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

A Phase 2a, Open-label, Pilot Study to Evaluate Efficacy, Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of MYK-224 in Participants With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction (MERCUTIO)

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)

Study Overview

• Status: Terminated
• Conditions: Cardiomyopathy, Hypertrophic
• Intervention / Treatment: Drug: MYK-224

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20138
    • Local Institution - 0029
  • BO
    • Bologna, BO, Italy, 40138
      • Local Institution - 0027
  • FI
    • Florence, FI, Italy, 50134
      • Local Institution - 0005
• Poland
  • Wroclaw, Poland, 54-049
    • Local Institution - 0030
  • Silesian Voivodeship
    • Katowice, Silesian Voivodeship, Poland, 40-555
      • Local Institution - 0011
• Spain
  • A Coruña, Spain, 15006
    • Local Institution - 0009
  • Barcelona, Spain, 08036
    • Local Institution - 0023
  • Majadahonda, Spain, 28035
    • Local Institution - 0010
  • A
    • Alicante, A, Spain, 03010
      • Local Institution - 0028
  • GR
    • Granada, GR, Spain, 18014
      • Local Institution - 0022
  • MA
    • Málaga, MA, Spain, 29010
      • Local Institution - 0008
  • MU
    • El Palmar, MU, Spain, 30120
      • Local Institution - 0002
  • V
    • Valencia, V, Spain, 46026
      • Local Institution - 0003
• United States
  • California
    • La Jolla, California, United States, 92037
      • Local Institution - 0026
    • Los Angeles, California, United States, 90048
      • Local Institution - 0014
    • San Francisco, California, United States, 94158-2156
      • Local Institution - 0016
  • Kansas
    • Kansas City, Kansas, United States, 66103-2937
      • Local Institution - 0001
  • New York
    • New York, New York, United States, 10032-3802
      • Local Institution - 0032
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Local Institution - 0013
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Local Institution - 0031
    • Cleveland, Ohio, United States, 44195-0001
      • Local Institution - 0015
  • Oregon
    • Portland, Oregon, United States, 97239-3011
      • Local Institution - 0024
  • Tennessee
    • Nashville, Tennessee, United States, 37205-2202
      • Local Institution - 0021
  • Texas
    • San Antonio, Texas, United States, 78229-3900
      • Local Institution - 0025
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Local Institution - 0006

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Participants will receive MYK-224 either as a monotherapy or in combination with standard-of-care consisting of a beta-blocker. Participants who complete Cohort 1 will be eligible for an optional open label extension period	Drug: MYK-224; Specified dose on specified days; Other Names: BMS-986435
Experimental: Cohort 2; Participants will receive MYK-224 in combination with standard-of-care consisting of either a calcium channel blocker or disopyramide (which is given in combination with either a beta-blocker or calcium channel blocker). Participants who complete Cohort 2 will be eligible for an optional open label extension period	Drug: MYK-224; Specified dose on specified days; Other Names: BMS-986435

