Clinical trial NCT02842242
Conditions: Cardiomyopathy, Hypertrophic Obstructive Left Ventricular Outflow Tract Obstruction
Sponsor: MyoKardia, Inc.
Start date: 2016-08-01; Completion date: 2017-11-01
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Detailed description:

Arms: arm 1: MYK-461
Interventions: intervention 1: MYK-461
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
 
 
 
MyoKardia, Inc. 
MYK-461 Protocol: MYK-461-004 
 
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CLINICAL STUDY PROTOCOL 
Protocol Number 
MYK-461-004 
Protocol Title: 
A Phase 2 Open-label Pilot Study to Evaluate Efficacy, 
Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of 
MYK-461 in Subjects With Symptomatic Hypertrophic Cardiomyopathy 
and Left Ventricular Outflow Tract Obstruction (Pioneer-HCM) 
Indication: 
Hypertrophic Cardiomyopathy 
Phase: 
2 
Investigational 
Medicinal Product 
MYK-461 
Sponsor: 
MyoKardia, Inc. 
333 Allerton Avenue 
South San Francisco, CA 94080 
Key Sponsor Contacts: 
Brianne Leary 
Senior Manager, Clinical Operations 
bleary@myokardia.com 
650.351.4657 
Michael Grimm 
Executive Director, Clinical Development 
mgrimm@myokardia.com 
650.351.4664 
 
Original Protocol Date: 
Amendment 1 Date: 
12 May 2016 
01 March 2017  
Amendment 2 Date: 
05 May 2017 
 
Confidentiality Statement 
This document contains trade secrets or otherwise confidential and/or proprietary information of 
MyoKardia, Inc. Access to and use of this information is strictly limited and controlled by 
MyoKardia, Inc. Acceptance of this document constitutes agreement by the recipient that the contents 
will be not be copied, distributed, or otherwise disclosed to third parties, and will not be used in any 
way, except as expressly authorized by MyoKardia, Inc. 
 


 
 
 
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PROTOCOL SYNOPSIS 
Protocol Number and Title: 
MYK-461-004: A Phase 2 Open-label Pilot Study to Evaluate Efficacy, Pharmacokinetics, 
Pharmacodynamics, Safety, and Tolerability of MYK-461 in Subjects With Symptomatic 
Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction 
(Pioneer-HCM) 
Name of Investigational Product: MYK-461 
Sponsor: MyoKardia, Inc. 
Phase: 2 
Study Objectives: 
Primary Objective: 
• To characterize the effect of 12 weeks of MYK-461 treatment on reducing post-exercise 
peak left ventricular outflow tract (LVOT) gradient in subjects with symptomatic 
hypertrophic cardiomyopathy (HCM) and LVOT obstruction 
 
Secondary Objectives: 
• To assess the proportion of subjects achieving an LVOT gradient response of 
post-exercise peak gradient < 30 mm Hg in subjects with symptomatic HCM and LVOT 
obstruction 
• To assess the effects of 12 weeks of MYK-461 treatment on dyspnea symptom score, 
peak oxygen uptake (pVO2), and volume expired (VE)/carbon dioxide production 
(VCO2) slope in subjects with symptomatic HCM and LVOT obstruction  
• To evaluate the pharmacokinetics (PK) of MYK-461 in subjects with symptomatic HCM 
and LVOT obstruction  
• To evaluate the pharmacodynamics (PD) of MYK-461 in subjects with symptomatic 
HCM and LVOT obstruction as assessed by a variety of echocardiographic imaging 
parameters in subjects with symptomatic HCM and LVOT obstruction 
• To evaluate the safety and tolerability of MYK-461 in subjects with symptomatic HCM 
and LVOT obstruction 
• To evaluate the posttreatment reversibility of the effects of MYK-461 after 4 weeks of 
washout in subjects with symptomatic HCM and LVOT obstruction 
 


 
 
