Mavacamten

Mechanism of Action

Mavacamten is an allosteric, selective, and reversible inhibitor of cardiac myosin ATPase.[3][12] This first-in-class medication reduces the formation of actin-myosin cross-bridges, thus reducing the probability of systolic and diastolic cross-bridge formation. Excessive myosin-actin cross-bridge arrangement and dysregulation of the relaxed state are characteristic of HCM. Mavacamten promotes an energy-sparing and super-relaxed state that translates as a reduction in LVOT obstruction and improvement of cardiac filling pressures.[13]

Pharmacokinetics

Absorption: Mavacamten is rapidly absorbed with an oral bioavailability of 85%. Meal timing does not affect its absorption, and the time to maximum concentration (Tmax) is 1 to 2 hours.

Distribution: The plasma protein binding of mavacamten is approximately 97%.[14]

Metabolism: Mavacamten is primarily metabolized by CYP2C19 and, to a lesser extent, by CYP3A4. The accumulation of mavacamten is significantly influenced by CYP2C19 metabolism status, particularly, with the most pronounced accumulation occurring in patients who are poor metabolizers of CYP2C19.[15][16]

Elimination: More than 80% of mavacamten is eliminated in urine.[12][13] The mean elimination half-life is about 8 days.[17]

Administration

Available Dosage Forms and Strengths

Mavacamten is administered orally in capsule form, with available doses of 2.5 mg, 5 mg, 10 mg, and 15 mg.

Adult Dosages

The recommended initial dosage of mavacamten is 5 mg once daily. Dose titration can occur every 4 weeks, with a maximum daily dose of 15 mg. The target plasma concentration ranges from 350 to 700 ng/mL, and it may take several weeks to reach steady-state levels and achieve the associated therapeutic effects.[17] The patient's clinical status, LVEF, and LVOT gradient should be assessed before starting treatment and monitored regularly during therapy. Please refer to the initial maintenance and treatment interruption protocol adapted from the prescribing information and the monitoring section for more details (see Images. Mavacamten Initiation, Mavacamten Maintenance, and Mavacamten Interruption).

Specific Patient Populations

Hepatic impairment: Mavacamten exposure (area under the curve [AUC]) significantly increases in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. The impact of severe hepatic impairment (Child-Pugh class C) is unknown; therefore, mavacamten should be used cautiously in these patients.

Renal impairment: Dosage adjustments are not necessary for patients with mild-to-moderate renal impairment (estimated glomerular filtration rate [eGFR]: 60-89 mL/min/1.73 m² and 30-59 mL/min/1.73 m², respectively). However, the effects of severe renal impairment (eGFR: 15-30 mL/min/1.73 m²) and kidney failure (eGFR: <15 mL/min/1.73 m², including patients on dialysis) remain uncertain.

Pregnancy considerations: Mavacamten was found to pose a risk of fetal toxicity based on animal studies. The absence of pregnancy should be confirmed before initiating treatment, and patients should be advised to use effective contraception during mavacamten therapy and for 4 months after treatment cessation. Combined hormonal contraceptives containing ethinyl estradiol and norethindrone are compatible with mavacamten. However, mavacamten may reduce the effectiveness of certain progestins. Therefore, it is recommended to use non-hormonal contraceptive methods alongside hormonal contraceptives during therapy and for 4 months after discontinuing mavacamten.[18]

Breastfeeding considerations: The presence of mavacamten in human or animal milk, its effects on the breastfed infant, and its impact on milk production are unknown. Therefore, when prescribing mavacamten to breastfeeding mothers, the benefits of breastfeeding should be weighed against the clinical necessity of the medication and the potential risks to the infant. 

Pediatric patients: The safety and effectiveness of mavacamten have not been established for pediatric patients.

Older patients: Studies involving mavacamten found no significant differences in safety or effectiveness in older patients.

