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

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

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03447990

Enrollment

Registered

2018-02-27

Start date

2018-02-06

Completion date

2019-10-24

Last updated

2023-02-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Dilated Cardiomyopathy, Heart Failure With Reduced Ejection Fraction

Brief summary

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.

Interventions

DRUGMYK-491

Single Ascending Dose and Multiple Ascending Dose of MYK-491

DRUGPlacebo

Single Ascending Dose and Multiple Ascending Dose of placebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Intervention 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.

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

Inclusion criteria

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.

Design outcomes

Primary

Measure	Time frame	Description
Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Baseline and at 6-hours post-dose	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.
Mean Change From Baseline in Vital Signs Part 1 - MAD Cohorts	Baseline and at 6-hours post-dose	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
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	From first dose to 30 days post last dose (Up to 2 months)	Number of participants with any grade of treatment-emergent adverse events (TEAEs) and any grade of serious adverse events (SAEs).
Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	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 ECGs QTcF, PR, and QRS intervals. Baseline is defined as the last non-missing value prior to the corresponding period.
Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Baseline, Day 1-16, 2 hours pre-dose and at 7-, 24-, and 48-hours post final dose	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.
Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts	Baseline and at 6-hours post-dose	Mean change from baseline in heart rate (HR) vital signs. Baseline is defined as the last non-missing value prior to the corresponding period.
Mean Change From Baseline in Vital Signs Part 2 - MAD Cohorts	Baseline and at 6-hours post-dose	Mean change from baseline in heart rate (HR) vital signs. Baseline is defined as the last non-missing value prior to first randomized dose
Number of Participants With a Troponin I Increase - SAD Cohorts	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 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.
Number of Participants With a Troponin I Increase - MAD Cohorts	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 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.
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 laboratory abnormalities.
Number of Participants With Clinically Significant Physical Examinations Abnormalities	From first dose to 30 days post last dose (Up to 2 months)	Number of participants with clinically significant physical examinations abnormalities.

Secondary

Measure	Time frame	Description
Danicamtiv Maximum Observed Plasma Concentration (Cmax)	1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose	Maximum observed plasma concentration (Cmax) for Danicamtiv. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported.
Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - MAD Cohorts	Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11	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
Danicamtiv Time of Maximum Observed Plasma Concentration (Tmax)	1 hour pre-dose and day 1-12 at 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, and 48 hours postdose	Time of maximum observed plasma concentration (Tmax) for Danicamtiv.
Area Under the Plasma Concentration-Time Curve (AUC)	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) 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.
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	Apparent first-order terminal elimination half-life (t1/2).
Danicamtiv Accumulation Ratio for Maximum Observed Plasma Concentration AR(Cmax) - MAD Cohorts	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 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.
Accumulation Ratio for Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours AR(AUC(0-12)) - MAD Cohorts	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)) for Danicamtiv. Geometric coefficient of variation was not calculated and the arithmetic coefficient of variation (% CV) is being reported.
Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - SAD Cohorts	Baseline, predose and at 3, 6, 9, and 24 hours post dose	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
Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - SAD Cohorts	Baseline, predose and at 3, 6, 9, and 24 hours post dose	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
Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 3 - SAD Cohorts	Baseline, predose and at 3, 6, 9, and 24 hours post dose	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
Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 1 - MAD Cohorts	Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11	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
Mean Change From Baseline in Transthoracic Echocardiogram (TTE) Parameter 2 - MAD Cohorts	Baseline, predose, and at 7 hours post dose on day 1,2,3, 4, 7, 9, 10, and 11	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

Countries

France, Germany, Netherlands, Poland, Sweden, United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
SAD Cohort 1 Participants received 3 double-blinded single ascending doses in random sequence (1 placebo, Danicamtiv 175mg and Danicamtiv 350mg) in Period A, B, and C with intervals between doses ranging from 3 to 14 days. Some participants received a fourth single dose of Danicamtiv ranging between 350mg-550mg in the optional open-label period D	8
SAD Cohort 2 Participants received 3 double-blinded single ascending doses in random sequence (1 placebo, Danicamtiv 400mg and Danicamtiv 500mg) in Period A, B, and C with intervals between doses ranging from 3 to 14 days	4
MAD Cohort 1 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 75mg (fasting) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.	6
MAD Cohort 2 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 50mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.	9
MAD Cohort 3 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 75mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.	9
MAD Cohort 4 Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded Danicamtiv 100mg (with food) twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.	6
MAD Placebo Participants received single-blinded placebo twice daily for 2 days. Participants then received double-blinded placebo twice daily for 7 days, and 2 days of monitoring following the last dose before discharge.	10
Total	52