 
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Exploratory Objectives: 
• To assess the proportion of subjects achieving an LVOT gradient response of 
post-exercise peak gradient < 10 mm Hg in subjects with symptomatic HCM and LVOT 
obstruction 
• To assess the effects of 12 weeks of MYK-461 treatment on New York Heart Association 
(NYHA) functional class, N-terminal pro B-type natriuretic peptide (NT-proBNP), and 
the Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score (OSS) 
in subjects with symptomatic HCM and LVOT obstruction 
• To assess the effects of MYK-461 treatment on arterial pulse wave morphology assessed 
using an optical biosensor in subjects with symptomatic HCM and LVOT obstruction 
• To assess the effect of MYK-461 treatment on heart rate and heart rhythm as assessed 
using a cardiac monitoring skin patch in subjects with symptomatic HCM and LVOT 
obstruction 
 
Eligibility Criteria: 
Inclusion Criteria: 
Each subject must meet the following criteria to be included in this study. 
1. Able to understand and comply with the study procedures, understand the risks involved 
in the study, and provide written informed consent according to federal, local, and 
institutional guidelines before the first study-specific procedure. 
2. Men or women 18 to 70 years of age at the Screening visit.  
3. Diagnosed with HCM (hypertrophied and non-dilated left ventricle in absence of 
systemic or other known cause), with left ventricular [LV] wall thickness ≥ 15 mm at 
time of initial diagnosis or ≥ 13 mm with a positive family history of HCM. 
4. Body mass index (BMI) 18 to 37 kg/m2, inclusive, at the Screening visit, calculated using 
the institution’s standard formula. 
5. All safety laboratory parameters (chemistry, hematology, and urinalysis) within normal 
limits (laboratory reference range) at the Screening visit as assessed by the central 
laboratory, or if outside of the limits must meet both of the following criteria: 
- 
considered by the investigator to be clinically unimportant 
- 
if a liver function test result, must be < 1.5 × the upper limit of the laboratory 
reference range. 
6. Has documented left ventricular ejection fraction (LVEF) ≥ 55% at the Screening visit as 
determined by the investigator and the investigational site’s echocardiography laboratory. 
7. Resting LVOT gradient ≥ 30 mg Hg and post-exercise peak LVOT gradient ≥ 50 mm Hg 
at the Screening visit as determined by the investigator and the investigational site’s 
echocardiography laboratory. 


 
 
 
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8. NYHA functional class II or higher, judged by the investigator to be due to LVOT 
obstruction. 
9. Has adequate acoustic windows, in the judgment of the investigator and the 
investigational site’s echocardiography laboratory, to enable accurate transthoracic 
echocardiograms (TTEs). 
10. Female subjects must not be pregnant or lactating and, if sexually active, must be using 
one of the following acceptable birth control methods from the Screening visit through 3 
months after the last dose of investigational medicinal product (IMP). Hormonal 
contraceptives are not considered highly effective contraception for this study because 
MYK-461 could reduce the effectiveness of hormonal contraceptives. 
 
- 
Double-barrier method (e.g., vasectomy or male using a condom and female using a 
diaphragm or cervical cap) 
- 
Barrier (e.g. male using a condom) plus non-hormonal intrauterine device (IUD) or 
intrauterine system (IUS) 
- 
Female is surgically sterile for 6 months or postmenopausal for 2 years. Permanent 
sterilization includes hysterectomy, bilateral oophorectomy, bilateral salpingectomy, 
and/or documented bilateral tubal occlusion at least 6 months prior to Screening. 
Females are considered postmenopausal if they have had amenorrhea for at least 
2 years or more following cessation of all exogenous hormonal treatments and 
follicle-stimulating hormone (FSH) levels are in the postmenopausal range. 
11. Male subjects with female partners (including postmenopausal partners) must agree to 
use highly effective contraceptive measures from the Screening visit through 3 months 
after the last dose of study medication. Highly effective contraception includes 
documented vasectomy, abstaining from sexual intercourse, double-barrier method (e.g., 
male using a condom and female using a diaphragm or cervical cap), or barrier plus 
hormonal contraception (e.g., male using a condom and female using hormonal 
contraception). As there may be a risk of drug being secreted in the ejaculate, male 
subjects (including men who have had vasectomies) whose partners are currently 
pregnant should use barrier methods for the duration of the study and for 3 months after 
the last dose of study medication. In addition, male subjects with sexual partners should 
use condoms for the duration of the study and for 3 months after the last dose of study 
medication, even if the partner is not pregnant or capable of becoming pregnant, in order 
to prevent passing MYK-461 to the partner in the ejaculate. 
12. Must be able to complete the Dyspnea Numeric Rating Scale (NRS) and the KCCQ per 
established guidelines. 
 
