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 (Olivotto I et.al. 2020), Valor-HCM (Desai MY et.al. 2021), 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 compared to placebo could be achieved (Desay MY et. al. 2022), (Saberi S et.al. 2021).

The active substance has a new mode of action and thus offers a promising new therapeutic option for patients with HOCM(hypertrophic obstructive cardiomyopathy), a rare, mostly genetic disease with changes in the sarcomere (myosin-binding protein C, beta-myosin heavy chains), which is chronically progressive and can already lead to a severe reduction in performance and quality of life in people aged between 40-60 years. Until now, only symptom-oriented drug therapies (and in advanced cases septal ablation and surgery) have been available for these patients, but no adequate specific drug therapy options (Braunwald et al. 2023).

Mavacampten is the first approved drug in this class (selective cardiac myosin inhibition) to target the underlying pathophysiology of HOCM (Braunwald et.al.2023).

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 (Braunwald et. al. 2023). It acts by specifically reducing the activity of cardiac myosin adenosine triphosphatase (myosin ATPase) on the heavy chains of cardiac myosin. The effect is dose-decreasing and reversible (Green et.al. 2016).

Remark: Effects on skeletal muscle cells are not expected, as the mechanism of action is based on a selective effect on cardiac myocytes (Green et.al. 2016).

For an overview of the mechanism of action, the current study situation, critical aspects relevant to treatment and expected future developments, see (Braunwald et.al. 2023).

Mavacampten is administered orally and rapidly absorbed. The time to maximum concentration (Tmax) is 1 to 2 hours. Plasma protein concentration: approx. 97%. Plasma half-life, accumulation (time to steady-state) and elimination are strongly dependent on the metabolization phenotype.

Mavacampten is mainly metabolized via cytochrome oxidase P450 (CYP) in the liver, with metabolism occurring mainly via the enzyme CYP2C19 and to a lesser extent via CYP3A4 (product information Camzyos). The exposure to mavacamptene is essentially determined by the genetically determined metabolization rate of CYP2C19. Phenotypically, slow, intermediate, normal, fast and over-fast metabolizers can be distinguished on the basis of genotyping.

Elimination is 80% via the kidneys.

Treatment of symptomatic hypertrophic obstructive cardiomyopathy (HOCM) in NYHA stage II-III with EF (ejection fraction) ≥ 55%. (If the ejection fraction is below 55%, the medication must not be used!) To improve cardiac function and symptoms. The indication, treatment and necessary ongoing therapy monitoring 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 mavacampten if optimal drug therapy with non-vasodilating beta blockers or calcium channel antagonists (and/or disopyramide) 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 (Arbelo E et al. 2023).

Mavacampten is embryotoxic and must therefore not be used during pregnancy. Pregnancy must be safely ruled out and reliable contraception must be ensured (hormonal contraception is not safe when mavacampten is administered! see Interactions!).

If you wish to have children, contraception must be continued for up to 6 months after discontinuation of mavacampten to ensure that there is no further exposure! (Camzyos production information)

Mavacampten should not be used during breastfeeding (safety data are not available)!

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!

The dose must be individually adjusted to the rate of metabolization, otherwise there is a risk of overdose, especially in the case of slow metabolization!

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

If there are clinical signs of heart failure or if LVEF falls ≤ 50%, the dose must be temporarily reduced or interrupted completely.

The most important and serious adverse effect is left ventricular dysfunction or heart failure in case of overdosage or excessive exposure to mavacampten.

The effect of mavacampten is reversible when the dose is reduced or interrupted. However, the long half-life/elimination time of mavacampten and the possible need for additional supportive medical measures to stabilize the circulation are problematic with regard to the risk. Continuous monitoring of clinical symptoms and medication is therefore essential as a precautionary measure!

Other common adverse effects are also:

Dizziness, syncope, dyspnea

Numerous medications are also metabolized in the liver via the cytochrome oxidase P450 (CYP) enzyme system. These include, for example, antibiotics, steroids, antidepressants, antiepileptic drugs, drugs against hypertension and cardiac arrhythmia and many others. This also includes some non-prescription drugs, many phytopharmaceuticals, toxins as well as stimulants and foods.

All these substances can influence the metabolism of mavacampten and thus the exposure and potentially lead to an overdose or reduced effect. This also applies to drugs that are inducers of the CYP enzyme systems when they are discontinued, as this also increases mavacampten exposure!

Conversely, mavacampten can also influence the effect of additional medication, e.g. the effect of hormonal contraception may be reduced and hormonal contraception can no longer be safely guaranteed in this case. Women of childbearing age who are treated with mavacampten must therefore use other safe methods of contraception if possible.

Interactions due to additional medications should be clarified accordingly before administering the medication (https://go.drugbank.com/categories/DBCAT000403) and require regular monitoring and dose adjustment if necessary.

Simultaneous administration of negative inotropic substances should be avoided if possible, as the negative inotropic effect of mavacampten can be enhanced. Strongly negative inotropic substances are contraindicated (see contraindications).

For further information on interactions, see Camzyos product information.

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).

Mavacampten is exceptionally expensive and is also associated with additional costs due to the comprehensive monitoring measures.

This once again raises the issue of adequate and guideline-based care for all patients with limited resources in the healthcare system.

The cost-benefit assessment by the Federal Joint Committee was positive and a considerable additional benefit for the care of the patients concerned is confirmed (Federal Joint Committee),(Bergmann MW 2024).

It remains to be seen whether additional new drugs in this new drug class that are already in development and testing will bring about a positive change in the cost situation.

1. Arbelo E et al. 2023 ESC guidelines for the management of cardiomyopathies: developed by the task force on the management of cardiomyopathies of the European Society of Cardiology (ESC). Eur Heart J. 2023;44:3503-3626.
2. Bergmann MW, Hohmann J. Conflict between guidelines and cost-effectiveness? Therapy of HOCM from a medical and legal perspective. Special publication, Deutscher Ärzteverlag, Management Aktuell; 03/24, 1-4 (on behalf of Bristol-Meyers-Squibb).
3. Braunwald E et al. Mavacamten: a first-in-class myosin inhibitor for obstructive hypertrophic cardiomyopathy. Eur Heart J. 2023;44:4622-4633.
4. Desai MY et al. Myosin inhibition in patients with obstructive hypertrophic cardiomyopathy referred for septal reduction therapy. J Am Coll Cardiol 2022;80:95-108.
5. Desai MY et al; Study design and rationale of VALOR-HCM: evaluation of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy who are eligible for septal reduction therapy. Am Heart J. 2021;239:80-89.
6. Green EM et al. A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science. 2016;351:617-621.
7. Federal Joint Committee; www.g-ba.de/bewertungsverfahren/nutzenbewertung/979/
8. https://go.drugbank.com/categories/DBCAT000403
9. Olivotto I et al; EXPLORER-HCM Study Investigators. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396:759-769.
10. Product information Camzyos Bristol Myers Squibb.
11. Saberi S et al. Mavacamten favorably impacts cardiac structure in obstructive hypertrophic cardiomyopathy: EXPLORER-HCM cardiac magnetic resonance substudy analysis. Circulation. 2021;143:606-608.