Adverse Effects

Mavacamten reduces systolic contraction and may lead to worsening heart failure or a complete block of ventricular function. A reduction in LVEF of up to 10% has been reported. In the phase III EXPLORER trial, dizziness (27%) and syncope (6%) were the most common adverse effects.[3][17] 

The potential adverse reactions associated with mavacamten therapy include:

• Acute stress cardiomyopathy
• Ventricular tachycardia
• Angina pectoris
• Headache
• Dyspnea
• Chest pain
• Fatigue
• Palpitations
• Pedal edema
• Atrial fibrillation [19]

Drug-Drug Interactions

The concurrent administration of weak CYP2C19 inhibitors or moderate CYP3A4 inhibitors with mavacamten increases drug exposure. In patients on stable therapy with these inhibitors, mavacamten should be initiated at a daily dose of 5 mg. For patients already on mavacamten, the dose should be reduced (eg, from 15 to 10 mg) when starting these inhibitors. Weak CYP2C19 and moderate CYP3A4 inhibitors should be avoided in patients receiving 2.5 mg of mavacamten due to the lack of a lower dosage option.

Concurrent administration of mavacamten with medications that have adverse inotropic effects may exacerbate cardiac dysfunction. Coadministration with disopyramide, ranolazine, verapamil, β-blockers, or diltiazem should be avoided due to the increased risk of left ventricular systolic dysfunction and heart failure. Rigorous monitoring of LVEF is crucial when initiating or titrating negative inotropic agents until stable dosing and clinical response are achieved.

Contraindications

As mavacamten is metabolized by CYP2C19 and CYP3A4 enzymes, coadministration with potent CYP2C19 or CYP3A4 inhibitors (eg, verapamil and ketoconazole) or potent CYP2C19 or CYP3A4 inducers (eg, rifampin) is associated with a higher risk of systolic dysfunction, heart failure exacerbation, or loss of medication effectiveness.

Box Warnings

Mavacamten should not be initiated in patients with an LVEF of less than 55% due to the risk of worsening systolic function. The use of this medication is also not recommended for patients taking disopyramide, ranolazine, or for those using a non-dihydropyridine calcium channel blocker in combination with a β-blocker, as interactions with these medications have not been studied, and there is potential for additive negative inotropic effects.[3]

Mavacamten use in pregnant women is not recommended due to fetal toxicity observed in animal studies. Effective contraception should be ensured before initiating therapy. Mavacamten may reduce the effectiveness of combined hormonal contraceptives, so non-hormonal contraceptive methods not affected by CYP450 enzymes are recommended. Contraception should continue for at least 4 months after discontinuing mavacamten.

Mavacamten is available only through a Risk Evaluation and Mitigation Strategy (REMS) program due to the potential risk of heart failure.[20]

Monitoring

Patients on mavacamten require continuous monitoring for exacerbation of heart failure and periodic echocardiographic follow-up to assess LVEF and LVOT gradient. Mavacamten has been associated with nearly complete resolution of mitral valve systolic anterior motion and a reduction in the LVOT gradient. Additionally, reductions in left ventricular mass index, left atrial volume index, and lateral E/e' have been observed in patients receiving mavacamten. These echocardiographic improvements are also associated with reductions in natriuretic peptides and cardiac troponin I, which are markers of myocardial injury and stress. Regarding cardiac structural changes, mavacamten use has not been associated with reductions in interventricular septum thickness or left ventricular end-diastolic diameter. However, compared to placebo, significant changes have been observed in inferolateral wall thickness and left ventricular end-systolic diameter.[21]

Once treatment is started, the LVOT gradient should be assessed after 4 weeks. For patients with an LVOT gradient of less than 20 mm Hg, the dose should be titrated to the next lower available dose (eg, from 5 to 2.5 mg daily), with reevaluation at 12 weeks. The current dose should be maintained if the patient's LVOT gradient is between 20 and 30 mm Hg with an LVEF of more than 50%. If the LVOT gradient exceeds 20 mm Hg, a repeat evaluation is recommended at 8 weeks. For patients on 2.5 mg daily, if the LVOT gradient is between 20 and 30 mm Hg at the 8-week evaluation, continuing the same dose is advised.

