Ahmad Masri, MD, MS, is the director of the Hypertrophic Cardiomyopathy Center at Oregon Health and Science University. 

Ahmad Masri, MD, MS

ACACIA-HCM: Aficamten Beats Placebo in Non-Obstructive Hypertrophic Cardiomyopathy

Aficamten has outperformed placebo among patients with 

symptomatic non-obstructive hypertrophic cardiomyopathy (nHCM)

, according to topline data from ACACIA-HCM.

These data were announced by parent company Cytokinetics on May 5, 2026, highlighting improvements in both Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and maximal exercise performance (pVO2). These results highlight aficamten’s potential as a treatment for the underlying hypercontractility associated with nHCM.

“Traditionally, we have placed more weight on peak oxygen consumption – it is a very hard endpoint to move,” Ahmad Masri, MD, cardiomyopathy section head at Oregon Health & Science University, director of the OHSU hypertrophic cardiomyopathy center and OHSU Knight Cardiovascular Institute Cardiac Amyloidosis Program, and co-author of the study, told 

 in an exclusive interview. “We’ve shown that the minimal change in peak VO2 that patients perceive as clinically significant is 0.5. Most of the heart failure therapies we use don’t even hit on pVO2, even when they improve mortality and heart failure hospitalizations.”

ACACIA-HCM is a multicenter, randomized, double-blind phase 3 trial comparing aficamten to placebo in adults with symptomatic nHCM. The trial itself was conducted across 180 locations worldwide and included patients with a body mass index (BMI) <40 kg/m2 who had been diagnosed with nHCM and had a screening echocardiogram with end-diastolic left ventricular wall thickness ≥15 mm in ≥1 myocardial segment. Additionally, patients were required to have NYHA class II or III, a respiratory exchange rate of ≥1 at screening, and a KCCQ-CSS score of ≤85, among other criteria.

Patients were excluded from ACACIA-HCM if they presented with significant valvular heart disease, known or suspected infiltrative, genetic, or storage disorders causing cardiac hypertrophy, or a history of LV systolic dysfunction, syncope, symptomatic ventricular arrhythmia, resistant hypertension, or sustained ventricular tachyarrhythmia with exercise, among other criteria.

The study consisted of 2 primary endpoints – change in KCCQ-CSS and change in pVO2 from baseline to week 36. Secondary endpoints included the proportion of patients with ≥1 class improvement in NYHA functional class and changes in the composite z-score of 2 cardiopulmonary exercise testing parameters of sub-maximal exercise performance, NT-proBNP, and left atrial volume index.

A total of 516 patients were enrolled in the trial and randomly assigned in a 1:1 ratio to either aficamten or placebo. Each patient was administered ≤4 escalating doses of aficamten or placebo based on echocardiographic guidance – those in the treatment arm began with 5 mg daily. Echocardiograms were performed at weeks 2, 4, and 6 to determine the safety of up-titrating to doses of 10, 15, or 20 mg. Escalation only occurred in the presence of LVEF ≥60%.

By week 36, patients in the aficamten arm saw improvements in KCCQ-CSS of 11.4 points (95% CI, 9.6 to 13.2) and of 0.64 mL/kg/min in pVO2 (95% CI, 0.32 to 0.95), compared to 8.4 points (95% CI, 6.6 to 10.2) and -0.03 mL/kg/min (95% CI, 0.22 to 1.1), respectively, in the placebo arm (

 = .021 and .003, respectively). The improvement in KCCQ was robust and consistent throughout treatment; however, following washout, it decreased among the aficamten arm to match placebo. pVO2 remained unchanged for patients on placebo despite increasing for those on aficamten, consistent with previous research.

Investigators also reported statistically significant improvements in NYHA functional class, the composite z-score of ventilatory efficiency and pVO2, and NT-proBNP. No new safety signals were identified, and only 2 participants receiving aficamten experienced serious adverse events of heart failure associated with LVEF <50%.

