Mavacamten

Breast Feeding; Lactation; Milk, Human; Cardiovascular Agents

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Liver test abnormalities are infrequent in patients treated with myosin inhibitors. In publications of placebo-controlled trials of mavacamten, results of serum aminotransferase, alkaline phosphatase, and bilirubin levels were usually not mentioned. The FDA review of the single large randomized controlled trial of mavacamten mentions that ALT elevations above 3 times the upper limit of normal (ULN) occurred in 2.4% of patients receiving mavacamten vs 3.9% receiving placebo. Moreover, in that study and other open label trials of mavacamten, there were no instances of serum aminotransferase elevations with jaundice. Since its approval and more wide scale use, there have been no reports of clinically apparent liver injury attributed to mavacamten. Clinical experience with mavacamten therapy has been limited, but ongoing trials, observational studies, and adverse event registries have supported its hepatic safety.

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.

C - Cardiovascular system

QC - Cardiovascular system

Mavacamten is a myosin inhibitor to prevent muscle hypercontractility. It binds to myosin and inhibits myosin interaction with actin at various stages of the thermomechanical cycle. Mechanistic studies show that mavacamten can inhibit myosin in both its active and relaxed form, thus effectively alleviating excess sarcomere power, a hallmark of hypertrophic cardiomyopathy. In the EXPLORER-HCM trial, patients achieved reductions in mean resting and provoked (Valsalva) LVOT gradient by Week 4 which were sustained throughout the 30-week trial. At Week 30, the mean (SD) changes from baseline in resting and Valsalva LVOT gradients were -39 (29) mmHg and -49 (34) mmHg, respectively, for the CAMZYOS group and -6 (28) mmHg and -12 (31) mmHg, respectively, for the placebo group. The reductions in the Valsalva LVOT gradient were accompanied by decreases in LVEF, generally within the normal range. Eight weeks after discontinuation of CAMZYOS, mean LVEF and Valsalva LVOT gradients were similar to baseline. Echocardiographic measurements of the cardiac structure showed a mean (SD) reduction from baseline at Week 30 in left ventricular mass index (LVMI) in the mavacamten group (-7.4 [17.8] g/m2) versus an increase in LVMI in the placebo group (8.9 [15.3] g/m2). There was also a mean (SD) reduction from baseline in left atrial volume index (LAVI) in the mavacamten group(-7.5 [7.8] mL/m2) versus no change in the placebo group (-0.1 [8.7] mL/m2). The clinical significance of these findings is unknown. A reduction in a biomarker of cardiac wall stress, NT-proBNP, was observed by Week 4 and sustained through the end of treatment. At Week 30 compared with baseline, the reduction in NT-proBNP after mavacamten treatment was 80% greater than for placebo (proportion of geometric mean ratio between the two groups, 0.20 [95% CI: 0.17, 0.24]). The clinical significance of these findings is unknown. In healthy volunteers receiving multiple doses of mavacamten, a concentration-dependent increase in the QTc interval was observed at doses up to 25 mg once daily. No acute QTc changes have been observed at similar exposures during single-dose studies. The mechanism of the QT prolongation effect is not known. A meta-analysis across clinical studies in HCM patients does not suggest clinically relevant increases in the QTc interval in the therapeutic exposure range. In HCM, the QT interval may be intrinsically prolonged due to the underlying disease, in association with ventricular pacing, or in association with drugs with the potential for QT prolongation commonly used in the HCM population. The effect of coadministration of mavacamten with QT-prolonging drugs or in patients with potassium channel variants resulting in a long QT interval has not been characterized.