Precision Pharmacogenetics and Genotype Class Based Prediction of Mavacamten Response in Obstructive Hypertrophic Cardiomyopathy (PRO-Gene Mava)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Hypertrophic Cardiomyopathy (HCM)
• Intervention / Treatment: Other: Observational study, no new intervention offered

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.

• Study Type: Observational
• Enrollment (Estimated): 140

Contacts and Locations

• Study Contact: Name: Wei Jun How; Phone Number: +441619987070; Email: weijun.how@manchester.ac.uk

Study Locations

• United Kingdom
  • Multiple Locations, United Kingdom
    • Manchester Centre for Genomic Medicine (MCGM)
    • Principal Investigator: William Newman
    • Contact: Wei Jun How; Phone Number: +441619987070; Email: weijun.how@manchester.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study will enroll adult patients with a diagnosis of symptomatic obstructive hypertrophic cardiomyopathy (oHCM). The target population consists of individuals who are either currently receiving mavacamten as part of their standard clinical care or are candidates for initiating therapy. Participants will be recruited from the specialist Inherited Cardiac Conditions (ICC) clinic at the study site.

Description

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)

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Observational Cohort of oHCM Patients on Mavacamten; This is a single, prospective, observational cohort of adult patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Participants are either currently receiving or newly initiating mavacamten as part of their standard clinical care. All treatment decisions, including drug initiation, dosing, and titration, are made by the participant's treating physician and are not influenced by the study protocol. This cohort serves as the population from which clinical, pharmacological, and genomic data will be collected for analysis.

Other: Observational study, no new intervention offered; Observational study, no new intervention offered

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in echocardiographic measure (LVOT gradient)	To assess the change in LVOT gradient (mmHg) following treatment with myosin inhibitors (mavacamten) according to genotype class and CYP2C19 status	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in LVEF in response to mavacamten	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	6 months
Cardiac Biomarker Response Depending on Genotype	To assess change in serum biomarkers (cardiac troponin and nT-proBNP) according to genotype class and CYP2C19 status in response to mavacamten	6 months

Collaborators and Investigators

• Sponsor: University of Manchester

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: February 6, 2026
• First Submitted That Met QC Criteria: February 6, 2026
• First Posted (Actual): February 13, 2026

Study Record Updates

• Last Update Posted (Actual): February 13, 2026
• Last Update Submitted That Met QC Criteria: February 6, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: pharmacogenetics; hypertrophic cardiomyopathy
• Additional Relevant MeSH Terms: Aortic Valve Disease; Cardiovascular Diseases; Heart Diseases; Heart Valve Diseases; Cardiomyopathies; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Cardiomyopathy, Hypertrophic; Investigative Techniques; Methods; Observation
• Other Study ID Numbers: 368062

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No