Cardiomyopathy, Hypertrophic Obstructive, Left Ventricular Outflow Tract Obstruction
Conditions
Brief summary
The purpose of this phase 2 open-label pilot study is to evaluate the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of MYK-461 in subjects with symptomatic HCM and LVOT obstruction aged 18-70 years.
Interventions
DRUGMYK-461
Sponsors
MyoKardia, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Diagnosed with HCM (hypertrophied and non-dilated left ventricle in absence of systemic or other known cause), with LV wall thickness ≥ 15 mm at time of initial diagnosis or ≥ 13 mm with a positive family history of HCM. * Age 18-70 * BMI 18-37kg/m2 * Documented LVEF ≥ 55% at the Screening visit as determined by the investigator and the investigational site's echocardiography laboratory. * Resting LVOT gradient ≥ 30 mg Hg and post-exercise peak LVOT gradient ≥ 50 mm Hg * NYHA functional class II or higher Key
Exclusion criteria
* History of sustained ventricular tachyarrhythmia. * History of syncope with exercise within past 6 months. * Active infection. * Persistent atrial fibrillation or atrial fibrillation at Screening or history of paroxysmal atrial fibrillation with resting rate document \> 100bpm within 1 year of screening. * Has QTc Fridericia (QTcF) \> 500 ms, or any other ECG abnormality considered by the investigator to pose a risk to subject safety (e.g. second degree atrioventricular block type II). * Aortic stenosis or fixed subaortic obstruction. * History of LV systolic dysfunction (LVEF \< 45%) at any time during their clinical course. * History of obstructive coronary artery disease. * History or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the investigator or MyoKardia physician, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion. * Part A: Ongoing therapy with beta blockers, calcium channel blockers, or disopyramide. Subjects on any of these medications who, in the opinion of the investigator, can safely be withdrawn are eligible as long as medication is discontinued at least 14 days prior to the Screening visit. * Part B: Ongoing therapy with calcium channel blockers or disopyramide. Subjects on any of these medications who, in the opinion of the investigator, can safely be withdrawn are eligible as long as medication is discontinued at least 14 days prior to the Screening visit. * Prior treatment with cardiotoxic agents such as doxorubicin or similar, or current treatment with antiarrhythmic drugs that have negative inotropic activity, e.g. flecainide or propafenone.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Post-exercise Peak LVOT Gradient From Baseline to Week 12 | Baseline and Week 12 | Post-exercise peak LVOT gradients are assessed after a treadmill stress test by echocardiography. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Global Longitudinal Strain (GLS) From Baseline to Week 12 | Baseline and Week 12 | GLS is assessed using echocardiography measures. |
| Change in Dyspnea Symptom Score From Baseline to Week 12 | Baseline and Week 12 | The scale name is Dyspnea Numeric Rating Scale (NRS). It is intended to measure how much shortness of breath you have had in the past week. 0 = no shortness of breath and 10 = shortness of breath as the worst possible. |
| Change in Peak VO2 From Baseline to Week 12 | Baseline and Week 12 | Peak VO2 is assessed using a cardiopulmonary exercise test. |
| Change in VE/VCO2 From Baseline to Week 12 | Baseline and Week 12 | VE/VCO2 is assessed from cardiopulmonary exercise testing results. |
| Number of Participants Achieving a Post-exercise Peak LVOT Gradient Response of < 30 mmHg. Gradient < 30 mmHg | Baseline and Week 12 | LVOT gradients are assessed after a treadmill stress test by echocardiography. |
| Change in Resting LVEF From Baseline to Week 12 | Baseline and Week 12 | LVEF is assessed by echocardiography. |
| Change in LV Fractional Shortening (LVFS) From Baseline to Week 12 | Baseline and Week 12 | LVFS is assessed using echocardiography measures. |
| Change in Post-exercise Peak LVOT Gradient From Week 12 to Week 16 | Weeks 12 and 16 | Post-exercise peak LVOT gradients are assessed after a treadmill stress test by echocardiography. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in NYHA Functional Class From Baseline to Week 12 | Baseline and Week 12 | — |
| Number of Subjects Achieving an LVOT Gradient Response of Post-exercise Peak Gradient < 10 mmHg at Week 12 | Baseline and Week 12 | Post-exercise peak LVOT gradients are assessed after a treadmill stress test by echocardiography. |
| Change in KCCQ OSS From Baseline to Week 12 | Baseline and Week 12 | — |
| Change in NT-proBNP From Baseline to Week 12 | 12 weeks | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A Mavacamten 10 to 20 mg/d without background medications | 11 |
| Cohort B Mavacamten 2 to 5 mg/d with beta-blockers allowed. | 10 |
| Total | 21 |
Baseline characteristics
| Characteristic | Cohort A | Cohort B | Total |
|---|---|---|---|
| Age, Customized Mean Age (range) | 56 years | 58 years | 57 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 10 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Postexercise LVOT gradient | 103 mm Hg STANDARD_DEVIATION 50 | 86 mm Hg STANDARD_DEVIATION 43 | 94.5 mm Hg STANDARD_DEVIATION 0 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 9 Participants | 20 Participants |
| Sex/Gender, Customized Female | 4 Participants | 5 Participants | 9 Participants |
| Sex/Gender, Customized Male | 7 Participants | 5 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 10 |
| other Total, other adverse events | 10 / 11 | 10 / 10 |
| serious Total, serious adverse events | 1 / 11 | 0 / 10 |
Outcome results
Primary
Change in Post-exercise Peak LVOT Gradient From Baseline to Week 12
Post-exercise peak LVOT gradients are assessed after a treadmill stress test by echocardiography.
