Evaluation of Efficacy, Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of BMS-986435 in Symptomatic Obstructive Hypertrophic Cardiomyopathy

Trial ID: 2023-508831-29-00
Protocol: CV029-009
Sponsor: Myokardia Inc.

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Diseases & Conditions

Hypertrophic cardiomyopathy

Objectives

The primary objective of this study is to assess the **safety** and **tolerability** of MYK-224 in participants with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Evaluating safety and tolerability is crucial as it determines the potential risks and adverse effects associated with the treatment, ensuring that the therapeutic benefits outweigh any potential harm to the patients.

Secondary objectives include:

Evaluating the effect of MYK-224 on the left ventricular outflow tract (LVOT) gradient in participants with symptomatic oHCM. This is clinically relevant as reducing the LVOT gradient can alleviate symptoms and improve cardiac function.
Assessing the pharmacokinetic/pharmacodynamic (PK/PD) relationship of MYK-224, which is important for understanding the drug's behavior in the body and its therapeutic effects.
Assessing the pharmacokinetics (PK) of MYK-224 in participants with symptomatic oHCM to determine the drug's absorption, distribution, metabolism, and excretion, which are essential for optimizing dosing regimens.

Participants

The clinical trial involves a total of **17 participants** diagnosed with **Symptomatic Hypertrophic Cardiomyopathy** and Left Ventricular Outflow Tract Obstruction. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, indicating adult and older adult participants. The trial population was selected based on specific criteria, including adequate acoustic windows for accurate transthoracic echocardiograms and a diagnosis consistent with established guidelines. Participants exhibit unexplained left ventricular hypertrophy with nondilated ventricular chambers and a maximal left ventricular wall thickness of at least 15 millimeters, or 13 millimeters with a positive family history or known mutation. The trial also considers lifestyle factors such as the presence of New York Heart Association functional class II or III symptoms. The study includes a vulnerable population, ensuring comprehensive safety and tolerability assessments of the investigational drug MYK-224.

Plans and Procedures

The clinical trial is designed as a **Phase 2a**, open-label, pilot study to evaluate the efficacy, pharmacokinetics, pharmacodynamics, safety, and tolerability of MYK-224 in participants with symptomatic **hypertrophic cardiomyopathy** and left ventricular outflow tract obstruction. The trial is not categorized as low intervention and involves a chemical origin medicinal product, BMS-986435, administered in tablet form via oral use. The study is expected to run from October 21, 2022, to October 5, 2027, with the primary objective of assessing the safety and tolerability of MYK-224 in participants with symptomatic obstructive hypertrophic cardiomyopathy (oHCM).

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate acoustic windows for echocardiography, a diagnosis of oHCM, and specific echocardiographic measurements. The trial includes a main study phase (Part A) and an optional 2-year open-label extension (Part B) for those who complete Part A. The primary endpoints focus on the incidence, severity, and causality of adverse events (AEs) and serious adverse events (SAEs), as well as various cardiac-related outcomes. Secondary endpoints include the effect on left ventricular outflow tract (LVOT) gradient and pharmacokinetic/pharmacodynamic relationships.

Participants are expected to be involved in the study for the duration of Part A, with the possibility of extending their participation into Part B. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or failure to meet ongoing eligibility criteria. The study aims to provide comprehensive data on the safety and efficacy of MYK-224, contributing to the understanding and management of symptomatic hypertrophic cardiomyopathy with left ventricular outflow tract obstruction.

Treatment

The clinical trial involves the administration of the experimental medication **BMS-986435**, which is provided in the form of a **tablet**. This medication is chemically synthesized and is developed by Bristol-Myers Squibb International Corporation. The **BMS-986435** tablets are intended for **oral use**. The dosage is measured in milligrams, with a maximum daily dose and total dose amount set at 9999 mg. The treatment period is also capped at 9999 days, although specific dosing schedules are not detailed in the provided data. The trial does not include a pediatric formulation, and the medication is not classified as an orphan drug.

In addition to the experimental treatment, the study may involve the use of non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details regarding these are not provided in the data. Participant compliance with the medication regimen will be monitored throughout the trial, ensuring adherence to the prescribed dosing schedule. The trial aims to evaluate the efficacy, pharmacokinetics, pharmacodynamics, safety, and tolerability of **MYK-224** in participants with symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract obstruction.

Efficacy

The efficacy of the investigational product MYK-224 in participants with symptomatic **Hypertrophic Cardiomyopathy** (HCM) and left ventricular outflow tract obstruction will be assessed through a series of primary and secondary endpoints. Primary endpoints include the incidence, severity, and causality of adverse events (AEs) and serious adverse events (SAEs), as well as the incidence of symptomatic resting left ventricular ejection fraction (LVEF) less than 50% as measured by transthoracic echocardiography (TTE). Additional primary endpoints involve the incidence of major adverse cardiovascular events (MACE), hospitalizations due to cardiovascular and non-cardiovascular events, heart failure (HF) events, atrial fibrillation/flutter, and ventricular tachyarrhythmias. Secondary endpoints focus on the effect of MYK-224 on the left ventricular outflow tract (LVOT) gradient, pharmacokinetic/pharmacodynamic (PK/PD) relationships, and PK concentrations.

Measurements will be collected using validated tools such as TTE for LVEF and LVOT gradient assessments, 12-lead electrocardiograms (ECG) for heart rate and rhythm evaluations, and clinical laboratory tests. The schedule for these assessments will be aligned with the study protocol, ensuring data collection at specified timepoints throughout the trial duration. The analysis of these efficacy parameters will be conducted using appropriate statistical methods to determine the therapeutic impact of MYK-224 on the target population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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.

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Exclusion Criteria

PART A: 1) 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.
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 subject'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
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 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
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 been treated with invasive septal reduction (surgical myectomy or percutaneous alcohol septal ablation [ASA]) following enrollment in Part A
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
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
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).
Heart transplant or listed for heart transplant following enrollment in Part A
Currently implanted LV assist device
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