A Long-term Safety Extension Study of Mavacamten (MYK-461) in Adults with Hypertrophic Cardiomyopathy Who Have Completed the MAVERICKHCM (MYK-461-006) or EXPLORER-HCM (MYK-461-005) Trials (MAVA-LTE)

The primary objective of this study is to evaluate the long-term **safety** and tolerability of **mavacamten** in participants with hypertrophic cardiomyopathy (HCM) who were previously enrolled in one of two placebo-controlled trials: MAVERICK-HCM for non-obstructive HCM and EXPLORER-HCM for obstructive HCM. This is clinically relevant as it aims to ensure the sustained safety of mavacamten, a therapeutic agent, in managing HCM, a condition characterized by thickened heart muscle that can lead to heart failure and arrhythmias.

Secondary objectives include:

• Assessing the long-term effects of mavacamten on symptoms and ECHO measures of cardiac function.
• Evaluating left ventricular outflow tract (LVOT) obstruction, as determined by Doppler echocardiography, in the EXPLORER-LTE cohort.

The clinical trial involves a total of **60 participants** diagnosed with **hypertrophic cardiomyopathy** (HCM), including both obstructive and non-obstructive forms. The study population comprises both male and female subjects, with an age range that includes adults and older adults. Participants were selected based on their prior enrollment in either the MAVERICK-HCM or EXPLORER-HCM placebo-controlled trials. The trial includes individuals who have completed the parent study within 90 days of signing consent, with specific criteria for those who may have discontinued prematurely. Participants are required to have a body weight greater than 45 kg and a left ventricular ejection fraction (LVEF) of at least 50% as determined by echocardiography. The study population is characterized by a general health status that allows for compliance with study procedures and the ability to provide informed consent. Lifestyle considerations such as diet and physical activity are not specified, but female participants must adhere to strict contraceptive measures if of childbearing potential. The trial also includes a vulnerable population, ensuring that all participants meet the necessary safety laboratory parameters and have adequate acoustic windows for accurate transthoracic echocardiograms (TTEs).

The clinical trial is designed to assess the long-term safety and tolerability of **mavacamten** in adults with **hypertrophic cardiomyopathy** (HCM) who have completed previous trials. This study is a long-term safety extension, involving participants from the MAVERICK-HCM and EXPLORER-HCM trials. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from May 2018 to April 2026, with a maximum treatment period of 252 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as body weight, echocardiography results, and laboratory parameters. Following the screening, participants will be enrolled and begin the treatment phase, which includes regular follow-up visits to monitor safety and efficacy outcomes. These visits will assess primary endpoints such as the incidence of major adverse cardiac events, hospitalizations, and heart failure events. Secondary endpoints include changes in echocardiographic parameters and cardiac function over time.

The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the long-term effects of mavacamten. Participants are expected to be involved in the study for the entire duration unless conditions arise that necessitate early termination, such as significant adverse events or withdrawal of consent. The trial is structured to ensure that all procedures comply with ethical standards and regulatory requirements, maintaining the integrity of the data collected throughout the study.

The clinical trial involves the administration of **Mavacamten**, a chemical compound with the active substance name **Mavacamten**. The pharmaceutical form of the medication is a capsule, and it is administered orally. The maximum daily dose of Mavacamten is 15 mg, with a total maximum dose of 26.4 g over the course of the treatment. The maximum treatment period is 252 days. The medication is produced by Bristol-Myers Squibb International Corporation and is identified by the sponsor product code BMS-986427/MYK-461. The chemical structure of Mavacamten is also known by several synonyms, including MYK-461 and SAR439152.

In this study, Mavacamten is the primary experimental treatment, and no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial aims to assess the long-term safety and tolerability of Mavacamten in participants with hypertrophic cardiomyopathy (HCM) who have previously completed the MAVERICK-HCM or EXPLORER-HCM trials. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.

The efficacy of **Mavacamten** in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the incidence of major adverse cardiac events such as death, stroke, and acute myocardial infarction, as well as hospitalizations related to cardiovascular and non-cardiovascular causes. Additionally, the trial will monitor the incidence of heart failure events, atrial fibrillation/flutter, ICD discharges, resuscitated cardiac arrest, and ventricular tachyarrhythmias. The occurrence of any adverse events potentially linked to QT prolongation, such as Torsade de pointes and sudden cardiac death, will also be evaluated. The frequency and severity of treatment-emergent adverse events, serious adverse events, and laboratory abnormalities, including trends in NT-proBNP, will be documented. For participants from the EXPLORER-HCM study, changes from Week 24 in left ventricular mass index will be measured, while for those from the MAVERICK-HCM study, changes from baseline in left ventricular mass index will be assessed.

Secondary endpoints focus on changes from baseline in echocardiographic parameters of systolic and diastolic function, including left ventricular ejection fraction and other related measures. The trial will also evaluate changes in resting and post-Valsalva left ventricular outflow tract gradient for EXPLORER-HCM participants, as well as changes in New York Heart Association functional class and NT-proBNP levels over time. The frequency of cardiac transplantation will be recorded. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the long-term effects of **Mavacamten** on cardiac mass and structure, as evaluated by cardiac magnetic resonance imaging (CMR).