Exclusion Criteria: 
Subjects who meet any of the following criteria will be excluded from the study. 
1. Hypersensitivity to MYK-461 or any of the components of the MYK-461 formulation. 


 
 
 
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2. Presence of any medical condition that precludes exercise stress testing. 
3. History of sustained ventricular tachyarrhythmia. 
4. History of syncope with exercise within past 6 months. 
5. Active infection. 
6. Persistent atrial fibrillation or atrial fibrillation at Screening or history of paroxysmal 
atrial fibrillation with resting rate documented >100 bpm within 1 year of screening. 
7. Has QTc Fridericia (QTcF) > 500 ms, or any other electrocardiogram (ECG) abnormality 
considered by the investigator to pose a risk to subject safety (e.g., second degree 
atrioventricular block type II). 
8. Aortic stenosis or fixed subaortic obstruction.  
9. History of LV systolic dysfunction (LVEF < 45%) at any time during their clinical 
course. 
10. History of obstructive coronary artery disease (stenosis of >70% of luminal diameter in 
one or more coronary arteries). 
11. History of malignancy of any type, with the following exceptions: in situ cervical cancer 
more than 5 years prior to Screening or surgically excised non-melanomatous skin 
cancers more than 2 years prior to Screening. 
12. Positive serologic test at Screening for infection with human immunodeficiency virus 
(HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV). 
13. Positive test for alcohol or drugs of abuse at Screening. 
14. History or evidence of any other clinically significant disorder, condition, or disease 
(with the exception of those outlined above) 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. 
15. Participated in a clinical trial where the subject received any investigational drug (or is 
currently using an investigational device) within 30 days prior to Screening, or at least 
5 times the respective elimination half-life (whichever is longer).  
16. Current use of tobacco- or nicotine-containing products exceeding 10 cigarettes per day 
or equivalent. 
17. Part A: Subjects who in the opinion of the investigator require ongoing therapy with 
β-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: Subjects who in the opinion of the investigator require 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. 


 
 
 
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18. 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. 
19. Unable to comply with the study restrictions/requirements, including the number of 
required visits to the clinical site. 
20. Is employed by, or is a relative of someone employed by MyoKardia, the investigator, or 
his/her staff or family. 
 
Study Treatment: 
Study medication will consist of MYK-461 immediate-release oral tablets, 2 mg, 5 mg, 
10 mg, and 20 mg.  
Part A: 
Subjects on β-blockers who, in the opinion of the investigator, can safely be withdrawn are 
eligible for this part of the study as long as medication is discontinued at least 14 days prior 
to the Screening visit. The starting dose will vary based on individual subjects’ weight. 
Subjects who weigh ≤ 60 kg will start at 10 mg and subjects who weigh > 60 kg will start at 
15 mg. Each subject will receive oral MYK-461 at their determined starting dose once daily 
(QD) beginning on Day 1 and continuing through Week 4. At Week 4, an individual 
subject’s daily dose may be adjusted based on predetermined criteria (see Study Design). The 
subject will subsequently receive that dose from Week 5 through Week 12. 
Part B: 
Subjects not currently taking beta blockers and subjects on a stable dose of β-blockers for at 
least 14 days, who in the opinion of the investigator require ongoing therapy with β-blockers 
at the same dose, are eligible for this part of the study. This includes patients treated with β-
blockers for rate control of paroxysmal atrial fibrillation.  The starting dose will be 2 mg 
MYK-461 QD beginning on Day 1 and continuing through Week 4. At Week 4, an 
individual subject’s daily dose may be adjusted based on predetermined criteria (see Study 
Design). The subject will subsequently receive that dose from Week 5 through Week 12. 
Number of Subjects Planned: Approximately 20 (10 in Part A, 10 in Part B) 
Number/Location of Investigational Sites: Approximately 7 sites in the United States 
Study Duration: Approximately 18 months  
Study Design: 
This is a phase 2 open-label pilot study to evaluate the efficacy, PK, PD, safety, and 
tolerability of MYK-461 in subjects with symptomatic HCM and LVOT obstruction. 
Approximately 20 adult subjects with symptomatic HCM, a resting LVOT gradient 
≥ 30 mm Hg, and post-exercise peak LVOT gradient ≥ 50 mm Hg will be enrolled. The study 
will have a 12-week treatment phase and a 4-week washout phase. 