Time frame: Baseline and Week 12
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort A | Change in Post-exercise Peak LVOT Gradient From Baseline to Week 12 | -89.5 mm Hg |
| Cohort B | Change in Post-exercise Peak LVOT Gradient From Baseline to Week 12 | -25.0 mm Hg |
Secondary
Change in Dyspnea Symptom Score From Baseline to Week 12
The scale name is Dyspnea Numeric Rating Scale (NRS). It is intended to measure how much shortness of breath you have had in the past week. 0 = no shortness of breath and 10 = shortness of breath as the worst possible.
Time frame: Baseline and Week 12
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort A | Change in Dyspnea Symptom Score From Baseline to Week 12 | -3.1 units on a scale |
| Cohort B | Change in Dyspnea Symptom Score From Baseline to Week 12 | -3.0 units on a scale |
Secondary
Change in Global Longitudinal Strain (GLS) From Baseline to Week 12
GLS is assessed using echocardiography measures.
Time frame: Baseline and Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A | Change in Global Longitudinal Strain (GLS) From Baseline to Week 12 | 0.56 Percent | Standard Deviation 3.778 |
| Cohort B | Change in Global Longitudinal Strain (GLS) From Baseline to Week 12 | 0.18 Percent | Standard Deviation 2.806 |
Secondary
Change in LV Fractional Shortening (LVFS) From Baseline to Week 12
LVFS is assessed using echocardiography measures.
Time frame: Baseline and Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A | Change in LV Fractional Shortening (LVFS) From Baseline to Week 12 | -18.60 Percent | Standard Deviation 13.05 |
| Cohort B | Change in LV Fractional Shortening (LVFS) From Baseline to Week 12 | -3.98 Percent | Standard Deviation 11.42 |
Secondary
Change in Peak VO2 From Baseline to Week 12
Peak VO2 is assessed using a cardiopulmonary exercise test.
Time frame: Baseline and Week 12
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort A | Change in Peak VO2 From Baseline to Week 12 | 3.5 mL/kg/min |
| Cohort B | Change in Peak VO2 From Baseline to Week 12 | 1.7 mL/kg/min |
Secondary
Change in Post-exercise Peak LVOT Gradient From Week 12 to Week 16
Post-exercise peak LVOT gradients are assessed after a treadmill stress test by echocardiography.
Time frame: Weeks 12 and 16
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A | Change in Post-exercise Peak LVOT Gradient From Week 12 to Week 16 | 55.22 mm Hg | Standard Deviation 40.84 |
| Cohort B | Change in Post-exercise Peak LVOT Gradient From Week 12 to Week 16 | 84.08 mm Hg | Standard Deviation 28.38 |
Secondary
Change in Resting LVEF From Baseline to Week 12
LVEF is assessed by echocardiography.
Time frame: Baseline and Week 12
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort A | Change in Resting LVEF From Baseline to Week 12 | -14.6 Percent change |
| Cohort B | Change in Resting LVEF From Baseline to Week 12 | -5.5 Percent change |
Secondary
Change in VE/VCO2 From Baseline to Week 12
VE/VCO2 is assessed from cardiopulmonary exercise testing results.
Time frame: Baseline and Week 12
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort A | Change in VE/VCO2 From Baseline to Week 12 | -2.2 Ratio |
| Cohort B | Change in VE/VCO2 From Baseline to Week 12 | -2.5 Ratio |
Secondary
Number of Participants Achieving a Post-exercise Peak LVOT Gradient Response of < 30 mmHg. Gradient < 30 mmHg
LVOT gradients are assessed after a treadmill stress test by echocardiography.
Time frame: Baseline and Week 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A | Number of Participants Achieving a Post-exercise Peak LVOT Gradient Response of < 30 mmHg. Gradient < 30 mmHg | 8 Participants |
| Cohort B | Number of Participants Achieving a Post-exercise Peak LVOT Gradient Response of < 30 mmHg. Gradient < 30 mmHg | 0 Participants |
Other Pre-specified
Change in KCCQ OSS From Baseline to Week 12
Time frame: Baseline and Week 12
Other Pre-specified
Change in NT-proBNP From Baseline to Week 12
Time frame: 12 weeks
Other Pre-specified
Change in NYHA Functional Class From Baseline to Week 12
Time frame: Baseline and Week 12
Other Pre-specified
Number of Subjects Achieving an LVOT Gradient Response of Post-exercise Peak Gradient < 10 mmHg at Week 12
Post-exercise peak LVOT gradients are assessed after a treadmill stress test by echocardiography.
Time frame: Baseline and Week 12