Hypertrophic Cardiomyopathy (HCM) is a genetic condition characterized by the abnormal thickening of the heart muscle. This hypercontractility causes the left ventricle to work inefficiently, often leading to symptoms like shortness of breath, chest pain, and fatigue. While traditional treatments focused on managing symptoms, the recent development of cardiac myosin inhibitors represents a significant shift. This new class of medication, including Mavacamten (Camzyos) and Aficamten, are the first drugs designed to directly target the underlying cause by normalizing the heart’s excessive force generation.
The Shared Mechanism of Action
Both Mavacamten and Aficamten share a fundamental mechanism: allosteric inhibition of cardiac myosin. Cardiac myosin is the motor protein responsible for muscle contraction, which is overly active in HCM due to genetic mutations. These inhibitors work by binding to the myosin protein, altering its shape and function. This action stabilizes the myosin heads in a resting or “off” state, reducing the number of active myosin-actin cross-bridges that can form during contraction. By decreasing cross-bridge formation, the drugs reduce the overall force of the heart’s squeeze, alleviating the obstruction in the left ventricular outflow tract (LVOT) and improving blood flow.
The two compounds interact with the myosin motor protein slightly differently. Mavacamten binds to the catalytic domain of the myosin S1 head, stabilizing the “off” state. Aficamten binds to a distinct allosteric site, which slows the release of phosphate and reduces cross-bridge cycling. Despite these subtle differences, the final result for both is a dose-dependent reduction in the forceful contraction that characterizes HCM.
Practical Differences in Dosing and Monitoring
The primary distinctions between Mavacamten and Aficamten lie in their pharmacokinetic profiles, which influence how they are prescribed and monitored. Mavacamten has a relatively long half-life, resulting in a lengthy wash-out period if the medication must be stopped. It is metabolized primarily through the CYP450 system, creating a high potential for drug-drug interactions (DDIs) with many common medications.
Due to the risk of unpredictable drug levels and excessive heart function suppression, Mavacamten is subject to a strict FDA-mandated Risk Evaluation and Mitigation Strategies (REMS) program. This program requires frequent echocardiogram monitoring to assess the left ventricular ejection fraction (LVEF) before and during dose titration and maintenance.
In contrast, Aficamten has a shorter half-life of approximately three to four days. This allows for a quicker drug wash-out period if treatment needs to be interrupted. Aficamten utilizes multiple CYP enzymes for its metabolism, which lowers its propensity for significant DDIs compared to Mavacamten. The simpler metabolism and more predictable relationship between drug concentration and LVEF reduction are intended to allow for less restrictive monitoring protocols.
Comparative Efficacy from Clinical Trials
Data from pivotal Phase 3 trials demonstrate that both drugs provide substantial clinical benefits in patients with symptomatic obstructive HCM. The EXPLORER-HCM trial for Mavacamten showed significant improvements in functional capacity and symptoms. Treatment resulted in a placebo-corrected improvement in peak oxygen uptake (pVO2) of 1.4 mL/kg/min, a measure of exercise capacity.
The VALOR-HCM trial further showed that Mavacamten significantly reduced the need for septal reduction therapy (SRT) in surgical candidates. In this study, the Valsalva LVOT gradient, a measure of obstruction, was reduced by a mean of 45.2 mm Hg from baseline, establishing Mavacamten as an effective pharmacological alternative to surgery.
For Aficamten, the Phase 3 SEQUOIA-HCM trial used pVO2 as its primary endpoint, showing a placebo-corrected increase of 1.74 mL/kg/min after 24 weeks. While direct head-to-head trials are unavailable, this magnitude of improvement suggests Aficamten’s efficacy is comparable, and potentially numerically superior, to Mavacamten. The SEQUOIA-HCM study also reported that a high percentage of patients achieved a complete hemodynamic response, defined by meeting multiple criteria for gradient reduction and symptom improvement.
Safety Profiles and Current Regulatory Status
The primary safety concern for this drug class is the risk of excessive reduction in contractility, leading to a transient reduction in the Left Ventricular Ejection Fraction (LVEF). Mavacamten trials showed a temporary LVEF reduction below 50% in approximately 6% of patients, often necessitating treatment interruption or dose adjustment. Longer-term data for Mavacamten also indicate a higher rate of treatment interruption due to LVEF reduction, reported at 8.7% in some analyses.
Aficamten’s clinical trials showed a more favorable safety signal regarding LVEF reduction. The rate of treatment interruption due to LVEF dropping below 50% was notably lower, reported at 0.5%. Aficamten trials also reported lower rates of adverse events such as atrial fibrillation and heart failure compared to Mavacamten, though comparisons are limited by the shorter duration of exposure in initial studies.
Mavacamten (Camzyos) is currently FDA-approved for the treatment of symptomatic obstructive HCM. Aficamten is in the final stages of regulatory review, with marketing applications submitted in the second half of 2024. The choice between the two will depend on a physician’s assessment of the patient’s overall medication list, given the DDI differences, and the tolerance for the intensive monitoring protocols associated with Mavacamten’s REMS program.