 
 
 
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At Screening, subjects will undergo TTE in the supine or left lateral decubitus position. In 
addition to a standardized complete TTE, both resting instantaneous peak LVOT gradient 
(baseline) and provoked peak LVOT gradient (Valsalva maneuver) will be collected. 
Subjects will then undergo a standard symptom-limited exercise test (hemodynamic stress 
echocardiography). Subjects will be assessed systematically for symptoms of dyspnea and/or 
angina. Instantaneous peak LVOT gradient will be assessed immediately post-exercise by 
TTE.  
On Day 1, resting TTE will be performed, blood samples will be drawn for PK, and subjects 
will have an assessment of pVO2, VE/VCO2, and other variables via cardiopulmonary 
exercise testing (CPET). After CPET, subjects will be dosed with open-label oral MYK-461 
at the investigational site and will be observed for at least 1 hour after dosing, with 
assessment of vital signs and ECGs at 1 hour postdose. Subjects will then be supplied with 
MYK-461 for QD dosing at home.  
Subjects will be evaluated at the investigational site at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, and 16. 
At each of these visits, resting TTE will be performed and blood samples will be drawn for 
PK. On study visit days, study medication will be administered at the investigational site in 
order to collect blood samples for PK ≤ 2 hours prior to dosing. At Weeks 4, 12, and 16, 
hemodynamic stress echocardiography will be performed and peak LVOT gradient will be 
assessed. CPET will be conducted between Weeks 10 and 12 (inclusive).  
Part A: 
The MYK-461 starting dose will be 10 mg for subjects who weigh ≤ 60 kg and 15 mg for 
subjects who weigh > 60 kg. At the end of Week 4 (Day 28), each subject’s LVEF will be 
evaluated, and the subject’s dose may be increased, decreased, or remain unchanged based on 
the predetermined criteria below, in consultation between the investigator and the medical 
monitor. If MYK-461 plasma concentration exceeds 750 ng/mL at Week 2, no dose increase 
is allowed, regardless of LVEF data at Week 4; however, dose decrease per LVEF data is 
allowed in this circumstance. The subject will subsequently receive that dose from Week 5 
through Week 12. 
 
Percent Decrease From Baseline in LVEF at the 
End of Week 4 (Day 28)  
Action for MYK-461 Dose 
Week 5-Week 12a  
< 10 
increase dose by 10 mg 
≥ 10 and < 15 
increase dose by 5 mg 
≥15 and < 20 
no change in dose 
≥ 20 
decrease dose by 5 mg 
a 
LVEF, left ventricular ejection fraction No dose increase allowed if plasma concentration of MYK-461 > 
750 ng/mL at Week 2. 


 
 
 
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Part B: 
The MYK-461 starting dose will be 2 mg. At the end of Week 4 (Day 28), each subject’s 
resting (non-provoked) peak instantaneous LVOT gradient and LVEF from the Week 4 TTE 
will be evaluated. The subject’s dose will be increased to 5 mg or remain unchanged based 
on the predetermined criteria below, in consultation between the investigator and the medical 
monitor. If MYK-461 plasma concentration exceeds 300 ng/mL at Week 2, no dose increase 
is allowed.  The subject will subsequently receive that dose from Week 5 (Day 29) through 
Week 12. 
Percent Decrease From Day 1  in Resting TTE 
Instantaneous Peak LVOT gradient at the End of 
Week 4 (Day 28)  
Action for MYK-461 Dose Week 5-Week 12a  
< 50% 
increase dose to 5 mg 
≥ 50% 
no change in dose 
a 
LVOT, left ventricular outflow tract; TTE, transthoracic echocardiogram; No dose increase allowed if 
plasma concentration of MYK-461 > 300 ng/mL at Week 2. 
 
