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1/2 Clinical Trial of a MEK Inhibitor for RASopathy-Associated Severe Infantile Hypertrophic Cardiomyopathy

Award Number: UG3HL185610
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/07/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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1/2 Clinical Trial of a MEK Inhibitor for RASopathy-Associated Severe Infantile Hypertrophic Cardiomyopathy - Noonan syndrome and the related genetic disorders, the RASopathies, are associated with severe infantile hypertrophic cardiomyopathy (RAS-HCM), which has a 35% one-year survival and for which conventional therapies are ineffective. Preclinical and retrospective clinical studies suggest that the MEK inhibitor trametinib might be an effective treatment for this condition. Trametinib has FDA approval for pediatric brain tumors and has adverse effects (AEs), primarily dermatologic, that are largely manageable. Equipoise remains due to methodological limitations in data about infants receiving standard of care (SOC) or treated with trametinib. We are proposing a 12-month Phase 3, multi-site, open-label trial, enrolling 25 affected infants < 6 months old with Class III or IV HF through Pediatric Heart Network (PHN) sites in the US. Outcomes will be compared to real-world data for ~100 infants who received SOC. Participants will be followed off treatment for another 12 months, with resumption of trametinib for those in whom HCM relapses. We will leverage the PHN's clinical trials infrastructure and its data coordinating center. For Aim 1, we hypothesize that infants presenting with Ross Class III or IV HF due to HCM caused by molecularly documented gain-of-function germline causal variation for a RASopathy will have a lower rate of a composite endpoint of death, heart transplant, or septal myomectomy after one year of oral trametinib treatment than comparable patients receiving only SOC between 2015-2019. As a secondary aim, we hypothesize that the treated participants will have a lower rate of death. For Aim 2, we will compare the trametinib-treated vs. SOC groups with respect to several secondary outcomes: 1) echocardiographic parameters of HCM and LV outflow tract gradients and 2) levels of HF as assessed with the Ross scale and serum marker NT-proBNP. For Aim 3, we will assess the frequency and nature of relapse in the year after cessation of trametinib, as well as to assess the response to reinstitution of treatment in the event of relapse. For Aim 4, we will assess the rates of AEs of trametinib treatment, either during the first year or if it is restarted, focusing on the rates, nature and severity of dermatologic issues, already known to be common, as well as the considerably rarer eye and cardiac adverse effects of trametinib. Whether or not trametinib is found to be superior to SOC for treatment of infantile RAS-HCM, the proposed trial will impact care of this devastating disorder. If proven effective, it will clear the way for insurance approval. The trial will also provide novel and important information about the impact of trametinib on other RASopathy- related complications that impact quality of life. If negative, this trial will curtail the growing trend to treat RAS- HCM with trametinib, reducing substantial individual and societal costs associated with its administration.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $946,567 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	000	1	9/8/2026	NEW	$946,567
														Subtotal = $946,567

Grand Total All Awards = $946,567

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1/2 Clinical Trial of a MEK Inhibitor for RASopathy-Associated Severe Infantile Hypertrophic Cardiomyopathy

Award Number: UG3HL185610

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/07/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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