For patients with an LVOT gradient of less than 20 mm Hg, treatment should be withheld, and reevaluation at week 12 is recommended.[22] To determine maintenance dosing, patients are assessed at week 12. The current mavacamten dose should be continued if the LVEF is 50% or greater and the LVOT gradient is less than 30 mm Hg. If the LVOT gradient exceeds 30 mm Hg, increasing to the next available dose and performing an echocardiographic evaluation at week 16 is recommended.[22]

Treatment should be discontinued if the patient's LVEF falls below 50%. Patients who experience severe infections requiring hospitalization or uncontrolled tachyarrhythmia are at higher risk of systolic dysfunction and should be evaluated to determine whether to continue or interrupt treatment. After discontinuation, an echocardiographic evaluation should be performed 4 weeks later to reassess the LVEF and LVOT gradient. When reinitiating mavacamten, the dose should be reduced to the next lower dose (eg, from 10 to 5 mg daily). Repeat evaluations are recommended at weeks 4 and 8 after treatment is restarted. If the patient's LVEF falls below 50% again, permanent discontinuation of mavacamten is advised.[22]

Toxicity

Signs and Symptoms of Overdose

Mavacamten overdose is associated with systolic dysfunction, which can manifest as worsening functional capacity and exacerbation of heart failure. Although no carcinogenic or mutagenic effects have been linked to mavacamten, animal studies have shown QT prolongation and cardiac osseous metaplasia in subjects receiving 10 mg/kg/d.[3][22]

Management of Overdose

An antidote for mavacamten does not exist. In cases of overdose, mavacamten should be discontinued immediately, and efforts should be made to maintain hemodynamic stability while closely monitoring left ventricular function. Activated charcoal can effectively reduce mavacamten absorption if administered within 2 hours of ingestion; however, it does not affect exposure levels if given 6 hours after dosing.[23] A poison control center or medical toxicologist should be contacted for updated recommendations.

Enhancing Healthcare Team Outcomes

Providing quality care for patients with heart failure necessitates a multidisciplinary and interprofessional team, including cardiologists, critical care and primary care clinicians, registered nurses, pharmacists, social workers, physical therapists, and rehabilitation staff. Before 2022, treatment for patients with obstructive HCM was primarily aimed at symptomatic relief through pharmacologic treatment or interventional approaches such as SRTs. Mavacamten is a first-in-class cardiac myosin inhibitor developed to target the underlying pathophysiology of obstructive HCM directly.[24]

Interprofessional strategies should be tailored to enhance patient outcomes. The prescribing clinician may consult with a cardiology-specialized pharmacist to determine the appropriateness of mavacamten for the patient and address potential drug-drug interactions collaboratively. Nurses are responsible for patient counseling and answering questions about the medication, with pharmacists reinforcing these points during dispensing. Any interprofessional healthcare team member who observes a significant change in the patient should promptly communicate with other team members to ensure coordinated, optimal patient care and keep everyone updated on the patient's status. Proper notations should be made in the patient's record. Therapists must also report any changes in the patient's condition to facilitate necessary adjustments in the treatment plan.

Mavacamten therapy can enhance the patient's NYHA functional class and improve various hemodynamic and structural parameters. Approved by the FDA for patients with obstructive HCM and symptomatic heart failure, mavacamten represents a significant therapeutic advance. The FDA has designated mavacamten as a 'breakthrough therapy.'[25] A thorough understanding of mavacamten's pharmacological and cardiovascular effects is essential for effective treatment guidance, monitoring, and adjustment in patients with obstructive HCM. Ongoing trials also evaluate mavacamten's safety and efficacy in patients with nonobstructive HCM or those with obstructive HCM who qualify for interventional therapy. An interprofessional team approach, with effective communication among clinicians, cardiologists, pharmacists, and nurses, is crucial for minimizing potential adverse effects, improving disease progression and quality of life, and enhancing patient outcomes.