Biological Collection for the Purpose of Exploring Genetic and Clinical-biological Factors Associated With Variability in Response to Mavacamten in the Treatment of Obstructive Hypertrophic Cardiomyopathy

Before the arrival of mavacamten, preventive and symptomatic management of patients with obstructive hypertrophic cardiomyopathy relied on the use of non-vasodilating beta-blockers or non-dihydropyridine calcium channel blockers, or the addition of disopyramide in combination therapy with a beta-blocker. When dynamic obstruction of the left ventricular outflow tract (LVOT) persisted, invasive septal reduction treatments were offered, which were associated with significant morbidity and mortality.

The introduction of mavacamten, the first reversible and selective inhibitor of cardiac myosin ATPase activity, made it possible to relieve LVOT obstruction and reduce myocardial hypercontractility after a period of titration, which varied in length depending on the patient, guided by echocardiography. The relationship between plasma concentrations of mavacamten and echocardiographic parameters has not been clearly established. However, this new drug is characterised by significant inter-individual pharmacokinetic variability, linked in part to genetic polymorphisms of CYP2C19, the hepatic enzyme responsible for its metabolism. Therefore, to ensure its safe use, the European Medicines Agency has required pre-treatment genotyping of CYP2C19 to determine the initial and maximum dosage, in order to avoid overexposure to mavacamten associated with a decrease in ventricular ejection fraction below 50% in slow metabolisers of CYP2C19 (AUC multiplied by 3.4). The study is a requalification for the search for DNA samples obtained during treatment in order to genotype the genes of interest. The primary objective of the study is to estimate, for each of the CYP2C19 phenotypes of interest determined by genotyping (ultra-rapid, rapid, normal/extensive and intermediate metabolisers), the proportion of patients who are non-responders to mavacamten at each time point (D0, Week 4, Week 8, Week 12 and Week 24 in the treatment of HCM). This is a multicentre (3 centres : La pitie Salpetriere hospital, Bicetre hospital and Ambroise Paré hospital). The study involves 2 non recruiting centres : the Molecular Genetics - Pharmacogenetics Service (which realize the genetic analyses) and the Biological ressources center (which preserves the bioological collection). The study aiming to include 300 patients with obstructive hypertrophic cardiomyopathy treated with Mavacamten who underwent or are undergoing CYP2C19 genotyping at the start of treatment. The inclusion period is 36 months. The recruitment of the patient is retrospective and prospective. The follow-up period is 6 months. The total duration of the study is 42 months.

• Response rate to Mavacamten treatment in the above-mentioned populations [Time frame: Day 0, Week4, Week 8, Week 12, Week 24]
• Response rate to Mavacamten treatment in the general population and in the above-mentioned populations [Time frame: Day 0, Week4, Week 8, Week 12, Week 24]
• Description of cardiac and other adverse effects (excluding reduced LVEF) in the general population and in the above-mentioned populations [Time frame: Day 0, Week4, Week 8, Week 12, Week 24]
• Variation in dosage of Mavacamten at weeks 4, week 8, week 12 and week 24 according to the different populations [Time frame: Weeks 4, week 8, week 12 and week 24]