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Aficamten for Symptomatic Nonobstructive Hypertrophic Cardiomyopathy
Ahmad MasriMartin S. MaronAnkit BhatiaMaria Luisa Peña-PeñaMark V. SherridEstêvão Lanna FigueiredoMichael AradRoberto Barriales-VillaLubna ChoudhuryBrian L. ClaggettCaroline CoatsEdileide de Barros CorreiaJuan Pablo CostabelPerry M. ElliottJorge E. Silva EncisoPablo Garcia-PaviaJunbo GeSheila M. HegdeGregory D. LewisRenato D. LopesMatthew W. MartinezMathew S. MaurerZi Michael MiaoMichelle MichelsSumeet S. MitterJesus PinoIacopo OlivottoAnjali T. OwensS H PoulsenFlorian RaderEthan J. RowinP. Christian SchulzeRóbert SeppNikhil SikandScott D. SolomonJohn A. SpertusCHARLES TEALEXiaoyan ZhaoPunag DivanjiStephen B. HeitnerDaniel L. JacobyStuart KupferFady I. MalikJoel Salazar‐MendiguchíaAmy WohltmanShu ZhuoCarolyn Y. Ho
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 welcome ACACIA-HCM as the first positive phase 3 trial in nonobstructive HCM, though several flag that the absolute improvements are modest and long-term outcomes remain unproven.
Clinicians broadly view this as a landmark for a population that had no targeted therapy, and the dual-endpoint win is seen as credible across multiple domains. However, the size of the symptom and exercise improvements has drawn scrutiny, with some questioning whether the gains cross a clinically meaningful threshold. The live question is which patient phenotypes benefit most and whether long-term safety and hard clinical outcomes will hold up.
Agreement
Multiple clinicians agree that ACACIA-HCM is the first positive phase 3 trial in symptomatic nonobstructive HCM, marking a milestone for a population with no prior targeted therapy.
4 clinicians say this directly
Main debate
Clinically meaningful win or modest effect that falls short?
Meaningful multidomain benefit2
Aficamten improved symptoms, exercise capacity, and biomarkers across multiple endpoints in a disease with no prior therapy.vs
Modest gains, open questions2
The KCCQ delta is below the usual 5-point threshold, hard events were not reduced, and serious heart failure signals warrant caution.+5Not placed10 reporting, watching, or context only
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
Which nonobstructive HCM phenotypes benefit most from aficamten remains unanswered. Long-term clinical outcomes and safety, including the LVEF reduction signal and early heart failure events during titration, await data from the FOREST-HCM extension study. Whether the KCCQ improvement crosses a clinically meaningful threshold for regulators and guideline writers is an open question.
Key expert perspectives
CPChristina PaitazoglouCardiologist, University Heart Center, GermanyContextAug 30
Nonobstructive HCM patients lacked a targeted therapy despite guideline-based care
Emphasizes that nonobstructive HCM patients remain symptomatic despite current heart-failure-guideline-based care and have lacked a targeted therapy, framing the unmet need the trial addresses.
Distilled from their postOriginal post
A real but modest win: KCCQ delta is below the usual 5-point threshold and hard events missed
Acknowledges the dual primary endpoints were met and this is the first positive nHCM phase 3 trial, but notes the KCCQ delta of +3.0 falls below the usual 5-point clinically meaningful threshold. Points to missed hard events, absent remodeling benefit, and a 4.3% rate of serious heart failure as concerns.
Distilled from their postX post
Questions whether a 3-point KCCQ improvement is clinically relevant
Reports both primary endpoints were met and notes two-thirds of patients had familial HCM, making the cohort less heterogeneous. Raises the question of whether a 3-point KCCQ change should be considered clinically relevant and flags this as the first positive trial in nonobstructive HCM.
Implication
Provides first targeted option for symptomatic nonobstructive HCM; extends myosin inhibition beyond obstructive disease.
Abstract
BACKGROUND: Nonobstructive hypertrophic cardiomyopathy (HCM) is a common condition that is associated with substantial morbidity and no proven medical therapy. Whether treatment with aficamten, a cardiac myosin inhibitor, can benefit patients with this condition is unknown. METHODS: In this phase 3, multinational, double-blind trial, we randomly assigned adults with symptomatic nonobstructive HCM in a 1:1 ratio to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for up to 72 weeks. The dual primary end points were the change from baseline to week 36 in peak oxygen uptake and in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; range, 0 to 100, with higher scores indicating better health status). RESULTS: A total of 258 patients were assigned to receive aficamten and 259 to receive placebo. The mean age of the patients was 55.1 years, and 53.6% were women. At 36 weeks, the change in the KCCQ-CSS was 11.4 points (95% confidence interval [CI], 9.6 to 13.2) in the aficamten group and 8.4 points (95% CI, 6.6 to 10.2) in the placebo group (least-squares mean difference, 3.0 points; 95% CI, 0.5 to 5.5; P = 0.02). The mean change in the peak oxygen uptake at week 36 was 0.64 ml per kilogram of body weight per minute (95% CI, 0.32 to 0.95) in the aficamten group and -0.03 ml per kilogram per minute (95% CI, -0.35 to 0.28) in the placebo group (least-squares mean difference, 0.67 ml per kilogram per minute; 95% CI, 0.22 to 1.11; P = 0.003). Reversible reductions in left ventricular ejection fraction to less than 50% occurred in 27 patients (10.5%) receiving aficamten and in 2 patients (0.8%) receiving placebo. Serious adverse events occurred in 52 patients (20.2%) and 38 patients (14.7%), respectively. CONCLUSIONS: Among patients with symptomatic nonobstructive HCM, treatment with aficamten resulted in a significantly greater change in exercise capacity and patient-reported health status than placebo at 36 weeks. (Funded by Cytokinetics; ACACIA-HCM ClinicalTrials.gov number, NCT06081894.).
NEJM · ESC 2026 · RCT. Aficamten improves symptoms in nonobstructive HCM, extending myosin inhibition beyond obstruction. ACACIA-HCM: Aficamten for Symptomatic Nonobstructive Hypertrophic Cardiomyopathy 517 adults: Symptomatic nonobstructive HCM, no approved specific therapy. Up to 72 weeks of treatment: Aficamten 5-20 mg vs Placebo. KCCQ-CSS change at week 36: Aficamten 11.4 vs Placebo 8.4. 3.0 points higher KCCQ-CSS. MD 3.0 (95% CI 0.5–5.5), P=0.02. Peak VO2 also improved: 0.67 ml/kg/min. Harms: reversible LVEF falls (placebo 0.8%): LVEF<50% 10.5%, Serious AEs 20.2%. Bottom line: First targeted option for symptomatic nonobstructive HCM, extending myosin inhibition.
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.