For all subjects who provide consent, blood will be drawn prior to dosing on Day 1 for 
assessment of HCM genotype and potentially additional deoxyribonucleic acid (DNA) 
sequencing. 
In addition, subjects may consent separately to collection of pharmacogenetic samples that 
will be stored for potential future analysis of genetic biomarkers of efficacy, safety-related, 
PD, or PK parameters as determined by future studies using clinically meaningful endpoints, 
through DNA sequencing or other genetic testing. 
Blood samples will be collected from all subjects prior to dosing on Day 1 and at Week 12 
and stored for exploratory circulating biomarker analysis, e.g., proteomic analysis related to 
disease activity, metabolic pathways, efficacy measures, or safety measures. 
Study Assessments and Procedures: 
The efficacy of MYK-461 will be evaluated using TTE and CPET. The primary endpoint 
will be the change from baseline to Week 12 in post-exercise peak LVOT gradient.  
Secondary endpoints include the proportion of subjects achieving a LVOT gradient response 
of post-exercise peak gradient < 30 mm Hg; change from baseline to Week 12 in the dyspnea 
symptom score, pVO2, VE/VCO2, LVEF (2-dimensional [2D] and 3-dimensional [3D]), 
global longitudinal strain, and left ventricular fractional shortening (LVFS); and change from 
Week 12 to Week 16 in post-exercise peak LVOT gradient. The plasma PK profile of 
MYK-461 is also a secondary endpoint. 
Exploratory endpoints include the proportion of subjects achieving an LVOT gradient 
response of post-exercise peak gradient < 10 mm Hg; change from baseline to Week 12 in 
NYHA functional class, NT-proBNP, and KCCQ OSS; change from baseline in arterial pulse 
wave morphology assessed using an optical biosensor; and change from baseline in heart rate 
and heart rhythm as assessed using a cardiac monitoring skin patch. 


 
 
 
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Safety endpoints include treatment-emergent AEs and serious adverse events (SAEs), and 
changes from baseline in laboratory test results, vital signs, and ECGs. Any abnormal ECG 
or vital sign finding judged by the investigator to be clinically important will be recorded as 
an AE. 
End of Study 
Subjects will be followed through completion of End of Study (EOS) procedures. All AEs, 
including SAEs and deaths, will be collected for the duration of the study, up to and 
including the EOS visit.  
If there is a significant clinical abnormality or a clinically significant laboratory abnormality 
in need of monitoring, the subject will be followed until resolution of the abnormality or until 
it is considered stable in the opinion of the investigator. 
Sample Size and Statistical Considerations: 
Sample Size: 
Approximately 10 subjects will be dosed in Part A and approximately 10 in Part B. The 
sample size is based on practical considerations and is consistent with this type of study. Ten 
subjects receiving MYK-461 will provide 80% power to detect a 30 mm Hg difference 
versus baseline in post-exercise LVOT peak gradient and a > 99% power to detect a 
50 mm Hg difference. This assumes a 1-sided α = 0.05 and a common standard deviation of 
35 mm Hg.  
Statistical Analyses: 
All efficacy and PD analyses will be performed on the Efficacy/PD Analysis Population, 
which comprises all subjects who receive at least 1 dose of MYK-461 and have primary or 
secondary endpoint data, including a baseline value and at least one post baseline value 
measured during the on-treatment period. 
Post-exercise peak LVOT gradient will be analyzed using a mixed-effect model with 
repeated measures (MMRM). All data available from baseline (Screening) to Week 16 (EOS) 
will be included and missing data will be accounted for by the MMRM model. The model 
will include the fixed categorical effects of timepoint: baseline Week 4, Week 12 (end of 
treatment), and Week 16 (EOS). This model will provide least-squares (LS) mean estimates 
with their corresponding standard errors at each time point. Comparison between baseline 
and Week 12 (end of treatment) will be based on the LS mean difference obtained from the 
MMRM, and will be presented with its associated 95% confidence interval. Statistical 
significance of the difference versus baseline will be evaluated at the 1-sided 0.05 level. 
The proportion of subjects achieving LVOT gradient responses of < 30 mm Hg and 
< 10 mm Hg will be summarized at each post-baseline visit. In case of missing data at a 
given visit, it will be assumed that the subject had not achieved an LVOT gradient response. 
Quantitative endpoints, including the Dyspnea NRS, pVO2, VE/CO2, LVEF, NYHA 
functional classification, NT-proBNP, and KCCQ OSS will be analyzed using the same 


