What is the role of Mavacamten (mavacamten) in the treatment of obstructive Hypertrophic Cardiomyopathy (HOCM)?

Obstructive Hypertrophic Cardiomyopathy and Mavacamten

What is Obstructive HCM?

Obstructive hypertrophic cardiomyopathy (HOCM) is a genetic disorder characterized by thickened heart muscle that creates dynamic left ventricular outflow tract (LVOT) obstruction, leading to symptoms of exertional dyspnea, chest pain, palpitations, and reduced functional capacity. 1

The pathophysiology involves:

• Excess myosin-actin cross-bridge formation causing both systolic force generation and residual diastolic cross-bridges 2
• Dynamic LVOT obstruction that worsens with exercise or Valsalva maneuver 1
• Impaired diastolic relaxation and compliance 1
• Mitral regurgitation secondary to systolic anterior motion 1

Mavacamten's Role in Treatment

Treatment Algorithm Positioning

Mavacamten is recommended as second-line therapy for adults with symptomatic NYHA class II-III obstructive HCM who remain symptomatic despite maximally tolerated first-line therapy with beta-blockers or nondihydropyridine calcium channel blockers. 3, 4, 5

The treatment hierarchy is:

1. First-line: Beta-blockers (titrated to resting heart rate <60-65 bpm) or nondihydropyridine calcium channel blockers (verapamil or diltiazem up to 480 mg/day) 3, 4

2. Second-line (for persistent symptoms): Mavacamten, disopyramide, or septal reduction therapy 3, 4

This represents a Class 1 recommendation from the American College of Cardiology and American Heart Association. 4, 5

Mechanism of Action

Mavacamten is a first-in-class cardiac myosin inhibitor that works by:

• Allosterically and reversibly inhibiting cardiac myosin 2
• Reducing the number of myosin heads that can enter "on actin" power-generating states 2
• Shifting the myosin population toward an energy-sparing, super-relaxed state 2
• Reducing dynamic LVOT obstruction and improving cardiac filling pressures 2

Clinical Efficacy

Mavacamten improves LVOT gradients, symptoms, and functional capacity in 30-60% of patients with obstructive HCM. 3, 4, 5

Specific improvements include:

• LVOT gradient reduction: Mean reductions of -39 mmHg (resting) and -49 mmHg (Valsalva) at 30 weeks, with effects visible by Week 4 2
• Functional capacity: Improvement in peak oxygen consumption 4
• Symptom relief: Reduction in NYHA functional class 4, 5
• Quality of life: Enhanced quality of life scores 4
• Cardiac biomarkers: 80% greater reduction in NT-proBNP compared to placebo 2
• Cardiac remodeling: Reduction in left ventricular mass index and left atrial volume index 2

Real-world data confirms these findings, with 46% of patients achieving ≥1 NYHA class improvement and mean Valsalva LVOT gradients decreasing from 72 mmHg to 29 mmHg at 4 weeks. 6

Critical Safety Considerations and Monitoring

Mandatory LVEF Monitoring

Mavacamten must be interrupted if LVEF falls below 50% at any visit. 3, 4

The risk profile includes:

• LVEF reduction <50%: Occurs in 5.7% of patients due to mavacamten alone, but up to 7-10% when considering intercurrent illnesses 3, 4
• Monitoring schedule: Echocardiography required before initiation and every 4 weeks during treatment 5
• Reversibility: LVEF and LVOT gradients return to baseline within 8 weeks after discontinuation 2

In real-world experience, only 2% of patients required temporary interruption for LVEF <50%, with clinically insignificant mean LVEF decreases. 7, 6

Absolute Contraindications

Pregnancy is an absolute contraindication due to teratogenic effects. 3, 4, 5

Requirements include:

• Mandatory negative pregnancy test before initiation in women of childbearing potential 3
• Effective contraception required until 4 months after the last dose 5

Drug Interactions and Special Populations

CYP2C19 poor metabolizers have 241% increased mavacamten exposure and prolonged half-life (23 days vs. 6-9 days). 2

Key interactions:

• Strong CYP3A4 inhibitors (ketoconazole): Increase mavacamten exposure by 130% 2
• Moderate CYP3A4 inhibitors (verapamil, diltiazem): Increase exposure by 16-55% 2
• Strong CYP2C19/CYP3A4 inducers (rifampin): Decrease exposure by 87% 2
• Disopyramide: Concomitant use not recommended due to additive negative inotropic effects 8

When transitioning from disopyramide to mavacamten, taper disopyramide while starting mavacamten rather than complete washout to avoid worsening heart failure symptoms. 8

Pediatric and Geriatric Use

• Not approved for pediatric use 4, 5, 2
• No dose adjustment needed in geriatric patients: Safety and efficacy similar in patients ≥65 years 2

Hepatic and Renal Impairment

• No dose adjustment required for mild-moderate hepatic impairment (Child-Pugh A-B), despite up to 220% increased exposure, due to the dose titration algorithm 2
• Severe hepatic impairment (Child-Pugh C): Effect unknown 2
• Renal impairment: No dose adjustment needed for mild-moderate impairment; severe impairment and dialysis effects unknown 2

Dosing Strategy

Mavacamten uses an echocardiography-based, clinically guided dose-titration strategy starting at 5 mg once daily, with adjustments based on Valsalva LVOT gradient and LVEF. 9, 6

This individualized approach:

• Identifies the lowest effective dose for each patient 9
• Provides favorable safety profile regardless of CYP2C19 metabolizer status 9
• Allows for dose adjustments during intercurrent illness 9

Common Pitfalls to Avoid

1. Do not initiate mavacamten before adequate trial of first-line beta-blockers or calcium channel blockers 3
2. Do not abruptly discontinue disopyramide when transitioning to mavacamten—use a tapering approach 8
3. Do not use in patients with severe outflow obstruction who are also on vasodilators or high-dose diuretics without careful monitoring 1
4. Do not overlook pregnancy screening in women of childbearing potential 3, 5
5. Do not continue mavacamten if LVEF persistently <50% 3, 4