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006
Overall Study	Withdrawal by Subject	0	0	0	0	0	0	1

Baseline characteristics

Characteristic	SAD Cohort 1	SAD Cohort 2	MAD Cohort 1	MAD Cohort 2	MAD Cohort 3	MAD Cohort 4	MAD Placebo	Total
Age, Continuous	57.1 Years STANDARD_DEVIATION 9.4	57.5 Years STANDARD_DEVIATION 5.07	62.7 Years STANDARD_DEVIATION 12.5	63.0 Years STANDARD_DEVIATION 9.86	56.8 Years STANDARD_DEVIATION 5.09	58.5 Years STANDARD_DEVIATION 5.36	58.6 Years STANDARD_DEVIATION 6.98	59.2 Years STANDARD_DEVIATION 8.11
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	8 Participants	4 Participants	6 Participants	9 Participants	9 Participants	6 Participants	9 Participants	51 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	6 Participants	1 Participants	3 Participants	1 Participants	2 Participants	0 Participants	3 Participants	16 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	2 Participants	3 Participants	3 Participants	8 Participants	7 Participants	6 Participants	7 Participants	36 Participants
Sex: Female, Male Female	3 Participants	1 Participants	3 Participants	3 Participants	2 Participants	1 Participants	1 Participants	14 Participants
Sex: Female, Male Male	5 Participants	3 Participants	3 Participants	6 Participants	7 Participants	5 Participants	9 Participants	38 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk	EG009 affected / at risk	EG010 affected / at risk	EG011 affected / at risk	EG012 affected / at risk	EG013 affected / at risk	EG014 affected / at risk
deaths Total, all-cause mortality	0 / 8	0 / 8	0 / 8	0 / 6	0 / 4	0 / 4	0 / 4	0 / 6	0 / 2	0 / 9	0 / 3	0 / 9	0 / 3	0 / 6	0 / 2
other Total, other adverse events	3 / 8	5 / 8	3 / 8	1 / 6	3 / 4	0 / 4	0 / 4	2 / 6	0 / 2	7 / 9	1 / 3	6 / 9	1 / 3	5 / 6	2 / 2
serious Total, serious adverse events	0 / 8	0 / 8	0 / 8	0 / 6	0 / 4	0 / 4	0 / 4	1 / 6	0 / 2	0 / 9	0 / 3	0 / 9	0 / 3	0 / 6	0 / 2

Outcome results

Primary

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

Time frame: Baseline and at 6-hours post-dose

Population: Pre-specified for data to be collected by combining all treated participants with vital signs measurements in MAD Cohorts per regimen only

Arm	Measure	Group	Value (MEAN)	Dispersion
SAD Cohort 1 Danicamtiv 175mg	Mean Change From Baseline in Vital Signs Part 1 - MAD Cohorts	Supine SBP	-4.86 mmHg	Standard Deviation 7.537
SAD Cohort 1 Danicamtiv 175mg	Mean Change From Baseline in Vital Signs Part 1 - MAD Cohorts	Supine DBP	-3.57 mmHg	Standard Deviation 7.323
SAD Cohort 1 Danicamtiv 350mg	Mean Change From Baseline in Vital Signs Part 1 - MAD Cohorts	Supine SBP	-6.33 mmHg	Standard Deviation 3.215
SAD Cohort 1 Danicamtiv 350mg	Mean Change From Baseline in Vital Signs Part 1 - MAD Cohorts	Supine DBP	-5.67 mmHg	Standard Deviation 3.055

