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Aficamten for Symptomatic Nonobstructive Hypertrophic Cardiomyopathy
Key result
Aficamten improves KCCQ scores by 3 points and peak VO2 vs placebo at 36 weeks.
- MD +3.0
- 95% CI 0.5 to 5.5
- P=0.02
- n=517
Why the trial?
Symptomatic nonobstructive hypertrophic cardiomyopathy has no approved disease-specific therapy, and cardiac myosin inhibition had only been proven in obstructive disease. ACACIA-HCM asked whether aficamten improves symptoms and exercise capacity when there is no outflow gradient to relieve.
Does aficamten improve exercise capacity and patient-reported health status in adults with symptomatic nonobstructive hypertrophic cardiomyopathy?
Key Points
- To evaluate the efficacy and safety of the cardiac myosin inhibitor aficamten in adults with symptomatic nonobstructive hypertrophic cardiomyopathy.
- Phase 3, multinational, double-blind randomized trial (ACACIA-HCM; NCT06081894) assigning 517 adults (258 aficamten, 259 placebo; mean age 55.1 years; 53.6% women) 1:1 to aficamten (5–20 mg) or placebo for up to 72 weeks.
- Assessed dual primary end points at week 36: change from baseline in peak oxygen uptake and in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS).
- At 36 weeks, KCCQ-CSS increased by 11.4 points (95% CI, 9.6 to 13.2) with aficamten versus 8.4 points (95% CI, 6.6 to 10.2) with placebo (least-squares mean difference, 3.0 points; 95% CI, 0.5 to 5.5; P = 0.02).
- Peak oxygen uptake improved with aficamten compared to placebo at week 36 (mean change: 0.64 ml/kg/min [95% CI, 0.32 to 0.95] vs -0.03 ml/kg/min [95% CI, -0.35 to 0.28]; least-squares mean difference, 0.67 ml/kg/min; 95% CI, 0.22 to 1.11; P = 0.003).
- Reversible reductions in left ventricular ejection fraction below 50% occurred in 10.5% (27/258) of aficamten recipients versus 0.8% (2/259) in the placebo group, with serious adverse events reported in 20.2% versus 14.7% of patients, respectively.
Evidence details
What drove the result?
| Outcome | Aficamten | Placebo |
|---|---|---|
| KCCQ-CSS change at week 36 | +11.4 | +8.4 |
| Dual primary - LS mean difference 3.0 points (95% CI 0.5-5.5); P=0.02 | ||
| Peak VO2 change at week 36 (ml/kg/min) | +0.64 | -0.03 |
| Dual primary - LS mean difference 0.67 (95% CI 0.22-1.11); P=0.003 | ||
Limitations & tradeoffs
Safety
Reversible LVEF reduction to <50% in 27/258 (10.5%) vs 2/259 (0.8%); serious adverse events 52/258 (20.2%) vs 38/259 (14.7%).
Statistical certainty
the placebo group also improved 8.4 points on KCCQ-CSS; the between-group difference was 3.0 points.
Design limitations
both primary endpoints are symptom and exercise measures, not clinical events, and primary assessment at 36 weeks is short relative to the chronic course of HCM.
Structured PICO
Does aficamten improve exercise capacity and patient-reported health status in adults with symptomatic nonobstructive hypertrophic cardiomyopathy?
P
Population
517 adults with symptomatic nonobstructive hypertrophic cardiomyopathy, followed 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).
Main Result
Mean Difference: 3 (95% CI 0.5–5.5)
Absolute Event Rate: 11.4% vs 8.4%
p-value: p=0.02
In patients with symptomatic nonobstructive hypertrophic cardiomyopathy, aficamten significantly improved exercise capacity and patient-reported health status at 36 weeks compared to placebo.
Discussion
2 takesKey questions
From the author
From the author
Member takes
Where experts stand
Experts broadly welcome ACACIA-HCM as the first positive phase 3 trial in nonobstructive HCM, though several flag the modest effect sizes and unresolved safety signals as reasons to temper enthusiasm.
Clinicians recognize aficamten as a landmark for a population that has lacked targeted therapy, and most frame the dual-endpoint win as clinically meaningful. The main tension is between those who see a clear practice shift ahead and those who note the small absolute benefit, the drop in ejection fraction, and the absence of hard clinical-event reduction. The open question is whether long-term data and phenotype-level selection will sharpen the risk-benefit profile enough to reshape guidelines.
Agreement
Multiple clinicians independently call ACACIA-HCM the first positive phase 3 trial in symptomatic nonobstructive HCM, marking a new therapeutic chapter for a phenotype that has lacked targeted treatment.
5 clinicians say this directly
What they’re arguing about
supportiveneutralcautiouscritical
Counts are expert takes we classified by axis. Tap a row to see the takes behind its count.
Still unclear
Whether the KCCQ improvement of 3 points reaches a clinically meaningful threshold remains debated, with at least one clinician questioning whether it clears the usual bar. Long-term safety data from FOREST-HCM are awaited to clarify the durability of benefit and the significance of LVEF drops and early heart failure events. Which HCM phenotypes are most likely to benefit from aficamten is an open question multiple experts flagged.
Key expert perspectives
AJACC Journal Scan
“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.”
The KCCQ gain of 3 points may not clear the bar for clinical relevance
Acknowledged this as the first positive trial in nonobstructive HCM with a less heterogeneous cohort, but questioned whether a 3-point KCCQ improvement should be considered clinically relevant. Noted that long-term data from FOREST-HCM are still needed.
Aficamten improved diastolic function markers, but the key question is which phenotypes benefit most
Noted improvements in septal e' on echo and highlighted that the discussant raised the question of which HCM phenotypes are most likely to benefit from treatment.
Distilled from their postX post
Implication
Provides first targeted option for symptomatic nonobstructive HCM; extends myosin inhibition beyond obstructive disease.
Coverage & sources
Journal, society, and media accounts. Useful signal, not independent expert judgment.
Cite This Study
Masri et al. (2026) conducted an RCT in Symptomatic nonobstructive hypertrophic cardiomyopathy (n=517). Aficamten vs. Placebo was evaluated on Change from baseline to week 36 in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) (MD 3.0, 95% CI 0.5 to 5.5, p=0.02). Aficamten significantly improved KCCQ-CSS (MD 3.0; 95% CI 0.5-5.5; P=0.02) and peak oxygen uptake (MD 0.67 ml/kg/min; P=0.003) compared to placebo at 36 weeks in nonobstructive HCM.