A Study to Evaluate the Efficacy, Safety, and Tolerability of MYK-224 in Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy

The purpose of this study is to characterize the safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of MYK-224 in participants with obstructive Hypertrophic Cardiomyopathy (oHCM)


Eligibility Criteria:
Inclusion Criteria:

* Has adequate acoustic windows, to enable accurate TTEs as determined by the echocardiography core laboratory.
* Men or women diagnosed with oHCM consistent with current American College of Cardiology Foundation/American Heart Association and European Society of Cardiology guidelines, satisfying both of the following criteria:

  * Has unexplained left ventricular (LV) hypertrophy with nondilated ventricular chambers in the absence of other cardiac (eg, hypertension, aortic stenosis) or systemic disease and with maximal LV wall thickness ≥ 15 millimeter (mm) (or ≥ 13 mm with positive family history of hypertrophic cardiomyopathy or with a known disease-causing mutation), as determined by core laboratory interpretation.

AND

-- Has a LVOT peak gradient during screening as assessed by echocardiography of ≥ 50 millimeters of mercury (mm Hg) at rest, or ≥ 30 mm Hg at rest and ≥ 50 mm Hg with Valsalva maneuver (confirmed by echocardiography core laboratory interpretation).

* Has resting LVEF ≥ 60% at the Screening visit as determined by echocardiography core laboratory.
* New York Heart Association (NYHA) functional class II or III symptoms at screening.
* Has a valid measurement of LVOT post-exercise peak gradient at screening as determined by echocardiography core laboratory.

Exclusion Criteria:

* Presence of any medical condition that precludes exercise stress testing.
* History of syncope or sustained ventricular tachyarrhythmia within 6 months prior to screening.
* Known infiltrative or storage disorder causing cardiac hypertrophy that mimics HCM, such as Fabry disease, amyloidosis, or Noonan syndrome with left ventricular hypertrophy.
* Prior treatment with mavacamten or aficamten. An exception may be made in cases where myosin inhibitor use was not within 4 months of the Screening visit, and with the agreement of both the Investigator and the Medical Monitor.
* Has been successfully treated with invasive septal reduction (surgical myectomy or percutaneous alcohol septal ablation \[ASA\]) within 6 months prior to Screening or plans to have either of these treatments during the study (Note: Individuals with an unsuccessful myectomy or percutaneous ASA procedure performed \> 6 months prior to Screening may be enrolled if study eligibility criteria for LVOT gradient criteria are met).
* Implantable cardioverter-defibrillator (ICD) placement or pulse generator change within 2 months prior to screening or planned new ICD placement during the study (pulse generator changes, if needed during the study are allowed).
* Has a history of resuscitated sudden cardiac arrest (any time) or known history of appropriate implantable cardioverter-defibrillator (ICD discharge for life-threatening ventricular arrhythmia within 6 months prior to screening.
* Has paroxysmal, atrial fibrillation with atrial fibrillation present per the Investigator's evaluation of the participant's ECG at the time of Screening.
* Has persistent or permanent atrial fibrillation not on anticoagulation for at least 4 weeks prior to Screening and/or not adequately rate controlled within 6 months prior to Screening (Note: Participants with persistent or permanent atrial fibrillation who are anticoagulated and adequately rate-controlled are allowed).
* Has QT interval with Fridericia correction (QTcF) \> 500 msec when QRS interval \< 120 msec or QTcF \> 520 msec when QRS ≥ 120 msec if participant has left bundle branch block or any other 12-lead ECG abnormality considered by the investigator to pose a risk to participant safety (eg, second-degree atrioventricular block type II).
* Has known moderate or severe (per investigator's judgment) aortic valve stenosis at screening.
* History of LV systolic dysfunction (LVEF \< 45%) at any time during their clinical course.
* Clinically significant pulmonary disease associated with exertional dyspnea.
* Has known significant unrevascularized obstructive coronary artery disease (\>70% stenosis in one or more main epicardial coronary arteries) or history of myocardial infarction Note: participants with prior coronary artery bypass grafting (CABG) or percutaneous coronary interventions (PCIs) are allowed if the procedure was performed at least 12 weeks prior to screening
* Prior treatment with cardiotoxic agents such as anthracyclines (eg, doxorubicin) or similar

Other protocol-defined criteria apply.