST-HCM include the open-label extension design, a small population of patients, “and you could argue that the changes are modest,” Fang said. “In terms of clinical practice, for me, I think there is still a long way to go.”

Fang acknowledged people with nonobstructive hypertrophic cardiomyopathy “are very difficult patients to take care of. To see that at least in a small population of patients that there are sustained improvements in both physiologic and qualitative measurements of quality of life 2 years later is really very impressive.”

‘Remarkable Study’

Turning to MAPLE-HCM, called the study “extremely well conducted, with really insightful” data on CPET.

Fang shared several observations: “It’s remarkable how much better they feel, but the peak VO₂ increase is 1 cc per kilo,” he said.

Patients also experienced gains in anaerobic threshold, and aerobic and ventilator efficiency. “I think it teases out why these patients feel so much better,” Fang said. Meanwhile, he added, “I think everybody was struck by how poorly metoprolol did. In almost every CPET parameter measure, the beta blocker arm did horribly.”

Masri said the FOREST-HCM trial is ongoing with a planned 5 years of follow-up. “We are eagerly awaiting the results of the phase 3 ACACIA-HCM trial comparing aficamten to placebo in patients with symptomatic nonobstructive hypertrophic cardiomyopathy.”

The FOREST-HCM and the MAPLE-HCM trials were funded by Cytokinetics, Inc. Masri reported receiving research grants and consulting fees from Cytokinetics, Inc. Lewis reported receiving funding and honoraria from Cytokinetics, Inc. Fang reported having no relevant financial conflicts of interest.

Damian McNamara is a freelance writer for Medscape Medical News.