 
 
 
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MMRM model as for the primary efficacy endpoint. The list of timepoints included in the 
MMRM will be adjusted according to the visits at which each endpoint will be measured. 
Data collected from the optical biosensor and cardiac monitoring skin patch will be analyzed 
descriptively. 
Plasma concentrations of MYK-461 will be determined and summarized descriptively.  


 
 
 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ............................................................................................1 
PROTOCOL SYNOPSIS ..........................................................................................................2 
TABLE OF CONTENTS .........................................................................................................11 
LIST OF TABLES ...................................................................................................................15 
LIST OF FIGURES .................................................................................................................15 
LIST OF APPENDICES ..........................................................................................................15 
LIST OF ABBREVIATIONS ..................................................................................................16 
1 
INTRODUCTION .................................................................................................18 
1.1 
Background ......................................................................................................18 
1.2 
Clinical Studies ................................................................................................18 
1.2.1 
MYK-461-002......................................................................................19 
1.2.2 
MYK-461-001......................................................................................19 
1.2.3 
MYK-461-003......................................................................................19 
1.3 
Known and Potential Benefits and Risks .........................................................20 
2 
RATIONALE FOR THE STUDY AND FOR DOSE AND DOSING 
SCHEDULE ...........................................................................................................21 
2.1 
Rationale for the Study ....................................................................................21 
2.2 
Rationale for Dose and Dosing Schedule ........................................................21 
3 
STUDY OBJECTIVES ..........................................................................................22 
3.1 
Primary Objective ............................................................................................22 
3.2 
Secondary Objectives.......................................................................................22 
3.3 
Exploratory Objectives ....................................................................................22 
4 
OVERALL STUDY DESIGN AND PLAN ..........................................................23 
4.1 
Study Duration .................................................................................................25 
4.2 
Independent Data Monitoring Committee .......................................................25 
5 
SELECTION AND WITHDRAWAL OF STUDY POPULATION.....................26 
5.1 
General Study Population and Clinical Sites ...................................................26 
5.2 
Inclusion Criteria .............................................................................................26 
5.3 
Exclusion Criteria ............................................................................................27 
5.4 
Screening and Enrollment ................................................................................28 
5.5 
Withdrawal and Replacement of Subjects .......................................................29 
5.5.1 
Withdrawal from the Study ..................................................................29 
5.5.2 
Replacement of Subjects ......................................................................29 
6 
RANDOMIZATION AND BLINDING PROCEDURES.....................................29 
6.1 
Randomization .................................................................................................29 
6.2 
Blinding............................................................................................................30 
7 
STUDY TREATMENT .........................................................................................30 


 
 
