A Phase 2 Open-label Pilot Study Evaluating MYK-461 in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction

Study Overview
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Brief Summary
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The purpose of this phase 2 open-label pilot study is to evaluate the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of MYK-461 in subjects with symptomatic HCM and LVOT obstruction aged 18-70 years.

Official Title
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A Phase 2 Open-label Pilot Study to Evaluate Efficacy, Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of MYK-461 in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction

Conditions
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Cardiomyopathy, Hypertrophic Obstructive, Left Ventricular Outflow Tract Obstruction

Intervention / Treatment
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* Drug: MYK-461


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosed with HCM (hypertrophied and non-dilated left ventricle in absence of systemic or other known cause), with LV wall thickness ≥ 15 mm at time of initial diagnosis or ≥ 13 mm with a positive family history of HCM. Age 18-70 BMI 18-37kg/m2 Documented LVEF ≥ 55% at the Screening visit as determined by the investigator and the investigational site's echocardiography laboratory. Resting LVOT gradient ≥ 30 mg Hg and post-exercise peak LVOT gradient ≥ 50 mm Hg NYHA functional class II or higher Key Exclusion Criteria: History of sustained ventricular tachyarrhythmia. History of syncope with exercise within past 6 months. Active infection. Persistent atrial fibrillation or atrial fibrillation at Screening or history of paroxysmal atrial fibrillation with resting rate document > 100bpm within 1 year of screening. Has QTc Fridericia (QTcF) > 500 ms, or any other ECG abnormality considered by the investigator to pose a risk to subject safety (e.g. second degree atrioventricular block type II). Aortic stenosis or fixed subaortic obstruction. History of LV systolic dysfunction (LVEF < 45%) at any time during their clinical course. History of obstructive coronary artery disease. History or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the investigator or MyoKardia physician, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion. Part A: Ongoing therapy with beta blockers, calcium channel blockers, or disopyramide. Subjects on any of these medications who, in the opinion of the investigator, can safely be withdrawn are eligible as long as medication is discontinued at least 14 days prior to the Screening visit. Part B: Ongoing therapy with calcium channel blockers or disopyramide. Subjects on any of these medications who, in the opinion of the investigator, can safely be withdrawn are eligible as long as medication is discontinued at least 14 days prior to the Screening visit. Prior treatment with cardiotoxic agents such as doxorubicin or similar, or current treatment with antiarrhythmic drugs that have negative inotropic activity, e.g. flecainide or propafenone.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open Label<br>MYK-461 | Drug: MYK-461<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Post-exercise Peak LVOT Gradient From Baseline to Week 12 | Post-exercise peak LVOT gradients are assessed after a treadmill stress test by echocardiography. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving a Post-exercise Peak LVOT Gradient Response of < 30 mmHg. Gradient < 30 mmHg | LVOT gradients are assessed after a treadmill stress test by echocardiography. | Baseline and Week 12 | 
| Change in Dyspnea Symptom Score From Baseline to Week 12 | The scale name is Dyspnea Numeric Rating Scale (NRS). It is intended to measure how much shortness of breath you have had in the past week. 0 = no shortness of breath and 10 = shortness of breath as the worst possible. | Baseline and Week 12 | 
| Change in Peak VO2 From Baseline to Week 12 | Peak VO2 is assessed using a cardiopulmonary exercise test. | Baseline and Week 12 | 
| Change in VE/VCO2 From Baseline to Week 12 | VE/VCO2 is assessed from cardiopulmonary exercise testing results. | Baseline and Week 12 | 
| Change in Resting LVEF From Baseline to Week 12 | LVEF is assessed by echocardiography. | Baseline and Week 12 | 
| Change in LV Fractional Shortening (LVFS) From Baseline to Week 12 | LVFS is assessed using echocardiography measures. | Baseline and Week 12 | 
| Change in Global Longitudinal Strain (GLS) From Baseline to Week 12 | GLS is assessed using echocardiography measures. | Baseline and Week 12 | 
| Change in Post-exercise Peak LVOT Gradient From Week 12 to Week 16 | Post-exercise peak LVOT gradients are assessed after a treadmill stress test by echocardiography. | Weeks 12 and 16 |