Trametinib, a mitogen-activated protein kinase (MEK) inhibitor, has demonstrated promising results in reducing mortality and morbidity in children with severe hypertrophic cardiomyopathy (HCM) caused by pathogenic variants in the RAS/MAPK pathway. The findings, published in JACC: Basic to Translational Science, offer strong evidence for personalized treatment targeting the underlying genetic causes of RASopathies, a group of rare disorders often leading to life-threatening cardiac complications.
Impact of Trametinib on Pediatric HCM
The study compared 30 children receiving trametinib to 31 children receiving standard care. The results indicated a significant reduction in the composite outcome of death, cardiac transplantation, or the need for cardiac surgery in the trametinib group. This suggests a potential for trametinib to improve outcomes in severe cases of RASopathy-associated HCM (RAS-HCM) in pediatric patients, where treatment options have been limited.
Gregor Andelfinger, MD, PhD, co-author of the study and cardiologist at CHU Saint-Justine in Montreal, stated, "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. 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."
Understanding Hypertrophic Cardiomyopathy and RASopathies
HCM, characterized by abnormal thickening of the heart muscle, is particularly dangerous in children and can lead to heart failure or premature death. Approximately 20% of patients with RASopathies develop HCM. RASopathy-associated HCM is often caused by genetic mutations in the RAS/MAPK signaling pathway, which regulates cell growth and development. This form of HCM tends to be more severe and carries a higher mortality rate.
Safety and Tolerability
While no life-threatening adverse events were observed in the trametinib group, dermatologic and mucous membrane side effects were common but manageable. This suggests that while monitoring for side effects is necessary, trametinib may offer a tolerable treatment option for children with severe RAS-HCM.
Expert Commentary
Douglas Mann, MD, FACC, Editor-in-Chief of JACC: Basic to Translational Science, commented on the study, stating, "The paper by Andelfinger and colleagues provides exciting data with respect to treating 'Rasopathies' in children with HCM. Rasopathies are a group of rare genetic disorders that are caused by mutations in genes that regulate the Ras/mitogen-activated protein kinase (MAPK) signaling pathway."
Mann further emphasized the importance of the study given the rarity of the condition and the lack of existing therapies, expressing hope that it will "advance the field by providing a foundation for future randomized clinical trials to definitively evaluate the safety and efficacy of Trametinib in children with HCM."
Study Limitations
Limitations of the study include potential biases due to its design and incomplete data collection for the control group. Additionally, the trametinib group included patients with prior heart surgeries, which could affect the results. The shorter follow-up for the trametinib group may also underestimate long-term side effects. Lastly, the study does not determine the optimal dosing of trametinib for RAS-HCM.
