Extension Study of Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Previously Enrolled in PIONEER

Primary outcomes

1. Number of Participants With Treatment Emergent Adverse Events and Treatment Emergent Serious Adverse Events

   Time frame: From first dose to end of treatment + 56 days (Approximately an average of 240 Weeks)

   AE is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product; it does not necessarily have to have a causal relationship with this treatment.

   An SAE is defined as any untoward medical occurrence at any dose that:

   • Results in death
   • Is immediately life-threatening (places the participant at immediate risk of death from the event as it occurred)
   • Requires inpatient hospitalization or prolongation of existing hospitalization
   • Results in persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions
   • Results in a congenital abnormality or birth defect
   • Is an important medical event that may not result in death, be life- threatening, or require hospitalization, but may be considered an SAE when, based upon appropriate medical judgment, it may require medical or surgical intervention to prevent any of the outcomes listed above.

2. Number of Participants Who Had Cardiovascular Death

   Time frame: From first dose to end of study, (approximately 260 weeks)

   Number of participants who had died due to cardiovascular reasons.

3. Number of Participants Who Experienced Sudden Death

   Time frame: From first dose to end of study, (approximately 260 weeks)

   Number of participants who experienced sudden death

4. Number of Participants Who Were Hospitalized for Cardiovascular Reasons.

   Time frame: From first dose to end of study, (approximately 260 weeks)

   Number of participants who were hospitalized for cardiovascular reasons.

5. Number of Participants With Heart Failure Due to Systolic Dysfunction, Defined as Asymptomatic LVEF < 50%

   Time frame: From first dose to end of study, (approximately 260 weeks)

   Number of participants with heart failure due to systolic dysfunction, defined as asymptomatic LVEF < 50%

6. Number of Participants With LVEF < 50% as Measured by Echocardiography.

   Time frame: From first dose to end of study, (approximately 260 weeks)

   Number of participants with LVEF < 50% as measured by echocardiography.

7. Number of Participants Who Were Experienced Myocardial Infarction

   Time frame: From first dose to end of study, (approximately 260 weeks)

   Number of participants who experienced myocardial infarction.

8. Number of Participants With Ventricular Arrhythmias.

   Time frame: From first dose to end of study, (approximately 260 weeks)

   Types of Ventricular Arrhythmias measured in this endpoint will be:

   Ventricular Tachycardia Ventricular Fibrilation Ventricular Flutter

9. Number of Participants Who Experienced Syncope

   Time frame: From first dose to end of study, (approximately 260 weeks)

   Number of participants who experienced syncope.

   Syncope will be defined as participants who experienced dizziness or orthostatic hypotension.

10. Number of Participants Who Experienced Seizures

    Time frame: From first dose to end of study, (approximately 260 weeks)

    Number of participants who were experienced seizures.

11. Number of Participants Who Were Experienced Strokes

    Time frame: From first dose to end of study, (approximately 260 weeks)

    Number of participants who were experienced strokes.

12. Number of Participants With a Change in QT and QTcF Intervals.

    Time frame: From first dose to end of study, (approximately 260 weeks)

    Number of participants with a change in QTcF intervals.

    QTcF: An electrocardiographic finding in which the QT interval corrected for heart rate using Fridericia's formula. QTc = QT/∛(RR/1000)

    RR = Respiration rate

    QT Interval: Ventricular depolarization plus ventricular repolarization Normal Range: 400 to 460 msec

13. Post-exercise Left Ventricular Outflow Tract (LVOT) Gradient Over Time

    Time frame: At Baseline, Week 4, Week 48, Week 72, Week 156, Week 204 and Week 252

    Number of participants with changes of Post-exercise left ventricular outflow tract (LVOT) gradient over time

14. Resting Left Ventricular Outflow Tract (LVOT) Gradient Over Time

    Time frame: At Baseline, Week 4, Week 48, Week 72, Week 156, Week 204 and Week 252

    Resting left ventricular outflow tract (LVOT) gradient over time

15. Post Valsalva Left Ventricular Outflow Tract (LVOT) Gradient Over Time

    Time frame: At Baseline, Week 4, Week 48, Week 72, Week 156, Week 204 and Week 252

    Post Valsalva left ventricular outflow tract (LVOT) gradient over time

16. Participants With >= 1 NYHA Function Class Improvement

    Time frame: At Baseline, Week 4, Week 8, Week 24, Week 48, Week 72, Week 96, Week 120, Week 144, Week 156, Week 180, Week 204, Week 228 and Week 252

    Participants with >= 1 NYHA function class improvement.

    The NYHA Functional Classification of heart failure assigns participants to 1 of 4 categories based on the participant's symptoms.

    Class 1: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath).

    Class 2: Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath).

    Class 3: Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea.

    Class 4: Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.

17. Mean Change From Baseline in the Overall KCCQ PRO Score.

    Time frame: At Baseline, Week 4, Week 8, Week 24, Week 48, Week 72, Week 96, Week 120, Week 144, Week 156, Week 180, Week 204, Week 228 and Week 252

    The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a self-administered 23-item questionnaire questionnaire that measure the participant's perception of their health status, including their heart failure (HF) symptoms, impact on physical and social function and how their HF impacts the quality of life. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 to 100, with 0 denoting the worst and 100 the best possible status. Overall KCCQ Pro score is the average of all the domains, symptom frequency and symptom burden scores, and transformed to a single score which ranged from 0 (worst) to 100 (the best possible status), where the higher score reflected better health status.

18. Mean Change From Baseline in Serum NT-proBNP.

    Time frame: At Baseline, Week 4, Week 8, Week 24, Week 48, Week 72, Week 96, Week 120, Week 144, Week 156, Week 180, Week 204, Week 228 and Week 252

    Mean change from baseline in Serum N-terminal pro B-type natriuretic peptide levels.

19. Number of Participants Who Received Septal Reduction Therapy

    Time frame: 252 weeks

    Number of participants who received septal reduction therapy

20. Plasma Concentration of Mavacamen Overtime

    Time frame: At Baseline, Week 4, Week 8, Week 24, Week 48, Week 72, Week 96, Week 120, Week 144, Week 156, Week 180, Week 204, Week 228 and Week 252

    Plasma concentration of Mavacamen overtime