New treatment option shows promise for severe hypertrophic cardiomyopathy in children

Trametinib, a mitogen-activated protein kinase (MEK) inhibitor, reduces mortality and morbidity in children with severe hypertrophic cardiomyopathy (HCM) caused by pathogenic variants in the RAS/MAPK pathway, according to a study published in JACC: Basic to Translational Science.

The study provides strong evidence for personalized treatment targeting the underlying genetic causes of RASopathies, a group of rare disorders that often lead to life-threatening cardiac complications.

“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,” said Gregor Andelfinger, MD, Ph.D., co-author of the study and a cardiologist at CHU Saint-Justine in Montreal.

“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.”

HCM, a condition where the heart muscle thickens abnormally, is particularly dangerous in children and can lead to heart failure or premature death. About 20% of patients with RASopathies have HCM; RASopathy-associated HCM is often caused by genetic mutations in the RAS/MAPK signaling pathway, which regulates cell growth and development.

It is often a more severe form of HCM and has a higher mortality rate. Until now, treatment options for severe cases of RASopathy-associated HCM (RAS-HCM) in pediatric patients have been limited.

The study, which involved 61 children with severe RAS-HCM, compared 30 children receiving trametinib to 31 children receiving standard care. The results showed a significant reduction in the outcome of death, cardiac transplantation, or the need for cardiac surgery in the trametinib group.

No life-threatening adverse events were observed, although dermatologic and mucous membrane side effects were common but manageable.

“This study provides crucial evidence that targeted therapies like trametinib could dramatically improve the outlook for children suffering from severe HCM,” Andelfinger said. “It underscores the importance of developing genotype-specific therapies for RASopathies and other rare diseases.”

“The paper by Andelfinger and colleagues provides exciting data with respect to treating ‘Rasopathies’ in children with HCM,” said Douglas Mann, MD, FACC, Editor-in-Chief of JACC: Basic to Translational Science. “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.”

“Given the rarity of this condition and the lack of existing therapies for these children, we felt it was important to publish this paper, with the 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,” Mann said.

Study limitations 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.

Trametinib, a mitogen-activated protein kinase (MEK) inhibitor, reduces mortality and morbidity in children with severe hypertrophic cardiomyopathy (HCM) caused by pathogenic variants in the RAS/MAPK pathway, according to a study published in JACC: Basic to Translational Science.

The study provides strong evidence for personalized treatment targeting the underlying genetic causes of RASopathies, a group of rare disorders that often lead to life-threatening cardiac complications.

“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,” said Gregor Andelfinger, MD, Ph.D., co-author of the study and a cardiologist at CHU Saint-Justine in Montreal.

“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.”

HCM, a condition where the heart muscle thickens abnormally, is particularly dangerous in children and can lead to heart failure or premature death. About 20% of patients with RASopathies have HCM; RASopathy-associated HCM is often caused by genetic mutations in the RAS/MAPK signaling pathway, which regulates cell growth and development.

It is often a more severe form of HCM and has a higher mortality rate. Until now, treatment options for severe cases of RASopathy-associated HCM (RAS-HCM) in pediatric patients have been limited.

The study, which involved 61 children with severe RAS-HCM, compared 30 children receiving trametinib to 31 children receiving standard care. The results showed a significant reduction in the outcome of death, cardiac transplantation, or the need for cardiac surgery in the trametinib group.

No life-threatening adverse events were observed, although dermatologic and mucous membrane side effects were common but manageable.

“This study provides crucial evidence that targeted therapies like trametinib could dramatically improve the outlook for children suffering from severe HCM,” Andelfinger said. “It underscores the importance of developing genotype-specific therapies for RASopathies and other rare diseases.”

“The paper by Andelfinger and colleagues provides exciting data with respect to treating ‘Rasopathies’ in children with HCM,” said Douglas Mann, MD, FACC, Editor-in-Chief of JACC: Basic to Translational Science. “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.”

“Given the rarity of this condition and the lack of existing therapies for these children, we felt it was important to publish this paper, with the 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,” Mann said.

Study limitations 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.