Precision Pharmacogenetics and Genotype Class Based Prediction of Mavacamten Response in Obstructive Hypertrophic Cardiomyopathy
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 140
- 试验地点
- 1
- 主要终点
- Change in echocardiographic measure (LVOT gradient)
研究概览
简要总结
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:
- 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.
- 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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
排除标准
- •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)
研究组 & 干预措施
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.
干预措施: Observational study, no new intervention offered (Other)
结局指标
主要结局
Change in echocardiographic measure (LVOT gradient)
时间窗: 6 months
To assess the change in LVOT gradient (mmHg) following treatment with myosin inhibitors (mavacamten) according to genotype class and CYP2C19 status
次要结局
- Change in LVEF in response to mavacamten(6 months)
- Cardiac Biomarker Response Depending on Genotype(6 months)
研究者
Wei Jun How
Cardiologist
University of Manchester