ACACIA-HCMHot Line 1CardiomyopathyNew England Journal of Medicine
Aficamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy
Aficamten for Symptomatic Nonobstructive Hypertrophic Cardiomyopathy
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Presenting authorAhmad MasriHeart Failure & Transplant · Oregon Health & Science University, Portland, USAAhmad Masri is an Associate Professor of Medicine in the Division of Cardiovascular Medicine at Oregon Health & Science University. He serves as the director of the Hypertrophic Cardiomyopathy Center and specializes in caring for patients with cardiomyopathies, including hypertrophic cardiomyopathy, amyloidosis, and Fabry’s disease. His research overlaps with his clinical focus on diagnostic approaches and therapeutics in cardiac conditions.
Overview
Provides first targeted option for symptomatic nonobstructive HCM; extends myosin inhibition beyond obstructive disease.
Key result
Aficamten significantly improved the KCCQ clinical summary score (mean difference 3.0; 95% CI 0.5-5.5) and peak oxygen uptake (mean difference 0.67; 95% CI 0.22-1.11) vs placebo at 36 weeks.
Discussion
ACACIA-HCM has reported — post the first read.
Expert takes
ACACIA-HCM is the first Phase 3 trial to show statistically significant improvements in both symptom burden (KCCQ-CSS) and exercise capacity (pVO2) with aficamten versus placebo in patients with symptomatic nonobstructive hypertrophic cardiomyopathy, a population with no approved disease-modifying therapies. The trial met both dual primary endpoints at 36 weeks, with consistent positive findings across secondary endpoints including NYHA class and NT-proBNP. There is meaningful context given the failure of mavacamten (ODYSSEY-HCM) in this same population. Safety concerns around LVEF reduction (10% with aficamten vs 1% placebo) and the modest magnitude of KCCQ improvement (3-point delta) have drawn attention, though full data presentation is still pending.
“For the first time, we have shown clinically meaningful improvements in symptoms and exercise capacity with a treatment that targets the cause of the disease.”
““This is a positive clinical trial, and you have multiple domains of benefit ... from symptoms to patient-reported health status, exercise [and] biomarkers.””
Ahmad Masri
Expert commentary
“We presented the ACACIA-HCM trial. A milestone for us and our patients, having a therapy that influences many important clinical domains that are relevant to patients and physicians alike. This is the start in nHCM. An impactful one. Paper simultaneously published in @NEJM https://t.co/344xfTvQN6”
Ahmad Masri
Expert commentary
“Today was a special day. We reported the results of 2 pivotal trials in HCM and in transthyrtin amyloidosis. My passion for both —and for the patients affected by these diseases—came full circle. More trials on Sunday - stay tuned ACACIA-HCM https://t.co/hRkM6EQdBX https://t.co/9EKffPzxiR”
Key Points
- Treatment with the cardiac myosin inhibitor aficamten significantly improved exercise capacity and health status in nonobstructive hypertrophic cardiomyopathy.
- Aficamten increased peak oxygen uptake by 0.67 ml per kilogram per minute (P=0.003) and KCCQ-CSS health scores by 3.0 points compared to placebo at week 36.
- Phase 3 double-blind trial in 517 adults showed reversible left ventricular ejection fraction reductions below 50% in 10.5% of aficamten recipients versus 0.8% on placebo.
Study Design
Type
RCT (n=517)
Blinding
Double-blind
Randomization
1:1
Multicenter
Yes
Structured PICO
Does aficamten improve peak oxygen uptake and patient-reported health status in adults with symptomatic nonobstructive hypertrophic cardiomyopathy?
P
Population
517 adults with symptomatic nonobstructive hypertrophic cardiomyopathy, randomized to aficamten or placebo for up to 72 weeks.
I
Intervention
Aficamten (starting dose 5 mg, maximum dose 20 mg) for up to 72 weeks.
C
Comparator
Placebo for up to 72 weeks.
O
Outcome
Dual primary end points: change from baseline to week 36 in peak oxygen uptake and in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS).patient reported
In patients with symptomatic nonobstructive hypertrophic cardiomyopathy, aficamten significantly improved exercise capacity and patient-reported health status at 36 weeks, though with an increased risk of reversible LVEF reduction.
Main Result
Mean Difference: 3 (95% CI 0.5–5.5)
Absolute Event Rate: 11.4% vs 8.4%
p-value: p=0.02