Hypertrophic Cardiomyopathy (HCM)
Conditions
Keywords
hypertrophic cardiomyopathy, pharmacogenetics
Brief summary
This research study, aims to understand why a specific heart medication called mavacamten works better for some people with hypertrophic cardiomyopathy (HCM) than for others. We believe the answer might be in our genes. The study focuses on two key areas: 1. The specific gene causing HCM:The study will investigate whether the type of gene causing the condition in a person influences how well mavacamten works for them. 2. Each individual carry a certain gene that helps metabolise and process medication (otherwise known as pharmacogenetics). Our research will closely examine a gene called CYP2C19 to see if a person's natural processing speed (slow, normal, or fast) affects the medicine's performance. The study will also look for rare genetic variations that standard tests might miss.
Detailed description
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: 1. 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. 2. 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.
Interventions
OTHERObservational study, no new intervention offered
Observational study, no new intervention offered
Sponsors
University of Manchester
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in echocardiographic measure (LVOT gradient) | 6 months | To assess the change in LVOT gradient (mmHg) following treatment with myosin inhibitors (mavacamten) according to genotype class and CYP2C19 status |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in LVEF in response to mavacamten | 6 months | Change in LVEF in response to mavacamten (%), in particular, temporary discontinuation of the medication due to significant decline in LVEF \<50%, depending on metaboliser status and genotype class |
| Cardiac Biomarker Response Depending on Genotype | 6 months | To assess change in serum biomarkers (cardiac troponin and nT-proBNP) according to genotype class and CYP2C19 status in response to mavacamten |
Countries
United Kingdom
Contacts
CONTACTWei Jun How
Outcome results
None listed