Cardiomyopathy, Hypertrophic
Conditions
Keywords
Obstructive Hypertrophic Cardiomyopathy, MYK-224, BMS-986435, HCM
Brief summary
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)
Interventions
DRUGMYK-224
Specified dose on specified days
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Number of Participants With Adverse Events and Serious Adverse Events | 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) | 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. |
| Part A: Number of Participants With at Least One Event of Arrhythmias | 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) | Arrhythmias included atrial fibrillation/flutter (new from screening and recurrent), ventricular tachyarrhythmias (ventricular tachycardia, ventricular fibrillation, and Torsades de Pointe). |
| 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 and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks) | 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. |
| Part A: Change From Baseline in Vital Signs - Mean Systolic Blood Pressure | Baseline and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks) | 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. |
| Part A: Change From Baseline in Vital Signs - Mean Diastolic Blood Pressure | Baseline and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks) | 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. |
| Part A: Change From Baseline in Vital Signs - Respiratory Rate | Baseline and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks) | 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. |
| Part A: Change From Baseline in Vital Signs - Temperature | Baseline and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks) | Baseline is defined as the last non-missing value in date/time recorded before the first dose of MYK-224. |
| Part A: Change From Baseline in Vital Signs - Weight | Baseline and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks) | Baseline is defined as the last non-missing value in date/time recorded before the first dose of MYK-224. |
| Part A: Number of Participants With Abnormal Physical Examination Results | Baseline and until study end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks) | 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. |
| Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Results | Baseline and until study end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks) | 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. |
| Part A: Number of Participants With Adverse Events Related to Clinical Laboratory Parameters (Hematology, Chemistry and Urinalysis) | Baseline and untill end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks) | Blood samples were collected to assess the clinical laboratory parameters. |
| Part A:Percentage of Participants With Incidence of Symptomatic Left Ventricular Ejection Fraction (LVEF) < 50% | 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) | 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. |
| Part A: Percentage of Participants With Incidence of Symptomatic Left Ventricular Ejection Fraction (LVEF) <= 30% | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks) | 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. |
| 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) | Treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks) | 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. |
| Part A: Percentage of Participants With Resting Left Ventricular Outflow Tract (LVOT) Peak Gradient < 30 mmHg and Valsalva LVOT Peak Gradient < 50 mmHg | Baseline and until treatment end date in Part A (Median 17.55 weeks and Maximum 54.9 weeks) | 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. |
| Part A: 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) | Blood samples were collected to assess plasma concentration of MYK-224. |
Countries
Italy, Poland, Spain, United States
Contacts
STUDY_DIRECTORBristol-Myers Squibb
Bristol-Myers Squibb
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 59.8 years STANDARD_DEVIATION 9.08 |
| BACKGROUND HCM THERAPY BETA BLOCKER USE AT BASELINE | 9 Participants |
| BACKGROUND HCM THERAPY CALCIUM CHANNEL BLOCKER USE AT BASELINE | 0 Participants |
| BACKGROUND HCM THERAPY DISOPYRAMIDE USE AT BASELINE | 0 Participants |
| BACKGROUND HCM THERAPY NONE | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Implantable Cardioverter Defibrillator (ICD) Therapy Use No ICD use | 13 Participants |
| Implantable Cardioverter Defibrillator (ICD) Therapy Use Yes | 5 Participants |
| Kansas City Cardiomyopathy Questionnaire (23-item version) Clinical Summary Score | 73.9583 Score on a Scale |
| LEFT VENTRICULAR EJECTION FRACTION | 65.4 percentage STANDARD_DEVIATION 4.23 |
| LVOT PEAK GRADIENT FOR POST-EXERCISE | 93.626 mmHg STANDARD_DEVIATION 38.6472 |
| LVOT PEAK GRADIENT FOR RESTING | 74.516 mmHg STANDARD_DEVIATION 35.5013 |
| LVOT PEAK GRADIENT FOR VALSALVA | 94.968 mmHg STANDARD_DEVIATION 35.6349 |
| Medical History Atrial Fibrillation | 5 Participants |
| Medical History Coronary Artery Disease | 3 Participants |
| Medical History Diabetes Mellitus | 3 Participants |
| Medical History Hypertension | 8 Participants |
| NT-PROBNP | 660.0 Pg/ml |
| NYHA FUNCTIONAL CLASS CLASS I | 1 Participants |
| NYHA FUNCTIONAL CLASS CLASS II | 12 Participants |
| NYHA FUNCTIONAL CLASS CLASS III | 5 Participants |
| NYHA FUNCTIONAL CLASS CLASS IV | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 16 |
| other Total, other adverse events | 15 / 18 | 6 / 16 |
| serious Total, serious adverse events | 0 / 18 | 3 / 16 |
Outcome results
None listed