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 (Lancet 2020; N=251; 30 weeks; 68 centres, 13 countries): Phase 3 RCT in obstructive HCM (LVOT ≥50 mmHg, NYHA II–III, LVEF ≥55%) — mavacamten (5–15 mg) vs placebo on background beta-blocker or CCB therapy. Primary composite (pVO2 + NYHA improvement): 37% vs 17% (+19.4%; p=0.0005). Post-exercise LVOT gradient: −35.6 mmHg (p<0.0001). NYHA ≥1 class improvement: 65% vs 31% (p<0.0001). KCCQ-CSS +9.1 points. Complete response (all LVOT <30 mmHg + NYHA I): 27% vs 1%. NT-proBNP 80% greater reduction; hs-cTnI 41% greater reduction. Safety similar to placebo; transient LVEF <50% in 7 mavacamten patients, all recovered. (sources/mavacamten-explorer-hcm-lancet-2020, rating: very high) (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)
- Aficamten (next-in-class cardiac myosin inhibitor): Aficamten has advanced beyond phase 2 (REDWOOD-HCM) to phase 3 evidence: SEQUOIA-HCM (NEJM 2024, vs placebo) and MAPLE-HCM (NEJM 2025, vs metoprolol as monotherapy). MAPLE-HCM showed aficamten superior to metoprolol on peak VO2, LVOTO gradient, NT-proBNP, and LAVi — first head-to-head evidence positioning cardiac myosin inhibitors over beta-blockers as monotherapy. See entities/Aficamten. (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)
- ODYSSEY-HCM trial (NEJM 2025) — Negative in nonobstructive HCM: Phase 3, double-blind, placebo-controlled RCT (N=580; 201 centers; 22 countries; 48 weeks). In symptomatic nonobstructive HCM (LVOTO <30 mmHg rest / <50 mmHg provocation), mavacamten did NOT significantly improve peak VO2 (difference +0.47 ml/kg/min; P=0.07) or KCCQ-CSS (difference +2.7 points; P=0.06) vs placebo. NT-proBNP was substantially reduced (geometric mean ratio 0.41), but this biomarker improvement did not translate to clinical benefit. Regimen interruption for LVEF <50% occurred in 25.7% vs 7.6% (placebo); serious CHF events in 6.6% vs 1.7%. Mavacamten is ineffective and potentially harmful in nonobstructive HCM. (sources/mavacamten-odysseyhcm-nejm-2025, rating: very high)
- 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)
- ODYSSEY-HCM (2025) — Mavacamten ineffective and potentially harmful in nonobstructive HCM: Phase 3 RCT (N=580, 48 weeks) showed mavacamten did NOT improve peak VO2 (P=0.07) or KCCQ-CSS (P=0.06) in symptomatic nonobstructive HCM. Despite large NT-proBNP reduction (geometric mean ratio 0.41), no clinical benefit was observed — biomarker benefit did not predict clinical efficacy. Serious CHF events occurred in 6.6% of mavacamten patients vs 1.7% placebo; LVEF <50% in 21.5% vs 1.7%. This contrasts sharply with beneficial effects in obstructive HCM, confirming that LVOTO relief is the primary mechanism of clinical benefit. Mavacamten is NOT indicated in nonobstructive HCM. (sources/mavacamten-odysseyhcm-nejm-2025)
Connections
- Related to entities/HCM
- Related to concepts/LVOTO
- Related to concepts/Septal-Reduction-Therapy
- Related to concepts/Calcium-Homeostasis-in-HCM
- Related to concepts/Sarcomere-Biology