What is the recommended treatment protocol for Mavacamten (mavacamten) in patients with symptomatic Hypertrophic Obstructive Cardiomyopathy (HoCM)?

Mavacamten Treatment Protocol for Symptomatic Obstructive Hypertrophic Cardiomyopathy

Treatment Positioning

Mavacamten is recommended as second-line therapy for adults with NYHA class II-III obstructive HCM who remain symptomatic despite maximally tolerated beta-blockers or nondihydropyridine calcium channel blockers. 1, 2, 3

Treatment Algorithm

First-Line Therapy:

• Initiate nonvasodilating beta-blockers, titrated to resting heart rate <60-65 bpm 1
• Alternative: verapamil or diltiazem (up to 480 mg/day) if beta-blockers are ineffective, contraindicated, or poorly tolerated 1

Second-Line Therapy:

• Add mavacamten for persistent symptoms despite adequate first-line therapy trial 1, 2, 3
• This represents a Class 1 recommendation from the American College of Cardiology and American Heart Association 2, 3

Pre-Treatment Requirements

Mandatory assessments before initiating mavacamten:

• Negative pregnancy test in all women of childbearing potential 1, 3
• Baseline echocardiogram with LVEF measurement 3
• Confirmation of adequate trial of first-line therapy 1

Absolute contraindications:

• Pregnancy (teratogenic effects) 1, 2, 3, 4
• Women of childbearing potential must use effective contraception until 4 months after the last dose 3

Dosing Protocol

Initial dosing:

• Start at 5 mg once daily 5
• Dose titrations performed using symptom assessment, LVOT gradient, and LVEF measurements 5
• Available doses: 2.5 mg, 5 mg, 10 mg, 15 mg for titration based on response and tolerability 4

CYP2C19 poor metabolizers:

• Mavacamten AUC increases by 241% and half-life extends to 23 days (versus 6-9 days in normal metabolizers) 4
• Approximately 13% of East Asians, 4% of individuals of African ancestry, and 2% of individuals of European ancestry are poor metabolizers 4

Monitoring Requirements

Echocardiographic monitoring schedule:

• Baseline, then every 4 weeks during treatment 3
• Assess LVEF and LVOT gradients (resting and Valsalva) at each visit 5

Critical monitoring timepoints:

• Week 4: Expect mean Valsalva LVOT gradient reduction from ~72 mmHg to ~29 mmHg 5
• Week 8: Sustained gradient reduction to ~29 mmHg 5
• Week 12: Continued gradient reduction to ~30 mmHg 5

Safety Thresholds and Mandatory Interventions

LVEF reduction <50%:

• Mandatory interruption of mavacamten if LVEF falls below 50% at any visit 1, 2, 3
• LVEF reduction risk: 5.7% attributable to drug alone, up to 7-10% when considering other clinical conditions 1, 2
• In real-world experience, only 2-3% of patients required temporary interruption for LVEF <50% 5, 6
• Mean LVEF decreases from ~66% at baseline to ~62% at 12 weeks 5

Persistent systolic dysfunction:

• Discontinue mavacamten if LVEF remains <50% 3
• Consider interruption during intercurrent illness that could affect cardiac function 3

Expected Clinical Outcomes

Efficacy data:

• 30-60% of patients achieve improvement in LVOT gradients, symptoms, and functional capacity 1, 2, 3
• 46% of patients experience ≥1 NYHA class improvement, with an additional 18% achieving ≥2 NYHA class improvement 5
• At 12 weeks, 70% of patients have Valsalva LVOT gradients reduced to <30 mmHg (from 100% at baseline) 5
• Peak oxygen consumption increases by mean of 3.5 mL/kg/min in patients without background medications 7

Long-term outcomes at 56 weeks:

• Only 8.9% of patients in the mavacamten group underwent SRT or remained SRT-eligible 8
• 89% of patients continued mavacamten long-term 8
• Sustained reduction in resting LVOT gradient by -34 mmHg and Valsalva gradient by -46 mmHg 8

Important Drug Interactions

Strong CYP3A4 inhibitors (e.g., ketoconazole):

• Predicted to increase mavacamten AUC by 130% and Cmax by 90% 4

Moderate CYP3A4 inhibitors (verapamil, diltiazem):

• Verapamil increases mavacamten AUC by 16% and Cmax by 52% 4
• Diltiazem predicted to increase AUC by 55% and Cmax by 42% in CYP2C19 poor metabolizers 4

Strong CYP2C19/CYP3A4 inducers (e.g., rifampin):

• Decrease mavacamten AUC by 87% in normal metabolizers 4

Hepatic Impairment Considerations

Dose adjustments needed:

• Mavacamten exposures increase up to 220% in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment 4
• Effect of severe hepatic impairment (Child-Pugh C) is unknown 4

Risk Evaluation and Mitigation Strategy (REMS)

Mandatory REMS program enrollment:

• All prescribers and patients must enroll in the REMS program 2, 5
• Regular echocardiographic monitoring is essential for program compliance 2, 3
• Real-world data demonstrates logistic feasibility of prescribing under REMS at tertiary care centers 5

Critical Caveats

Age restrictions:

• Mavacamten is approved only for adult patients, not for pediatric use 2, 3

Patients without symptomatic improvement:

• Even in 40 patients reporting no symptomatic improvement, mean Valsalva LVOT gradient still decreased significantly from 73 mmHg to 30 mmHg at 12 weeks 5
• This suggests objective hemodynamic improvement may occur independent of subjective symptom relief 5

Adverse events:

• Mostly mild (80%) and unrelated to drug (79%) 7
• Most common drug-related adverse events: decreased LVEF at higher plasma concentrations and atrial fibrillation 7
• In real-world experience, adverse events were rare and seen primarily in patients with advanced disease not represented in clinical trials 6