Mavamcampten

Selective, cardiac myosin inhibitor. Mavacampten is the first and so far only drug approved in this drug class. (Approved in Europe since 2023, approved in the USA since 2022).

Mechanism of action: Mavacampten is an allosteric, selective and reversible inhibitor of cardiac myosin. The approval is based on the results of the Phase III studies (Explorer-HCM, Valor-HCM), in which it was shown that mavacamten leads to a clinically relevant reduction in the outflow gradient in the left ventricular outflow tract (LVOT) compared to placebo without a significant reduction in left ventricular pump function. Improved performance, maximum oxygen saturation (V O2 max) and thus improvement of the NYHA stage were achieved compared to placebo (1),(2).

The active substance has a new mode of action and thus offers a promising new treatment option for patients with HOCM, a rare, mostly genetic disease that is chronically progressive and can lead to a severe reduction in exercise capacity and quality of life in people between the ages of 40 and 60. Until now, symptom-oriented drug therapies have been available for these patients, but no adequate specific drug therapy options have been available.

Mavacampten is the first approved drug in this class (selective cardiac myosin inhibition) to target the underlying pathophysiology of HOCM.

The drug reduces myocardial contractility by inhibiting the formation of excess myosin-actin cross-bridges, which are causative for hypercontractility, left ventricular hypertrophy, reduced myocardial elasticity and narrowing of the LVOT (3). It acts by specifically reducing the activity of adenosine triphosphatase on the heavy chains of cardiac myosin. The effect is strictly dose-dependent and reversible (4).

Remark: Effects on skeletal muscle cells are not expected as the mechanism of action is based on a selective effect on myocytes (4).

The indication, further treatment and necessary ongoing monitoring of patients should be carried out by cardiologists with experience in the treatment of patients with cardiomyopathies. The ESC guidelines from fall 2023 give a class IIa recommendation for treatment with mavacamptene if optimal drug therapy with non-vasodilating beta-blockers or calcium channel antagonists and/or disopyramide (first-line therapy) is ineffective (IIa B) or is not tolerated or contraindications exist (IIa A). A recommendation for first-line treatment with mavacampten was not given due to a lack of comparative studies with the currently available first-line drug therapy (5).

The drug is available orally and is offered in the form of hard capsules in strengths of 2.5, 5, 10 and 15 mg.

Genotyping of CYP2C19 is mandatory for individual dose determination and to avoid overdose in every patient!

There are different phenotypes for metabolization via the enzyme system with the help of cytochrome P450 in the liver, which differ greatly in the rate of metabolization (from slow to intermediate and normal to fast metabolizers). These can be precisely determined by genotyping.

Since the effect of the drug is strictly dose-dependent, the dose must be individually adapted to the metabolization rate, as otherwise there is a risk of overdosing, especially with slow metabolizers!

The titration of the dose is carried out according to appropriate schemes and additional clinical monitoring of cardiac function by means of echocardiography (EF and LVOT) (6)

The drug is only approved for adults.

Not to be used for systolic dysfunction defined as asymptomatic LVEF ≤50%. Echocardiography with determination of EF is mandatory before starting therapy!

There is also an increased risk of systolic dysfunction in patients with serious illnesses such as infection, cardiac arrhythmias, including atrial fibrillation or uncomplicated tachycardia, or in patients undergoing heart surgery!

Mavacampten must not be used during pregnancy and in women of childbearing potential who are not using reliable contraception.

There is a partial contraindication for concomitant treatment with CYP2C19 inhibitors or CYP3A4 inhibitors (see Camzyos Information for healthcare professionals).

Note: The drug is still subject to increased pharmacovigilance, as long-term data are not yet available!

^Camzyos®

The drug has been approved in Europe since 2023 (approved in the USA since 2022).