What happened
Aficamten improves KCCQ scores by 3 points and peak VO2 vs placebo at 36 weeks.
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.
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.
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.
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Author’s perspective
“Results from the ACACIA-HCM trial provide really positive news for patients with symptomatic non-obstructive HCM. 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.”
Dr. Ahmad Masri
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.
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.
This opens a new therapeutic chapter for a phenotype previously limited to symptom management
Frames the result as the first positive phase 3 trial in symptomatic nonobstructive HCM after a prior neutral experience with mavacamten. Argues this potentially opens a new therapeutic chapter for a phenotype where treatment had been limited to symptom management.
Asks which phenotypes are most likely to benefit from aficamten in nonobstructive HCM
Notes improvements in exercise capacity and symptoms and highlights the echo finding of improved septal e'. Raises the key unanswered question of which patient phenotypes are most likely to benefit.
“nHCM patients remain symptomatic despite current heart-failure-guideline-based care and have lacked a targeted therapy.”
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.
Summarizes the trial design and congratulates the team on the NEJM publication.
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Reports that aficamten improved health status, peak oxygen uptake, and symptoms at 36 weeks.
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Calls the trial an important milestone and step forward for patients with nonobstructive HCM.
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“#ACACIAHCM at #ESCCongress Can we finally improve symptoms AND exercise capacity in symptomatic non-obstructive #HCM? 516 patients Aficamten placebo 36 weeks both primary endpoints were positive: KCCQ-CSS: +3.0 vs placebo (P=.021) Peak VO₂: +0.67 mL/kg/min”
X ↗“@ESC_Journals Aficamten first drug for non-obstructive HCM to change outcomes ACACIA-HCM - KCCQ-CSS LSM difference +3.0 (0.5–5.5), p=0.021 - pVO2 +0.67 mL/kg/min (0.22–1.1), p=0.003. - LVEF <50% in 10% vs 1%; two HF SAEs with LVEF <50% on drug; dose interruptions for LVEF”
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Highlights aficamten as the first drug to beat placebo in a phase 3 nonobstructive HCM trial.
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Notes aficamten significantly improved KCCQ and VO2 max versus placebo in nonobstructive HCM.
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Reports both primary endpoints were met with specific numbers at week 36.
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Calls it a remarkable day for nonobstructive HCM and notes both primary endpoints were met.
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“ACACIA-HCM is the first-ever positive clinical trial in non-obstructive HCM. As shown in presentation and publication, the results from ACACIA-HCM are both statistically robust, consistent across prespecified subgroups and other secondary endpoints, and clinically impactful for these patients with non-obstructive HCM. As such, these data may potentially translate into a new treatment option for patients with HCM with no available medical treatments that directly address their underlying disease. If approved, we look forward to seeing aficamten become the first cardiac myosin inhibitor to treat the full spectrum of symptomatic HCM.”
News Coverage ↗
“Patients with non-obstructive HCM have no therapies approved to treat the underlying hypercontractility associated with the disease. We hope that will change with ACACIA-HCM which is the first clinical trial to demonstrate statistically significant improvements in exercise capacity and symptom burden in patients with non-obstructive HCM. We believe that the totality and consistency of evidence favoring aficamten across multiple patient-reported and physician-assessed endpoints of symptom improvement and physical function are clinically meaningful for patients with non-obstructive HCM.”
News Coverage ↗
“More than half of aficamten-treated patients achieved improvement across three or more of the five clinical, functional and biological measures evaluated, compared with 13% of placebo-treated patients.”
Conference Coverage ↗Bhavneesh Sharma: MD, MBA in Finance - NYU Stern
“Cytokinetics, $CYTK: Comments on today's data: ACACIA-HCM is a real but modest win: dual primaries hit (KCCQ +3.0, pVO2 +0.67), first positive nHCM Phase 3, sNDA in Q4, but the KCCQ delta is below the usual 5-point MCID, hard events and remodeling missed, and serious HF was 4.3%”
X ↗Lucent Ion 🧬
“$CYTK A few of our thoughts on ACACIA-HCM data this morning after some time to digest (pending additional physician feedback): KCCQ data positive & stat sig as previously disclosed, with the delta diverging from +3.1 vs. placebo at wk36 (p=0.021) to +7.0 by wk72 (p<0.005) -”
X ↗Michel Doepke
“$CYTK "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." Primary endpoints below. $BMY $MYOK”
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Answers are grounded in this paper and cite their sources.
Why the trial, key points, tables, limitations, PICO, abstract, media & sources
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?
| Outcome | Aficamten | Placebo |
|---|---|---|
| KCCQ-CSS change at week 36 Dual primary - LS mean difference 3.0 points (95% CI 0.5-5.5); P=0.02 | Aficamten +11.4 | Placebo +8.4 |
| Peak VO2 change at week 36 (ml/kg/min) Dual primary - LS mean difference 0.67 (95% CI 0.22-1.11); P=0.003 | Aficamten +0.64 | Placebo -0.03 |
Does aficamten improve exercise capacity and patient-reported health status in adults with symptomatic nonobstructive hypertrophic cardiomyopathy?
In patients with symptomatic nonobstructive hypertrophic cardiomyopathy, aficamten significantly improved exercise capacity and patient-reported health status at 36 weeks compared to placebo.
Expert reaction
NEJM · ESC Congress 2026
What 6 experts said about this trial's result
Expert labels are toward ACACIA-HCM's result, from named public quotes (n=6). As of Oct 14, 2026.
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.
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.
Clinically meaningful win or modest effect that falls short?
What they’re arguing about
supportiveneutralcautiouscritical
Counts are expert takes we classified by axis. Tap a row to see the takes behind its count.
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.
Provides first targeted option for symptomatic nonobstructive HCM; extends myosin inhibition beyond obstructive disease.
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.
Journal, society, and media accounts. Useful signal, not independent expert judgment.
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.
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