Hypertrophic cardiomyopathy (HCM) is a genetic heart condition characterized by a thickening of the heart muscle, particularly the left ventricle. This thickening can impede the heart’s ability to pump blood effectively, leading to various symptoms and potential complications. Cardiac myosin inhibitors, such as aficamten and mavacamten, represent a new class of targeted therapies designed to address the underlying cause of this disease. These medications aim to improve cardiac function and alleviate patient symptoms.
Understanding Hypertrophic Cardiomyopathy and Its Treatment
Hypertrophic cardiomyopathy involves the thickening and stiffening of the left ventricle walls. This thickening can make it difficult for the heart to fill with blood and pump it out efficiently. Many people with HCM experience symptoms like shortness of breath, chest pain, fatigue, dizziness, and heart palpitations, especially during physical activity.
Traditional treatments for HCM focus on symptom management and preventing complications. Medications like beta-blockers and calcium channel blockers are commonly used to slow the heart rate and relax the heart muscle, improving blood flow. For individuals with significant obstruction, procedures such as septal myectomy or alcohol septal ablation may be considered to widen the pathway for blood leaving the heart.
Shared Mechanism of Action
Both aficamten and mavacamten function as cardiac myosin inhibitors, a targeted approach to treating hypertrophic cardiomyopathy. This class of drugs modulates the interaction between myosin and actin, the proteins responsible for muscle contraction. In HCM, excessive formation of these connections leads to a hypercontractile heart muscle.
These inhibitors reduce the number of active myosin heads that can bind to actin, decreasing the force of muscle contraction. This action alleviates the excessive contractility of the heart muscle, improving the heart’s ability to relax and fill with blood. This enhances its pumping efficiency and reduces the obstruction of blood flow out of the left ventricle.
Key Distinctions and Clinical Considerations
While both aficamten and mavacamten target cardiac myosin, they have distinct characteristics. Mavacamten, approved by the FDA in April 2022, is dosed once daily and requires careful titration based on patient response and echocardiographic monitoring of left ventricular ejection fraction (LVEF). Aficamten, currently under regulatory review, may allow for more rapid dose adjustments due to its pharmacokinetic profile.
Pharmacokinetically, aficamten has a shorter half-life than mavacamten, allowing quicker dose titration and drug washout. Mavacamten is primarily metabolized by certain liver enzymes (CYP2C19 and CYP3A4), which can lead to drug-drug interactions. Aficamten is metabolized through multiple CYP enzymes, resulting in fewer drug-drug interactions.
Monitoring requirements also differ. Mavacamten necessitates a Risk Evaluation and Mitigation Strategy (REMS) program due to concerns about transient LVEF reductions. This program ensures healthcare providers are educated on risks and patients receive appropriate monitoring, including regular echocardiograms. While aficamten can also cause transient LVEF reductions, its overall monitoring requirements may be less extensive.
Efficacy and Safety Profiles
Clinical trials have demonstrated the effectiveness of both mavacamten and aficamten in improving symptoms and cardiac function in patients with obstructive hypertrophic cardiomyopathy. Mavacamten’s efficacy was shown in the EXPLORER-HCM trial, significantly improving exercise capacity and reducing left ventricular outflow tract (LVOT) obstruction. The SEQUOIA-HCM study for aficamten reported significant improvements in peak oxygen uptake and reductions in LVOT gradients.
Regarding safety, both drugs are generally well-tolerated. Mavacamten has been associated with higher rates of treatment interruption due to LVEF reductions below 50% compared to aficamten. Some studies suggest mavacamten may have a higher incidence of atrial fibrillation and heart failure events, though aficamten trials have shorter follow-up, limiting direct long-term comparisons. Transient LVEF reductions are a known effect for both medications, typically responding to dose reduction.