Primary

Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts

Time frame: Baseline and at 6-hours post-dose

Population: All treated participants in SAD Cohorts per regimen dosage

Arm	Measure	Group	Value (MEAN)	Dispersion
SAD Cohort 1 Danicamtiv 175mg	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine DBP	-5.50 mmHg	Standard Deviation 12.14
SAD Cohort 1 Danicamtiv 175mg	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine SBP	-10.13 mmHg	Standard Deviation 12.23
SAD Cohort 1 Danicamtiv 350mg	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine DBP	9.50 mmHg	Standard Deviation 6.44
SAD Cohort 1 Danicamtiv 350mg	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine SBP	-11.38 mmHg	Standard Deviation 9.9
SAD Cohort 1 Placebo	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine SBP	-1.38 mmHg	Standard Deviation 15.02
SAD Cohort 1 Placebo	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine DBP	-5.75 mmHg	Standard Deviation 13.04
SAD Cohort 1 Danicamtiv 450mg	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine SBP	16.00 mmHg	—
SAD Cohort 1 Danicamtiv 450mg	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine DBP	12.00 mmHg	—
SAD Cohort 1 Danicamtiv 525mg	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine SBP	-7.00 mmHg	Standard Deviation 19.8
SAD Cohort 1 Danicamtiv 525mg	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine DBP	-1.00 mmHg	Standard Deviation 5.66
SAD Cohort 1 Danicamtiv 550mg	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine DBP	-4.00 mmHg	Standard Deviation 8.49
SAD Cohort 1 Danicamtiv 550mg	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine SBP	-9.50 mmHg	Standard Deviation 2.12
SAD Cohort 2 Danicamtiv 400mg	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine DBP	4.00 mmHg	Standard Deviation 9.933
SAD Cohort 2 Danicamtiv 400mg	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine SBP	2.50 mmHg	Standard Deviation 4.359
SAD Cohort 2 Danicamtiv 500mg	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine SBP	01.75 mmHg	Standard Deviation 15.65
SAD Cohort 2 Danicamtiv 500mg	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine DBP	-2.25 mmHg	Standard Deviation 17.27
SAD Cohort 2 Placebo	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine DBP	-3.00 mmHg	Standard Deviation 14.674
SAD Cohort 2 Placebo	Mean Change From Baseline in Vital Signs Part 1 - SAD Cohorts	Supine SBP	0.00 mmHg	Standard Deviation 11.633

Primary

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

Time frame: Baseline and at 6-hours post-dose

Population: Pre-specified for data to be collected by combining all treated participants with vital signs measurements in MAD Cohorts per regimen only

Arm	Measure	Value (MEAN)	Dispersion
SAD Cohort 1 Danicamtiv 175mg	Mean Change From Baseline in Vital Signs Part 2 - MAD Cohorts	3.71 Beats/min	Standard Deviation 2.563
SAD Cohort 1 Danicamtiv 350mg	Mean Change From Baseline in Vital Signs Part 2 - MAD Cohorts	3.33 Beats/min	Standard Deviation 2.517

Primary

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.

Time frame: Baseline and at 6-hours post-dose

Population: All treated participants in SAD Cohorts per regimen dosage

Arm	Measure	Value (MEAN)	Dispersion
SAD Cohort 1 Danicamtiv 175mg	Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts	7.13 Beats/min	Standard Deviation 6.2
SAD Cohort 1 Danicamtiv 350mg	Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts	-1.25 Beats/min	Standard Deviation 5.75
SAD Cohort 1 Placebo	Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts	3.00 Beats/min	Standard Deviation 5.5
SAD Cohort 1 Danicamtiv 450mg	Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts	5.00 Beats/min	—
SAD Cohort 1 Danicamtiv 525mg	Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts	5.50 Beats/min	Standard Deviation 0.71
SAD Cohort 1 Danicamtiv 550mg	Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts	-1.50 Beats/min	Standard Deviation 2.12
SAD Cohort 2 Danicamtiv 400mg	Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts	3.75 Beats/min	Standard Deviation 9.743
SAD Cohort 2 Danicamtiv 500mg	Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts	-0.50 Beats/min	Standard Deviation 5
SAD Cohort 2 Placebo	Mean Change From Baseline in Vital Signs Part 2 - SAD Cohorts	-6.50 Beats/min	Standard Deviation 13.699

Primary

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.

Time frame: 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

Population: Pre-specified for data to be collected by combining all treated participants in MAD Cohorts per regimen only

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
SAD Cohort 1 Danicamtiv 175mg	Number of Participants With a Troponin I Increase - MAD Cohorts	7 Participants
SAD Cohort 1 Danicamtiv 350mg	Number of Participants With a Troponin I Increase - MAD Cohorts	0 Participants

Primary

Number of Participants With a Troponin I Increase - SAD Cohorts

Time frame: Baseline, day 1-3, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose

Population: Pre-specified for data to be collected by combining all treated participants in SAD Cohorts per regimen only

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
SAD Cohort 1 Danicamtiv 175mg	Number of Participants With a Troponin I Increase - SAD Cohorts	3 Participants
SAD Cohort 1 Danicamtiv 350mg	Number of Participants With a Troponin I Increase - SAD Cohorts	0 Participants

Primary

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.

