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

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safely be withdrawn are eligible as long as medication is discontinued at least 14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of these medications who, in the opinion of the investigator, can safely be withdrawn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.