v4 Study Evaluating the Safety, Tolerability and Preliminary Pharmacokinetics and Pharmacodynamics of MYK-491

Study Overview
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Brief Summary
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The purpose of this Phase 1b/2a study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of MYK-491 in patients with stable heart failure.

Official Title
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Randomized, Double-blind, Placebo-controlled, Two-Part, Adaptive Design Study of Safety, Tolerability, Preliminary Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Oral Doses of MYK-491 in Patients With Stable Heart Failure With Reduced Ejection Fraction

Conditions
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Heart Failure With Reduced Ejection Fraction, Dilated Cardiomyopathy

Intervention / Treatment
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* Drug: MYK-491
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Has stable chronic heart failure with reduced ejection fraction Has adequate acoustic windows for echocardiography Key Exclusion Criteria: Any significant structural cardiac abnormalities on Screening TTE At Screening, symptomatic hypotension or hypertension or bradycardia. Routinely scheduled outpatient intravenous (IV) infusions for heart failure (e.g., inotropes, vasodilators [e.g., nesiritide], diuretics) or routinely scheduled ultrafiltration. Presence of protocol specified laboratory abnormalities at Screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a a two part study. The first part is a randomized, crossover, double-blind, placebo-controlled, two cohort, sequential ascending single dose study. All patients will receive placebo and active doses of MYK-491. The second part is a randomized, parallel, double-blind, placebo-controlled, sequential ascending multiple dose study. All patients will receive placebo and/or active doses of MYK-491.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Part 1/SAD and Part 2/MAD - drug<br>Part 1/SAD: Crossover, Single ascending dose of MYK-491/placebo Part 2/MAD: Parallel, multiple ascending dose of MYK-491/placebo | Drug: MYK-491<br>* Single Ascending Dose and Multiple Ascending Dose of MYK-491<br>|
| Other: Part 1/SAD and Part 2/MAD - placebo<br>Part 1/SAD: Crossover, Single ascending dose of MYK-491/placebo Part 2/MAD: Parallel, multiple ascending dose of MYK-491/placebo | Drug: Placebo<br>* Single Ascending Dose and Multiple Ascending Dose of placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Number of participants with any grade of treatment-emergent adverse events (TEAEs) and any grade of serious adverse events (SAEs). | From first dose to 30 days post last dose (Up to 2 months) | 
| Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts | Number of participants with change from baseline in ECGs QTcF, PR, and QRS intervals. Baseline is defined as the last non-missing value prior to the corresponding period. | Baseline, day 1-16, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose | 
| Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts | Number of participants with change from baseline in ECGs QTcF, PR, and QRS intervals. Baseline is defined as the last non-missing value prior to first randomized dose. | Baseline, Day 1-16, 2 hours pre-dose and at 7-, 24-, and 48-hours post final dose | 
| Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts | Mean change from baseline in supine systolic blood pressure (SBP) and supine diastolic blood pressure (DBP) vital signs. Baseline is defined as the last non-missing value prior to the corresponding period. | Baseline and at 6-hours post-dose | 
| Mean Change From Baseline in Vital Signs Part 1 - MAD Cohorts | Mean change from baseline in supine systolic blood pressure (SBP) and supine diastolic blood pressure (DBP) vital signs. Baseline is defined as the last non-missing value prior to first randomized dose | Baseline and at 6-hours post-dose | 
| Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts | Mean change from baseline in heart rate (HR) vital signs. Baseline is defined as the last non-missing value prior to the corresponding period. | Baseline and at 6-hours post-dose | 
| Mean Change From Baseline in Vital Signs Part 2 - MAD Cohorts | Mean change from baseline in heart rate (HR) vital signs. Baseline is defined as the last non-missing value prior to first randomized dose | Baseline and at 6-hours post-dose | 
| Number of Participants With a Troponin I Increase - SAD Cohorts | Number of participants with a troponin increase is defined as when one of the following conditions was met (1) if the participant's troponin I value was normal prior to dosing (≤0.03 ng/mL), an elevated level on at least one measurement after start of dosing >2×ULN for the specific assay (>0.06 ng/mL) through Day 16. (2) If the participant's troponin I value was above the ULN for the specific assay prior to dosing, an increase >0.03 ng/mL compared to baseline on at least one measurement after start of dosing through Day 16. | Baseline, day 1-3, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose | 
