From the Guidelines
Mavacamten is a cardiac myosin inhibitor that works by reducing excessive contractility in the heart muscle, specifically targeting and inhibiting the ATPase activity of cardiac myosin, thus decreasing cardiac contractility and reducing left ventricular outflow tract obstruction, as stated in the 2024 hypertrophic cardiomyopathy guideline-at-a-glance 1.
Key Points
- Mavacamten's mechanism of action is particularly beneficial in hypertrophic cardiomyopathy (HCM), a condition characterized by excessive cardiac contractility and impaired relaxation.
- The drug's selective action on cardiac myosin means it affects heart muscle function without significantly impacting other muscle types.
- Typical dosing starts at 5 mg once daily and may be adjusted based on echocardiographic assessment of left ventricular ejection fraction and clinical response, with maximum doses up to 15 mg daily.
- Regular cardiac monitoring is essential during treatment to avoid excessive reduction in cardiac function, as noted in the 2024 aha/acc/amssm/hrs/paces/scmr guideline for the management of hypertrophic cardiomyopathy 2, 3, 4, 5, 6, 7, 8.
Clinical Considerations
- Mavacamten can be beneficial for patients with obstructive HCM who do not derive adequate symptomatic relief from first-line drug therapy.
- The choice among available treatment options, including cardiac myosin inhibitors, disopyramide, and septal reduction therapies, should be approached through a comprehensive discussion with the patient, considering the success rates, benefits, and risks of each option.
- Patients with HCM and persistent or paroxysmal atrial fibrillation have a sufficiently increased risk of stroke, and oral anticoagulation with direct-acting oral anticoagulants or warfarin should be considered the default treatment option, as recommended in the 2024 guideline 2, 3, 4, 5, 6, 7, 8.
From the FDA Drug Label
Mavacamten is an allosteric and reversible inhibitor selective for cardiac myosin. Mavacamten modulates the number of myosin heads that can enter “on actin” (power-generating) states, thus reducing the probability of force-producing (systolic) and residual (diastolic) cross-bridge formation Excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are mechanistic hallmarks of HCM. Mavacamten shifts the overall myosin population towards an energy-sparing, recruitable, super-relaxed state.
The mechanism of action of Mavacamten is as an allosteric and reversible inhibitor of cardiac myosin, which reduces the probability of force-producing and residual cross-bridge formation. This action shifts the myosin population towards an energy-sparing and super-relaxed state, reducing dynamic LVOT obstruction and improving cardiac filling pressures in HCM patients 9.
- Key points:
- Inhibition of cardiac myosin
- Reduction of force-producing cross-bridge formation
- Shift to energy-sparing and super-relaxed state
From the Research
Mavacamten Mechanism of Action
- Mavacamten is a first-in-class, targeted, cardiac-specific myosin inhibitor that normalizes myosin and actin cross-bridging to decrease contractility and ultimately reduce left ventricular outflow tract gradients to maximize cardiac output 10.
- It reduces hypercontractility, a central mechanism in the pathogenesis of hypertrophic cardiomyopathy (HCM) 11.
- Mavacamten is a novel, first-in-class, allosteric inhibitor of cardiac myosin ATPase, which reduces actin-myosin cross-bridge formation, thereby reducing myocardial contractility and improving myocardial energetic consumption in experimental HCM models 12.
- The mechanism of action of mavacamten involves reducing excessive myosin adenosine triphosphatase activation and actin-myosin cross-bridging, which are major underlying causes of HCM 13.
Key Effects of Mavacamten
- Reduces left ventricular outflow tract gradients 14, 10, 13, 12.
- Improves exercise capacity and symptoms 14, 13, 12.
- Associated with improvements in patient-reported outcomes and circulating biomarkers 14.
- Evidence of favourable cardiac remodelling in multi-modality imaging studies 14.
- Reduces guideline eligibility for septal reduction therapy candidates with obstructive HCM and drug-refractory symptoms 14.