Aficamten Boosts Exercise Capacity in Nonobstructive Heart Enlargement Trial
A phase III trial finds aficamten improves peak oxygen uptake and symptoms in nonobstructive hypertrophic cardiomyopathy patients who had no prior treatment options.
Summary
A large phase III trial called ACACIA-HCM tested aficamten, a cardiac myosin inhibitor, in 517 patients with nonobstructive hypertrophic cardiomyopathy — a heart-thickening condition with no approved treatments. Over 36 weeks, patients on aficamten gained meaningfully more peak oxygen uptake compared to placebo, a key measure of cardiorespiratory fitness and a strong predictor of long-term survival. They also reported better quality of life and fewer symptoms. Secondary measures including heart failure biomarkers and functional class all favored the drug. Results were published simultaneously in the New England Journal of Medicine. Aficamten is already FDA-approved for the obstructive form of this disease; this trial extends its potential reach to a broader patient population living with exercise intolerance and progressive cardiac decline.
Detailed Summary
Hypertrophic cardiomyopathy (HCM) is a genetic heart condition causing abnormal thickening of the heart muscle. The nonobstructive form — where blood flow is not physically blocked — has historically had no approved drug therapies despite causing significant exercise limitation, symptoms and reduced quality of life. This trial addresses that unmet need directly.
The ACACIA-HCM trial enrolled 517 patients in a double-blind, placebo-controlled design over 36 weeks. Aficamten, a selective cardiac myosin inhibitor, was tested against placebo on two co-primary endpoints: peak oxygen uptake (VO2 peak) and patient-reported health status via the Kansas City Cardiomyopathy Questionnaire. Both endpoints were met. The aficamten group gained 0.64 mL/kg/min in VO2 peak versus a decline of 0.03 mL/kg/min in placebo — a statistically significant difference. Health status scores rose 11.4 points versus 8.4 points in placebo.
Secondary outcomes reinforced the picture. New York Heart Association functional class improved, a composite exercise Z-score favored aficamten, and NT-proBNP — a biomarker of cardiac wall stress — fell with treatment. A responder analysis published in Circulation confirmed benefit across symptom burden and diastolic function domains.
These findings matter beyond cardiology. VO2 max is among the strongest known predictors of all-cause mortality; any intervention that halts or reverses its decline in people with heart disease has direct longevity implications. For the roughly half of HCM patients with the nonobstructive phenotype, this represents the first positive phase III evidence for a drug therapy.
Caveats apply. The magnitude of benefit was more modest than seen in obstructive HCM trials. Serious adverse events were higher on aficamten (20.2%) versus placebo (14.7%), and heart failure events occurred more frequently on the drug. Researchers and discussants stressed that nonobstructive HCM is not a single phenotype, and further work is needed to identify which patients benefit most and to define therapeutic targets for clinical response optimization.
Key Findings
- Aficamten increased peak VO2 by 0.67 mL/kg/min more than placebo over 36 weeks in nonobstructive HCM patients.
- Patient-reported health status improved significantly, with a 3-point greater gain on the KCCQ clinical summary score versus placebo.
- All secondary endpoints — functional class, exercise composite, and NT-proBNP biomarker — favored aficamten over placebo.
- This is the first definitively positive phase III trial in nonobstructive HCM, a population with no approved treatments.
- Serious adverse events and heart failure rates were higher on aficamten, requiring careful patient selection and monitoring.
Methodology
This is a news report of a peer-reviewed phase III randomized controlled trial (ACACIA-HCM) published simultaneously in the New England Journal of Medicine, a top-tier journal. The trial was double-blind, placebo-controlled with 517 participants over 36 weeks, representing high-quality evidence. The report covers conference presentation at the European Society of Cardiology annual meeting, with additional data in Circulation.
Study Limitations
The article is a conference news report and does not provide full trial data or subgroup analyses. The modest effect size and higher adverse event rates in the treatment arm warrant scrutiny of the full NEJM publication. Long-term safety and durability of benefit beyond 36 weeks remain unknown.
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