Time frame: Baseline, Day 1-16, 2 hours pre-dose and at 7-, 24-, and 48-hours post final dose

Population: All treated participants in MAD Cohorts per regimen dosage

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
SAD Cohort 1 Danicamtiv 175mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in QTcF from Baseline > 30msec	2 Participants
SAD Cohort 1 Danicamtiv 175mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in QTcF from Baseline > 60msec	0 Participants
SAD Cohort 1 Danicamtiv 175mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in PR from baseline > 25%	0 Participants
SAD Cohort 1 Danicamtiv 175mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in QRS from baseline > 25%	1 Participants
SAD Cohort 1 Danicamtiv 350mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in QTcF from Baseline > 60msec	0 Participants
SAD Cohort 1 Danicamtiv 350mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in PR from baseline > 25%	0 Participants
SAD Cohort 1 Danicamtiv 350mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in QRS from baseline > 25%	2 Participants
SAD Cohort 1 Danicamtiv 350mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in QTcF from Baseline > 30msec	5 Participants
SAD Cohort 1 Placebo	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in PR from baseline > 25%	0 Participants
SAD Cohort 1 Placebo	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in QTcF from Baseline > 60msec	1 Participants
SAD Cohort 1 Placebo	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in QRS from baseline > 25%	0 Participants
SAD Cohort 1 Placebo	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in QTcF from Baseline > 30msec	1 Participants
SAD Cohort 1 Danicamtiv 450mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in QRS from baseline > 25%	2 Participants
SAD Cohort 1 Danicamtiv 450mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in QTcF from Baseline > 60msec	1 Participants
SAD Cohort 1 Danicamtiv 450mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in QTcF from Baseline > 30msec	3 Participants
SAD Cohort 1 Danicamtiv 450mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - MAD Cohorts	Change in PR from baseline > 25%	1 Participants

Primary

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.

Time frame: Baseline, day 1-16, 2 hours pre-dose and at 3-, 5-, 9-, 12-, 24-, and 36-hours post-dose

Population: All treated participants in SAD Cohorts per regimen dosage

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
SAD Cohort 1 Danicamtiv 175mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 30msec	1 Participants
SAD Cohort 1 Danicamtiv 175mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 60msec	0 Participants
SAD Cohort 1 Danicamtiv 175mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in PR from baseline > 25%	1 Participants
SAD Cohort 1 Danicamtiv 175mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QRS from baseline > 25%	1 Participants
SAD Cohort 1 Danicamtiv 350mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QRS from baseline > 25%	1 Participants
SAD Cohort 1 Danicamtiv 350mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 30msec	1 Participants
SAD Cohort 1 Danicamtiv 350mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 60msec	0 Participants
SAD Cohort 1 Danicamtiv 350mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in PR from baseline > 25%	0 Participants
SAD Cohort 1 Placebo	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 60msec	0 Participants
SAD Cohort 1 Placebo	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QRS from baseline > 25%	0 Participants
SAD Cohort 1 Placebo	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in PR from baseline > 25%	0 Participants
SAD Cohort 1 Placebo	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 30msec	0 Participants
SAD Cohort 1 Danicamtiv 450mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 30msec	0 Participants
SAD Cohort 1 Danicamtiv 450mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 60msec	0 Participants
SAD Cohort 1 Danicamtiv 450mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in PR from baseline > 25%	0 Participants
SAD Cohort 1 Danicamtiv 450mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QRS from baseline > 25%	0 Participants
SAD Cohort 1 Danicamtiv 525mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 30msec	0 Participants
SAD Cohort 1 Danicamtiv 525mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QRS from baseline > 25%	0 Participants
SAD Cohort 1 Danicamtiv 525mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in PR from baseline > 25%	0 Participants
SAD Cohort 1 Danicamtiv 525mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 60msec	0 Participants
SAD Cohort 1 Danicamtiv 550mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in PR from baseline > 25%	0 Participants
SAD Cohort 1 Danicamtiv 550mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QRS from baseline > 25%	0 Participants
SAD Cohort 1 Danicamtiv 550mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 60msec	0 Participants
SAD Cohort 1 Danicamtiv 550mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 30msec	0 Participants
SAD Cohort 2 Danicamtiv 400mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 60msec	0 Participants
SAD Cohort 2 Danicamtiv 400mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QRS from baseline > 25%	0 Participants
SAD Cohort 2 Danicamtiv 400mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in PR from baseline > 25%	0 Participants
SAD Cohort 2 Danicamtiv 400mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 30msec	1 Participants
SAD Cohort 2 Danicamtiv 500mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 30msec	1 Participants
SAD Cohort 2 Danicamtiv 500mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 60msec	0 Participants
SAD Cohort 2 Danicamtiv 500mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QRS from baseline > 25%	0 Participants
SAD Cohort 2 Danicamtiv 500mg	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in PR from baseline > 25%	0 Participants
SAD Cohort 2 Placebo	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QRS from baseline > 25%	0 Participants
SAD Cohort 2 Placebo	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in PR from baseline > 25%	0 Participants
SAD Cohort 2 Placebo	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 60msec	1 Participants
SAD Cohort 2 Placebo	Number of Participants With Change From Baseline in Electrocardiograms (ECG) Intervals - SAD Cohorts	Change in QTcF from Baseline > 30msec	2 Participants

