Mavacamten
Details
Mavacamten is a first-in-class cardiac myosin adenosine triphosphatase (ATPase) inhibitor approved for symptomatic obstructive hypertrophic cardiomyopathy (HCM). It acts by reducing actin–myosin cross-bridge formation, thereby decreasing contractility, reducing LVOT gradients, and improving myocardial energetics. It represents the first disease-targeted pharmacological therapy for HCM.
Key Facts
- Mechanism: Inhibits cardiac myosin ATPase → reduces actin–myosin cross-bridge formation → reduces hypercontractility and dynamic LVOT obstruction → improves energetics. (sources/esc-cmp-2023)
- EXPLORER-HCM trial: In adults with symptomatic obstructive HCM (NYHA II–III, LVEF >55%), mavacamten significantly reduced LVOT gradient and improved exercise capacity vs. placebo; 27% of patients achieved LVOT gradient <30 mmHg and NYHA class I. (sources/esc-cmp-2023)
- VALOR-HCM trial: In patients with obstructive HCM referred for SRT due to intractable symptoms, mavacamten significantly reduced the proportion meeting criteria for SRT at 16 and 32 weeks. (sources/esc-cmp-2023)
- CMR/echo substudies: Mavacamten may lead to positive myocardial remodelling — reduction in LV mass, wall thickness, and left atrial volume. (sources/esc-cmp-2023)
- Safety: Generally well tolerated; a small subset develops transient LV systolic dysfunction, which resolves after temporary discontinuation. LVEF must be monitored by echocardiography during dose up-titration. (sources/esc-cmp-2023)
- ESC Recommendation: Class IIa, Level A — as addition to beta-blocker (or, if not possible, with verapamil/diltiazem) in adult patients with resting or provocable LVOTO remaining symptomatic on optimal medical therapy. (sources/esc-cmp-2023)
- Positioning in algorithm: Second-line therapy after beta-blockers; alternative to disopyramide (not used together due to lack of safety data). (sources/esc-cmp-2023)
- Pipeline agent: Aficamten (next-in-class cardiac myosin inhibitor, CK-3773274) showed significant reduction in LVOT gradients and NT-proBNP in Phase II REDWOOD-HCM trial. (sources/esc-cmp-2023)
- Molecular mechanism (bench): In transgenic HCM mouse models, MYK-461 prevented development of LV hypertrophy and fibrosis. In iPSC-CMs, it improved the proportion of myosin heads in the overrelaxation state. (sources/HCM-VA-FCVMed-2022)
- Clinical trials for HCM: Proven effective and safe in PIONEER-HCM (NCT02842242), EXPLORER-HCM (NCT03470545), MAVERICK-HCM (NCT03442764), and VALOR-HCM (NCT04349072). (sources/HCM-VA-FCVMed-2022)
- Arrhythmia and SCD: No direct trial evidence on ventricular arrhythmia or SCD prevention; the hypothesis is that improved functional status, LV remodeling reversal, and reduced Ca²⁺ sensitivity may indirectly reduce arrhythmic risk — this remains to be studied. (sources/HCM-VA-FCVMed-2022)
- Do NOT use with disopyramide. May be coadministered with beta-blockers or calcium antagonists. (sources/esc-cmp-2023)
- AHA 2024 — Class I recommendation (upgraded from ESC IIa): Mavacamten is now Class I (Level B-R) as a step-3 option alongside disopyramide or SRT for adult patients with persistent obstructive HCM symptoms despite beta-blockers or calcium channel blockers. (sources/HCM-AHA-2024)
- REMS (Risk Evaluation and Mitigation Strategy) required: LVEF <50% attributable to mavacamten occurs in 5.7% (as high as 7–10% when confounders are included); requires echocardiographic LVEF monitoring throughout treatment. (sources/HCM-AHA-2024)
- Mandatory discontinuation (Class I, Level B-R): Mavacamten MUST be discontinued in patients who develop persistent LVEF <50%, regardless of symptoms; may be restarted at lower dose if LVEF recovers. (sources/HCM-AHA-2024)
- Absolute contraindication in pregnancy (Class III: Harm — NEW 2024): Mavacamten is contraindicated during pregnancy due to potential teratogenic effects. (sources/HCM-AHA-2024)
- Mavacamten is approved for adult patients only in the AHA 2024 guideline; pediatric use is not endorsed. (sources/HCM-AHA-2024)
Contradictions / Open Questions
- AHA 2024 Class I vs. ESC 2023 Class IIa — divergent treatment tier: AHA 2024 positions mavacamten as Class I step-3 therapy (equivalent to disopyramide or SRT) for adult obstructive HCM. ESC 2023 places it at Class IIa, step 4 — considered only after disopyramide has failed or is not tolerated. No head-to-head trial comparing mavacamten directly to disopyramide exists; the different tiers reflect guideline committee interpretation of the same trial data. (sources/HCM-AHA-2024, sources/esc-cmp-2023)
- No direct arrhythmia/SCD evidence: Mavacamten's potential to reduce ventricular arrhythmia or SCD is entirely hypothetical — postulated through improved hemodynamics, LV remodeling reversal, and reduced Ca²⁺ sensitivity. None of the pivotal trials (PIONEER, EXPLORER, MAVERICK, VALOR) included SCD or VA as primary endpoints. The approved indication is symptom relief and LVOT gradient reduction, not arrhythmia prevention. (sources/HCM-VA-FCVMed-2022)
- REMS and mandatory LVEF monitoring — real-world adherence: LVEF <50% attributable to mavacamten occurs in 5.7–10% of patients; it requires echocardiographic monitoring throughout treatment under a formal REMS program. Real-world adherence to monitoring schedules and whether discontinuation rates mirror trial conditions is unknown. (sources/HCM-AHA-2024)
Connections
- Related to entities/HCM
- Related to concepts/LVOTO
- Related to concepts/Septal-Reduction-Therapy
- Related to concepts/Calcium-Homeostasis-in-HCM