Multiple Dose Study to Evaluate Efficacy, Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of MYK-224 in Participants with Symptomatic Obstructive Hypertrophic Cardiomyopathy (MERCUTIO)

Korábbi kezelés

• Has known significant unrevascularized obstructive coronary artery disease (>70% stenosis in one or more main epicardial coronary XML File Identifier: 4aHMkMObTnpietQCrlOf/erzF34= Page 19/33 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 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 Sponsor Medical Monitor. Prior treatment with cardiotoxic agents such as anthracyclines (eg, doxorubicin) or similar
  • Part B: Medical conditions 1) Presence of any medical condition that precludes exercise stress testing
• Has been treated with invasive septal reduction (surgical myectomy or percutaneous alcohol septal ablation [ASA]) following enrollment in Part A
• History of syncope or sustained ventricular tachyarrhythmia within 6 months prior to screening.
• Has persistent or permanent atrial fibrillation not on anticoagulation for at least 4 weeks prior to Screening for Part B and/or not adequately rate controlled (Note: Participants with persistent or permanent atrial fibrillation who are anticoagulated and adequately rate-controlled are allowed. Please see restricted therapies in Appendix 5).
• 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 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

Más betegség

• PART A: 1) Presence of any medical condition that precludes exercise stress testing.
• Clinically significant pulmonary disease associated with exertional dyspnea
• Interval history of syncope or sustained ventricular tachyarrhythmia between the Part A EOS visit and the Part B Screening visit for participants that have a separate Screening visit for Part B
• Active infection
• Has an interval history of resuscitated sudden cardiac arrest or of appropriate implantable cardioverter-defibrillator (ICD) discharge for life-threatening ventricular arrhythmia between Part A EOS visit and Screening for Part B
• Heart transplant or listed for heart transplant following enrollment in Part A
• Clinically significant pulmonary disease associated with exertional dyspnea
• Has known significant unrevascularized obstructive coronary artery disease (> 70% stenosis in one or more epicardial coronary arteries) or history of myocardial infarction since enrollment in Part A
• Known infiltrative or storage disorder causing cardiac hypertrophy that mimics HCM, such as Fabry disease, amyloidosis, or Noonan syndrome with left ventricular hypertrophy.

Laborértékek

• History of LV systolic dysfunction (LVEF < 45%) at any time during their clinical course
• 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)

Egyéb

• Has known moderate or severe (per investigator's judgment) aortic valve stenosis at screening
• Has paroxysmal, intermittent atrial fibrillation with atrial fibrillation present per the Investigator's evaluation of the subject's ECG at the time of Screening for Part B
• Currently implanted LV assist device
• Has paroxysmal, atrial fibrillation with atrial fibrillation present per the Investigator's evaluation of the subject's ECG at the time of Screening

• PART A: 1) 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. - Has a LVOT peak gradient during screening as assessed by echocardiography of ≥ 50 millimeters of mercury (mm Hg) at rest, or ≥ XML File Identifier: 4aHMkMObTnpietQCrlOf/erzF34= Page 18/33 30 mm Hg at rest and ≥ 50 mm Hg after Valsalva maneuver (confirmed by echocardiography core laboratory interpretation).
• Has resting LVEF ≥ 60% at the Screening visit as determined by echocardiography core laboratory.
• Has a valid measurement of LVOT post-exercise peak gradient at screening as determined by echocardiography core laboratory. - NYHA functional class II or III symptoms at screening
• NYHA functional class II or III symptoms at screening
  • PART B: Participants that have successfully completed Part A of the study may enroll in Part B, an optional, 2-year open-label extension study. Eligibility for Part B will be assessed following completion of informed consent. Participants that have completed Part A EOS assessments within the Part B 28-day screening window may use those assessments for eligibility determination. Where possible, participants should enroll in Part B of the study on the same background therapy on which they completed Part A.