Precision Pharmacogenetics and Genotype Class Based Prediction of Mavacamten Response in Obstructive Hypertrophic Cardiomyopathy

The PRO-Gene Mava study is a prospective, observational cohort study designed to investigate the genetic and pharmacogenomic determinants of response to mavacamten in adults with obstructive hypertrophic cardiomyopathy (oHCM). While mavacamten, a cardiac myosin inhibitor, has demonstrated efficacy in reducing left ventricular outflow tract (LVOT) obstruction, significant inter-individual variability in clinical response exists.

This study is predicated on two primary hypotheses:

• Genotype-Dependent Efficacy: Pre-clinical data suggest mavacamten's mechanism of action may be more effective in normalising hypercontractility driven by thick-filament sarcomeric variants (e.g., MYH7) compared to thin-filament variants (e.g., TNNT2, TNNI3), which primarily increase myofilament calcium sensitivity. This study will test this hypothesis in a real-world clinical setting.
• Pharmacogenomic Variability: Mavacamten is metabolised predominantly by CYP2C19. The Summary of Product Characteristics (SmPC) recommends dose adjustments for known poor metabolizers (PMs). However, standard clinical genotyping panels typically only assess common loss-of-function alleles (e.g., *2, *3), potentially misclassifying patients with rare alleles. Furthermore, the clinical impact on intermediate (IM) and ultra-rapid (UM) metabolizers is not well-characterised.The study aims to bridge this knowledge gap by integrating deep genetic data with longitudinal clinical outcomes.

Inclusion criteria

• Participants above the age of 18 years, with a confirmed diagnosis of oHCM, not solely explained by abnormal loading conditions (e.g. significant hypertension, valvular disease).

Exclusion criteria

• HCM phenocopies (e.g., amyloid, Fabry's disease)
• Prior septal reduction therapy (within 6 months)
• Contraindications to mavacamten (e.g., baseline LVEF < 55%, pregnancy, uncontrolled heart failure)