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Trametinib Reduces in Mortality, Morbidity for Children With Hypertrophic Cardiomyopathy
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Key Takeaways
- Trametinib significantly reduced mortality and morbidity in children with severe HCM linked to RAS/MAPK mutations.
- The study involved 23 centers across multiple countries, comparing trametinib plus standard therapy to standard therapy alone.
Hypertrophic cardiomyopathy is caused by abnormal genes in the heart muscle, causing the left ventricle to become thicker and effecting blood flow.
Trametinib (Mekinist; Novartis), a mitogen-activated protein kinase inhibitor, showed reductions in mortality and morbidity in children with severe hypertrophic cardiomyopathy (HCM) caused by pathogenic variants to the RAS/MAPK pathway, according to results of a study in JACC: Basic to Translational Science.1
Trametinib (Mekinist; Novartis) reduced mortality and morbidity in children with severe hypertrophic cardiomyopathy. | Image Credit: H_Ko | stock.adobe.com
“Our findings represent a breakthrough in the treatment of HCM in children, particularly those suffering from severe forms of the disease due to genetic variants in the RAS/MAPK pathway,” Gregor Andelfinger, MD, PhD, co-author of the study and a cardiologist at CHU Saint-Justine in Montreal, said in a news release.“The positive results we observed with trametinib are a promising step forward in addressing an urgent medical need for children whose condition has not responded to standard therapies.”2
HMC is caused by abnormal genes in the heart muscle, causing the left ventricle to become thicker and effecting blood flow, according to the American Heart Association. HCM can be obstructive, which is when the thickened part of the heart muscle blocks or reduces blood flow, or nonobstructive, when the blood flow is not blocked. The condition can be asymptomatic or develop symptoms over time. Signs and symptoms can include chest pains (particularly with physical exertion), shortness of breath, fatigue, arrhythmias, dizziness, or lightheadedness. As the disease progresses, it can cause other health issues, such as atrial fibrillation, blood clots, stroke, and heart failure.3
The study was a retrospective cohort analysis that included 23 tertiary care centers specializing in congenital heart disease and pediatric cardiology and patients were included from the United States, Canada, Austria, Denmark, Finland, Germany, Ireland, Italy, the Netherlands, and the United Kingdom. Investigators collected clinical data for patients that. Had a genetic diagnosis of RASopathy, echocardiographic diagnosis of HCM, and admission to a hospital since 2000 with either heart failure and/or severe outflow tract obstruction that required intervention. There were 2 treatment arms, which included individuals who received trametinib in addition to standard therapies and those who received standard therapies alone. The primary end point included a composite of cardiac surgery for outflow tract resection, heart transplantation, or death, and the secondary end point included cardiac surgery for outflow tract resection, death or heart transplantation, and death or heart transplantations in a subgroup of patients with severe heart failure.1
Investigators included 61 patients, with 30 being male and a median age of 7.4 months, who were admitted to the hospital between 2000 to 2024. Approximately 66% were admitted within their first 12 months of life, and the most common reason for hospitalization was heart failure with outflow tract obstruction in 48% of patients, and severe outflow tract obstruction without heart failure of 38% of patients, according to the study authors. Thirty-one patients received the standard of care and 49% received trametinib.1
A composite of cardiac surgery for outflow tract resection, heart transplantation, or death occurred in 32 patients, with 5 in the trametinib group and 27 in the control group (HR: 0.09; 95% CI: 0.04-0.25; P < .001). For the secondary end points, 21 patients experienced cardiac surgery for outflow tract resection (1 [3%] in the trametinib group vs 20 [65%] control subjects; HR: 0.03; 95% CI: 0.004-0.22; P < .001), 13 patients experienced transplantation or death (4 [13%] in the trametinib group vs 9 [29%] control subjects; HR: 0.42; 95% CI: 0.13-1.38; P = .14), and 9 patients were in the subgroup who had severe heart failure (3 [30%] in the trametinib group vs 6 [100%] control subjects; HR: 0.13; 95% CI: 0.03-0.53; P = .001).!
Further, there were no life-threatening adverse events (AEs) occurring with trametinib and AEs requiring symptomatic treatment occurred in 10 patients. The severity of AEs was due to temporary cessation and/or dose reduction for 7 patients.1
“This study provides crucial evidence that targeted therapies like trametinib could dramatically improve the outlook for children suffering from severe HCM,” Andelfinger said in the news release. “It underscores the importance of developing genotype-specific therapies for RASopathies and other rare diseases.”2