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Number of Participants With Adverse Events and Serious Adverse Events	An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization.	From first dose (Day 1) until study end date in Part A or 30 days after early termination date (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Number of Participants With at Least One Event of Arrhythmias	Arrhythmias included atrial fibrillation/flutter (new from screening and recurrent), ventricular tachyarrhythmias (ventricular tachycardia, ventricular fibrillation, and Torsades de Pointe).	From first dose (Day 1) until study end date in Part A or 30 days after early termination date (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Number of Participants With at Least One Event of Appropriate Implantable Cardioverter Defibrillator Therapy and Resuscitated Cardiac Arrest		From first dose (Day 1) until study end date in Part A or 30 days after early termination date (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Change From Baseline in Vital Signs - Heart Rate	Baseline is defined as the last non-missing value in date/time recorded before the first dose of MYK-224. Heart rate was measured in rested state.	Baseline and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Change From Baseline in Vital Signs - Mean Systolic Blood Pressure	Baseline is defined as the last non-missing value in date/time recorded before the first dose of MYK-224. Systolic blood pressure was measured in rested state.	Baseline and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Change From Baseline in Vital Signs - Mean Diastolic Blood Pressure	Baseline is defined as the last non-missing value in date/time recorded before the first dose of MYK-224. Diastolic blood pressure was measured in rested state.	Baseline and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Change From Baseline in Vital Signs - Respiratory Rate	Baseline is defined as the last non-missing value in date/time recorded before the first dose of MYK-224. Respiratory rate was measured in rested state.	Baseline and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Change From Baseline in Vital Signs - Temperature	Baseline is defined as the last non-missing value in date/time recorded before the first dose of MYK-224.	Baseline and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Change From Baseline in Vital Signs - Weight	Baseline is defined as the last non-missing value in date/time recorded before the first dose of MYK-224.	Baseline and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Number of Participants With Abnormal Physical Examination Results	The complete physical examination included weight and calculated BMI, a neurological examination (gross motor and deep tendon reflexes),and an assessment of the following: general appearance, skin, head and neck, mouth, lymph nodes, thyroid, abdomen, musculoskeletal, cardiovascular, neurological, and respiratory systems with other systems included, as directed by interval history.	Baseline and until study end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Results	Twelve-lead ECG evaluations will be performed in the supine position after 10 minutes of rest at Screening and at selected clinic visits prior to MYK-224 dosing and before any blood sample collection. QTc prolongation is defined by either the mean of QTcF > 499 or mean of QTcB > 499 according to the project requirement specification from Clario.	Baseline and until study end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Number of Participants With Adverse Events Related to Clinical Laboratory Parameters (Hematology, Chemistry and Urinalysis)	Blood samples were collected to assess the clinical laboratory parameters.	Baseline and untill end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks)
Part A:Percentage of Participants With Incidence of Symptomatic Left Ventricular Ejection Fraction (LVEF) < 50%	LVEF was assessed using transthoracic echocardiogram (TTE) in resting state. 90% CIs are calculated based on Exact Binomial proportion test. LVEF value was calculated by Simpson Biplane method.	From first dose (Day 1) until study end date in Part A or 30 days after early termination date (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Percentage of Participants With Incidence of Symptomatic Left Ventricular Ejection Fraction (LVEF) <= 30%	LVEF was assessed using transthoracic echocardiogram (TTE) in resting state. 90% CIs are calculated based on Exact Binomial proportion test. LVEF value was calculated by Simpson Biplane method.	From first dose (Day 1) until study end date in Part A or 30 days after early termination date (Median 17.55 weeks and Maximum 54.9 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Aggregate Mean of Left Ventricular Ejection Fraction (LVEF)		Treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Change From Baseline in Left Ventricular Ejection Fraction (LVEF)	Baseline is defined as the last non-missing value in date/time recorded before the first dose of MYK-224. Participants with data available at the timepoint were included in the analysis.	Baseline and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Aggregate Mean of Left Ventricular Outflow Tract (LVOT) Peak Gradient (Post-Exercise, Resting, and Valsalva)		Treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Change From Baseline in Left Ventricular Outflow Tract (LVOT) Peak Gradient (Post-Exercise, Resting, and Valsalva)	Baseline is defined as the last non-missing value in date/time recorded before the first dose of MYK-224. Participants with data available at the timepoint were included in the analysis.	Treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Percentage of Participants With Resting Left Ventricular Outflow Tract (LVOT) Peak Gradient < 30 mmHg and Valsalva LVOT Peak Gradient < 50 mmHg	Baseline is defined as the last non-missing value in date/time recorded before the first dose of MYK-224. 90%CIs are calculated based on Normal approximation.	Baseline and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks)
Part A: Plasma Concentration of MYK-224	Blood samples were collected to assess plasma concentration of MYK-224.	Pre-dose and 1 hour post-dose end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks)

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Investigators: Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2023
• Primary Completion (Actual): August 19, 2024
• Study Completion (Actual): February 27, 2025

Study Registration Dates

• First Submitted: September 23, 2022
• First Submitted That Met QC Criteria: September 23, 2022
• First Posted (Actual): September 27, 2022

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: HCM; MYK-224; Obstructive Hypertrophic Cardiomyopathy; BMS-986435
• Additional Relevant MeSH Terms: Aortic Valve Disease; Cardiovascular Diseases; Heart Diseases; Heart Valve Diseases; Cardiomyopathies; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Cardiomyopathy, Hypertrophic
• Other Study ID Numbers: CV029-009; 2022-001292-14 (EudraCT Number); U1111-1276-3555 (Registry Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: BMS will provide access to individual anonymized participant data upon request from qualified researchers, and subject to certain criteria. Additional information regarding Bristol Myers Squibb's data sharing policy and process can be found at: https://www.bms.com/researchers-and-partners/clinical-trials-and-research/disclosurecommitment.html
• IPD Sharing Time Frame: See Plan Description
• IPD Sharing Access Criteria: See Plan Description
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No