“What we are looking at here is symptom improvement as a continuous variable. You’re looking at the mean average population change,” Masri said. “We all know that there are some patients who might report feeling better, some who report feeling worse, and so you will have to understand, who are the patients who felt better? What is the categorical change of having 5 or more points of improvement in KCCQ? That’s where we don’t have the data yet, and I think that data will help us understand the symptom perspective.”

Editors’ Note: Masri reports disclosures with Pfizer, Attralus, Eidos, Ionis, Cytokinetics, BioMarin, and others.

Cytokinetics. Cytokinetics Announces Positive Topline Results from ACACIA-HCM, the Pivotal Phase 3 Clinical Trial of Aficamten in Patients with Non-Obstructive Hypertrophic Cardiomyopathy. May 5, 2026. Accessed May 8, 2026. 

https://ir.cytokinetics.com/press-releases/press-release-details/2026/Cytokinetics-Announces-Positive-Topline-Results-from-ACACIA-HCM-the-Pivotal-Phase-3-Clinical-Trial-of-Aficamten-in-Patients-with-Non-Obstructive-Hypertrophic-Cardiomyopathy/default.aspx

Cytokinetics. Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic nHCM (ACACIA-HCM). ClinicalTrials.gov Identifier: NCT06081894. Updated February 2, 2026. Accessed May 8, 2026. 

https://clinicaltrials.gov/study/NCT06081894

Videos

Ahmad Masri, MD, from OHSU, discusses the positive topline results from this phase 3 trial, highlighting a new path forward for nHCM.

To close the discussion, Dr Maron and Dr Masri address how surgical myectomy and alcohol septal ablation fit into a therapeutic ecosystem that now includes potent sarcomere-directed drugs. Masri stresses that clinicians have an obligation to present all reasonable options—medical and invasive—and to individualize decisions through shared decision-making. Although cardiac myosin inhibitors offer a noninvasive, reversible approach that can be maintained long term, patients must understand that therapy is generally chronic, and gradients and symptoms recur when treatment is discontinued. By contrast, septal reduction, particularly surgical myectomy, can offer a more definitive “one-and-done” solution, albeit with higher upfront procedural risk and recovery.

Integrating Myosin Inhibitors With Septal Reduction and Future Directions in Nonobstructive HCM

Maron underscores that a subset of patients with complex LVOT and mitral valve anatomy may have residual obstruction and symptoms despite optimal myosin inhibition. For these individuals, structural intervention remains essential to address anatomic contributors that pharmacologic modulation cannot fully overcome. Younger patients, women planning pregnancy, and individuals strongly averse to lifelong pharmacotherapy and monitoring may also reasonably favor septal reduction, provided they understand and accept procedural risks. The experts agree that myosin inhibitors are unlikely to obviate the need for expert septal reduction centers but will instead complement and refine referral patterns.

Finally, the discussion looks ahead to nonobstructive HCM. Masri cites the neutral ODYSSEY-HCM trial of mavacamten in nonobstructive disease but expresses optimism regarding the ongoing ACACIA-HCM trial evaluating aficamten in this population. Both clinicians regard nonobstructive HCM as a major remaining unmet need, given the lack of targeted therapies that reliably improve exercise capacity and symptoms. Maron concludes that results from trials like ACACIA-HCM will be pivotal in determining whether the benefits of myosin inhibition can extend beyond obstructive physiology, potentially redefining care for an even broader spectrum of patients with HCM.

Maron and Masri define the ongoing role of surgical myectomy and alcohol septal ablation in the myosin inhibitor era and preview emerging trials of aficamten in nonobstructive HCM.

In this segment, Dr Maron poses a key practical question: in newly presenting, treatment-naive patients with symptomatic obstructive HCM, should clinicians still begin with traditional beta-blockers or calcium channel blockers, or has the evidence base matured sufficiently to justify first-line use of cardiac myosin inhibitors? Dr Masri responds by highlighting the MAPLE-HCM trial, in which aficamten, used as first-line monotherapy, outperformed metoprolol in terms of LVOT gradient reduction and symptomatic improvement. Notably, metoprolol was associated with worsening exercise capacity, higher N-terminal pro–brain natriuretic peptide levels, and increased left atrial volume index.