Primary

Number of Participants With Clinically Significant Laboratory Abnormalities

Number of participants with clinically significant laboratory abnormalities.

Time frame: From first dose to 30 days post last dose (Up to 2 months)

Population: Pre-specified for data to be collected by combining all treated participants per SAD and MAD Cohort only

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
SAD Cohort 1 Danicamtiv 175mg	Number of Participants With Clinically Significant Laboratory Abnormalities	1 Participants
SAD Cohort 1 Danicamtiv 350mg	Number of Participants With Clinically Significant Laboratory Abnormalities	1 Participants

Primary

Number of Participants With Clinically Significant Physical Examinations Abnormalities

Number of participants with clinically significant physical examinations abnormalities.

Time frame: From first dose to 30 days post last dose (Up to 2 months)

Population: Pre-specified for data to be collected by combining all treated participants per SAD and MAD Cohort only

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
SAD Cohort 1 Danicamtiv 175mg	Number of Participants With Clinically Significant Physical Examinations Abnormalities	0 Participants
SAD Cohort 1 Danicamtiv 350mg	Number of Participants With Clinically Significant Physical Examinations Abnormalities	0 Participants

Primary

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).

Time frame: From first dose to 30 days post last dose (Up to 2 months)

Population: All treated participants per regimen dosage

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
SAD Cohort 1 Danicamtiv 175mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	TEAEs	2 Participants
SAD Cohort 1 Danicamtiv 175mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	SAEs	0 Participants
SAD Cohort 1 Danicamtiv 350mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	TEAEs	5 Participants
SAD Cohort 1 Danicamtiv 350mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	SAEs	0 Participants
SAD Cohort 1 Placebo	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	TEAEs	3 Participants
SAD Cohort 1 Placebo	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	SAEs	0 Participants
SAD Cohort 1 Danicamtiv 450mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	TEAEs	0 Participants
SAD Cohort 1 Danicamtiv 450mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	SAEs	0 Participants
SAD Cohort 1 Danicamtiv 525mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	SAEs	0 Participants
SAD Cohort 1 Danicamtiv 525mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	TEAEs	0 Participants
SAD Cohort 1 Danicamtiv 550mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	SAEs	0 Participants
SAD Cohort 1 Danicamtiv 550mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	TEAEs	1 Participants
SAD Cohort 2 Danicamtiv 400mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	TEAEs	3 Participants
SAD Cohort 2 Danicamtiv 400mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	SAEs	0 Participants
SAD Cohort 2 Danicamtiv 500mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	TEAEs	0 Participants
SAD Cohort 2 Danicamtiv 500mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	SAEs	0 Participants
SAD Cohort 2 Placebo	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	TEAEs	0 Participants
SAD Cohort 2 Placebo	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	SAEs	0 Participants
MAD Cohort 2 Danicamtiv 50mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	SAEs	0 Participants
MAD Cohort 2 Danicamtiv 50mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	TEAEs	7 Participants
MAD Cohort 1+3 Danicamtiv 75mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	SAEs	1 Participants
MAD Cohort 1+3 Danicamtiv 75mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	TEAEs	6 Participants
MAD Cohort 4 Danicamtiv 100mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	TEAEs	4 Participants
MAD Cohort 4 Danicamtiv 100mg	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	SAEs	0 Participants
MAD Cohort Placebo	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	SAEs	0 Participants
MAD Cohort Placebo	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	TEAEs	4 Participants

Secondary

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.