| Number of Participants With a Troponin I Increase - MAD Cohorts | Number of participants with a troponin increase is defined as when one of the following conditions was met (1) if the participant's troponin I value was normal prior to dosing (≤0.03 ng/mL), an elevated level on at least one measurement after start of dosing >2×ULN for the specific assay (>0.06 ng/mL) through Day 16. (2) If the participant's troponin I value was above the ULN for the specific assay prior to dosing, an increase >0.03 ng/mL compared to baseline on at least one measurement after start of dosing through Day 16. | Baseline, pre-dose and 7hr post dose on treatment day 1, day 2, day 5 and pre-dose and at 7-, 24-, and 48-hours post final dose | 
| Number of Participants With Clinically Significant Laboratory Abnormalities | Number of participants with clinically significant laboratory abnormalities. | From first dose to 30 days post last dose (Up to 2 months) | 
| Number of Participants With Clinically Significant Physical Examinations Abnormalities | Number of participants with clinically significant physical examinations abnormalities. | From first dose to 30 days post last dose (Up to 2 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Danicamtiv Maximum Observed Plasma Concentration (Cmax) | Maximum observed plasma concentration (Cmax) for Danicamtiv. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. | 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose | 
| Danicamtiv Time of Maximum Observed Plasma Concentration (Tmax) | Time of maximum observed plasma concentration (Tmax) for Danicamtiv. | 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose | 
| Area Under the Plasma Concentration-Time Curve (AUC) | Area under the plasma concentration-time curve (AUC) for Danicamtiv including the following time points: (AUC(0-12))=from time 0 to 12 hours; (AUC(0-24))=from time 0 to 24 hours; (AUC(0-48))=from time 0 to 48 hours; (AUClast)=from time 0 up to the last measurable concentration; (AUC(0-∞))=from time 0 to infinity. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. | 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose | 
| Apparent First-order Terminal Elimination Half-life (t1/2) | Apparent first-order terminal elimination half-life (t1/2). | 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose | 
| Danicamtiv Accumulation Ratio for Maximum Observed Plasma Concentration AR(Cmax) - MAD Cohorts | Accumulation ratio for maximum observed plasma concentration AR(Cmax) for Danicamtiv. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. | 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose | 
| Accumulation Ratio for Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours AR(AUC(0-12)) - MAD Cohorts | Accumulation ratio for area under the plasma concentration-time curve from time 0 to 12 hours AR(AUC(0-12)) for Danicamtiv. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported. | 1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose | 
| Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - SAD Cohorts | Mean change from baseline in TTE parameter systolic ejection time (SET) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to the corresponding period. Reporting arms are not mutually exclusive | Baseline, predose and at 3, 6, 9, and 24 hours post dose | 
| Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - SAD Cohorts | Mean change from baseline in TTE parameter left ventricular stroke volume (LVSV) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to the corresponding period. Reporting arms are not mutually exclusive | Baseline, predose and at 3, 6, 9, and 24 hours post dose | 
| Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - SAD Cohorts | Mean change from baseline in TTE parameter left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to the corresponding period. Reporting arms are not mutually exclusive | Baseline, predose and at 3, 6, 9, and 24 hours post dose | 
| Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - MAD Cohorts | Mean change from baseline in TTE parameter systolic ejection time (SET) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to first randomized dose. Reporting arms are not mutually exclusive | Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11 | 
| Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - MAD Cohorts | Mean change from baseline in TTE parameter left ventricular stroke volume (LVSV) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to first randomized dose. Reporting arms are not mutually exclusive | Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11 | 
| Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - MAD Cohorts | Mean change from baseline in TTE parameter left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) according to Danicamtiv plasma concentration ranges. Baseline is defined as the last non-missing value prior to first randomized dose. Reporting arms are not mutually exclusive | Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11 |