Positioning Cardiac Myosin Inhibitors as First-Line Therapy: Evidence Versus Beta-blockers

Both faculty members emphasize that, while formal head-to-head comparisons of beta-blockers with mavacamten are lacking, the limited and largely nonrandomized evidence for beta-blockers contrasts sharply with the robust phase 3 data for myosin inhibitors. Given the magnitude and consistency of gradient reduction and symptom improvement, Masri explains that in his practice, he moves rapidly toward myosin inhibition in highly symptomatic, markedly obstructed patients rather than spending prolonged periods titrating conventional agents to maximal tolerated doses. Maron argues that, based on current data, it is reasonable to consider aficamten as initial monotherapy in suitable patients.

The clinicians also acknowledge real-world constraints, including payer requirements that may still mandate a trial of traditional negative inotropes before authorizing myosin inhibitors. Maron clarifies that this first-line positioning pertains specifically to treatment of obstruction-related symptoms and does not supersede beta-blocker use when indicated for other conditions such as atrial fibrillation or hypertension. Nonetheless, both experts concur that the totality of evidence now supports consideration of aficamten as a legitimate first-line option for symptomatic obstructive HCM, reflecting a substantial evolution in standard of care.

Maron and Masri discuss whether myosin inhibitors, particularly aficamten, should be considered first-line therapy for symptomatic obstructive HCM in treatment-naive patients, in light of data from trials like MAPLE-HCM.

Here, Dr Masri outlines the pivotal phase 3 data for mavacamten, beginning with the EXPLORER-HCM trial, a randomized, placebo-controlled study that demonstrated significant improvements in peak oxygen consumption and New York Heart Association (NYHA) functional class in symptomatic obstructive HCM. 

Phase 3 Evidence and Safety Framework for Myosin Inhibitors: EXPLORER, VALOR, SEQUOIA, and REMS

Here, Dr Masri outlines the pivotal phase 3 data for mavacamten, beginning with the EXPLORER-HCM trial, a randomized, placebo-controlled study that demonstrated significant improvements in peak oxygen consumption and New York Heart Association (NYHA) functional class in symptomatic obstructive HCM. These clinical benefits paralleled substantial reductions in LVOT gradients and favorable changes in biomarkers of wall stress and myocardial injury. The subsequent VALOR-HCM trial enrolled patients already referred for septal reduction therapy and showed that mavacamten could avert or defer invasive intervention in a large proportion of participants by effectively lowering gradients and improving symptoms.

Dr Maron then summarizes phase 3 experience with aficamten, particularly the SEQUOIA-HCM trial, which similarly showed marked gradient reduction, consistent symptom relief, and improvement in health status metrics such as NYHA class and Kansas City Cardiomyopathy Questionnaire scores. Both physicians stress that, across studies, a high percentage of treated patients achieve LVOT gradients below 30 mm Hg, aligning hemodynamic improvements with observed functional gains. These data underpin the positioning of cardiac myosin inhibitors as high-benefit therapies capable of restoring many patients to good or excellent quality of life.

The discussion transitions to safety, especially treatment-emergent systolic dysfunction. Maron notes that both mavacamten and aficamten can, in a minority of patients, reduce left ventricular ejection fraction (LVEF) below the desired range. Consequently, the FDA mandated Risk Evaluation and Mitigation Strategy (REMS) programs for both agents, centered on serial echocardiographic monitoring and algorithmic dose adjustment. Masri highlights that aficamten’s development relied exclusively on echocardiographic guidance (without drug-level monitoring), showed a lower incidence of systolic dysfunction, and was not associated with clinical heart failure events in SEQUOIA-HCM. These features, along with fewer drug–drug interactions and more flexible titration, are reflected in a comparatively streamlined and clinician-friendly REMS structure for aficamten.

Maron and Masri review pivotal phase 3 trials of mavacamten and aficamten and explain how efficacy and systolic function monitoring shaped their respective REMS programs.

Ahmad Masri, MD, MS

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