Myosin inhibitors are drugs that directly target muscle function by reducing the interaction between actin and myosin, thereby decreasing contractility.
They are primarily used in medicine to treat hypertrophic cardiomyopathy (HCM), a genetic heart condition.
HCM is a condition characterized by thickened heart muscle (left ventricular hypertrophy) and hypercontractility, often caused by genetic mutations in sarcomere proteins.
This leads to impaired relaxation and, in many cases, obstruction of blood flow from the left ventricle (obstructive HCM or oHCM).
Myosin inhibitors shift a larger proportion of myosin heads into an inactive, super-relaxed (SRX) state, reducing the number of active cross-bridges with actin.
This action decreases myocardial contractility, improves diastolic function by relaxation, reduces the left ventricular outflow tract (LVOT) gradient (obstruction), and has been shown to induce favorable reverse remodeling of the heart structure over time.
Mavacamten (Camzyos) is the first-in-class, FDA-approved cardiac-specific myosin inhibitor for adults with symptomatic oHCM.
Clinical trials (EXPLORER-HCM, VALOR-HCM) have demonstrated significant improvements in symptoms, exercise capacity, and quality of life, often reducing or eliminating the need for invasive septal reduction therapy (SRT).
Aficamten is a second-in-class myosin inhibitor in advanced clinical development. It has a shorter half-life than mavacamten, allowing for faster dose adjustments and potentially a more favorable safety profile with a lower incidence of LVEF reduction.
It has similar efficacy to mavacamten in improving outcomes for oHCM patients.
The use of myosin inhibitors for other conditions where muscle hypercontractility is implicated, including: Non-obstructive HCM (nHCM) Heart failure with preserved ejection fraction (HFpEF) Certain skeletal myopathies Glaucoma, by reducing intraocular pressure