Mavacamten: The Newer Molecule for HOCM
Mavacamten is the newer molecule for hypertrophic obstructive cardiomyopathy (HOCM), representing the first FDA-approved cardiac myosin inhibitor specifically designed to treat this condition. 1
Mechanism and Drug Class
Mavacamten is a first-in-class cardiac myosin inhibitor that works by allosterically inhibiting cardiac myosin ATPase, reducing actin-myosin cross-bridge formation, thereby decreasing myocardial contractility and improving myocardial energetics. 2
This represents a paradigm shift from traditional therapies (beta-blockers, calcium channel blockers, disopyramide) because it directly targets the underlying pathophysiology of HCM rather than just managing symptoms. 3, 2
Current Guideline-Based Positioning
The 2024 AHA/ACC guidelines now recommend mavacamten as a Class 1 indication for adult patients with obstructive HCM who have persistent symptoms (NYHA class II-III) despite first-line therapy with beta-blockers or nondihydropyridine calcium channel blockers. 4
Treatment Algorithm:
- First-line: Beta-blockers or nondihydropyridine calcium channel blockers (verapamil, diltiazem) 4
- Second-line (if symptoms persist): Add mavacamten (adult patients only), OR disopyramide (with AV nodal blocking agent), OR septal reduction therapy at experienced centers 4
Clinical Efficacy
Mavacamten improves LVOT gradients, symptoms, and functional capacity in 30-60% of patients with obstructive HCM. 4, 5
Demonstrated significant reductions in both resting and post-exercise LVOT gradients, improvement in peak oxygen consumption, reduction in NYHA functional class, and enhanced quality of life scores. 5, 3
Unique advantage: Unlike other medications, mavacamten can delay or even obviate the need for septal reduction therapy, as demonstrated in the VALOR-HCM trial. 3, 6
Critical Safety Concerns and Monitoring Requirements
Mandatory REMS Program:
- Mavacamten is only available through a Risk Evaluation and Mitigation Strategy (REMS) program due to the risk of heart failure from systolic dysfunction. 1, 5
LVEF Monitoring:
- LVEF reduction <50% occurs in 5.7% of patients attributable solely to the drug, but up to 7-10% when other clinical conditions are considered. 4, 5
- Do not initiate if LVEF <55%; interrupt treatment if LVEF falls <50% or if clinical status worsens. 1
- Mandatory echocardiographic monitoring is required before initiation and every 4 weeks during treatment. 4, 1
Absolute Contraindications:
- Pregnancy: Mavacamten is contraindicated due to teratogenic effects; females of reproductive potential must use effective contraception until 4 months after the last dose. 4, 1
- Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors (increased heart failure risk) 1
- Moderate to strong CYP2C19 or CYP3A4 inducers (loss of effectiveness) 1
Drug Interactions:
- Weak CYP2C19 inhibitors and moderate CYP3A4 inhibitors require dose reduction and additional monitoring. 1
- Close supervision required when combining with other negative inotropes; avoid certain combinations. 1
Important Clinical Caveats
Age Restriction:
When to Discontinue:
- Must discontinue if persistent systolic dysfunction (LVEF <50%) develops. 4, 5
- Consider interruption during intercurrent illness that could affect cardiac function. 1
Not for Asymptomatic Patients:
- No role for mavacamten in asymptomatic patients with HCM, including those with apical HCM—treatment should only be initiated if symptoms develop. 7
Comparison to Traditional Therapies
Unlike beta-blockers and calcium channel blockers, which have vasodilating properties that can be limiting, mavacamten directly reduces hypercontractility without these hemodynamic effects. 4
Unlike disopyramide, which requires combination with AV nodal blocking agents due to risk of rapid AF conduction, mavacamten does not have this requirement. 4
Unlike septal reduction therapy (surgical myectomy or alcohol septal ablation), mavacamten is non-invasive and reversible, though it requires ongoing monitoring and medication adherence. 4, 3