 
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7.1 
MYK-461, Administration, and Schedule .......................................................30 
7.2 
Treatment Compliance .....................................................................................30 
7.3 
Dose Adjustment ..............................................................................................31 
7.4 
Hepatotoxicity Stopping and Rechallenge Rules .............................................31 
7.4.1 
Criteria for Permanent Withholding of MYK-461 Due to Potential 
Hepatotoxicity ......................................................................................31 
7.4.2 
Criteria for Conditional Withholding of MYK-461 Due to Potential 
Hepatotoxicity ......................................................................................32 
7.4.3 
Criteria for Rechallenge of MYK-461 After Potential 
Hepatotoxicity ......................................................................................32 
7.5 
Guidelines for the Management of an Exaggerated Pharmacologic Effect .....32 
7.6 
Overdose ..........................................................................................................33 
7.7 
Prior and Concomitant Treatment ....................................................................34 
7.7.1 
Prior Therapy .......................................................................................34 
7.7.2 
Concomitant Therapy...........................................................................34 
7.7.3 
Prohibited Therapy...............................................................................34 
8 
RISKS AND PRECAUTIONS ..............................................................................34 
8.1 
General .............................................................................................................34 
8.2 
Pregnancy .........................................................................................................35 
8.2.1 
Avoidance of Pregnancy ......................................................................35 
8.2.2 
Restrictions for Male Subjects .............................................................35 
8.2.3 
Acceptable Forms of Contraception ....................................................35 
8.2.4 
Reporting and Follow-up of Pregnancies ............................................36 
9 
STUDY ASSESSMENTS AND PROCEDURES .................................................36 
9.1 
Efficacy and Pharmacodynamic Assessments .................................................36 
9.1.1 
Echocardiography and Cardiopulmonary Exercise Testing ................36 
9.1.2 
Dyspnea Numeric Rating Scale ...........................................................37 
9.1.3 
Kansas City Cardiomyopathy Questionnaire .......................................37 
9.1.4 
New York Heart Association Class .....................................................37 
9.1.5 
Exploratory Assessments .....................................................................38 
9.2 
Pharmacokinetic, Pharmacogenetic, and Biomarker Assessments ..................39 
9.2.1 
Pharmacokinetic Assessments .............................................................39 
9.2.2 
Genotype/Pharmacogenetic/Biomarker Assessment ...........................39 
9.3 
Safety Assessments ..........................................................................................39 
9.3.1 
Medical History ...................................................................................39 
9.3.2 
Physical Examination...........................................................................40 
9.3.3 
12-Lead ECG .......................................................................................40 
9.3.4 
Vital Signs ............................................................................................40 
9.3.5 
Other Safety Assessments ....................................................................40 


 
 
 
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9.4 
Subject Restrictions During This Study ...........................................................41 
9.5 
Study Procedures by Visit ................................................................................41 
9.5.1 
Screening (Day -28 to Day -1) .............................................................41 
9.5.2 
Day 1 ....................................................................................................42 
9.5.3 
Day 4 ....................................................................................................43 
9.5.4 
Weeks 1, 2, 3, 4, 5, 6, 7, and 8 .............................................................44 
9.5.5 
Week 10 ...............................................................................................44 
9.5.6 
Week 12/Early Termination .................................................................45 
9.5.7 
Week 16/End of Study .........................................................................46 
9.5.8 
Unscheduled Visits ..............................................................................46 
9.6 
Visit Window and Missed Visits .....................................................................46 
10 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE 
EVENTS ................................................................................................................47 
10.1 
Definitions........................................................................................................47 
10.1.1 
Adverse Event ......................................................................................47 
10.1.2 
Serious Adverse Event .........................................................................48 
10.2 
Adverse Event Reporting and Descriptions .....................................................48 
10.2.1 
Reporting Period and Follow-Up .........................................................48 
10.2.2 
Adverse Event Attributes .....................................................................48 
10.3 
Reporting and Evaluation of Serious Adverse Events .....................................50 
11 
STATISTICAL METHODS ..................................................................................50 
11.1 
Determination of Sample Size .........................................................................50 
11.2 
Study Endpoints ...............................................................................................51 
11.2.1 
Primary Endpoint .................................................................................51 
11.2.2 
Secondary Endpoints ...........................................................................51 
11.2.3 
Exploratory Endpoints .........................................................................51 
11.2.4 
Safety Endpoints ..................................................................................52 
11.3 
Statistical Analysis ...........................................................................................52 
11.3.1 
Analysis Populations ............................................................................52 
11.3.2 
General Considerations ........................................................................52 
11.3.3 
Subject Disposition ..............................................................................53 
11.3.4 
Demographics and Baseline Characteristics ........................................53 
11.3.5 
Efficacy/Pharmacodynamic Analyses .................................................53 
11.3.6 
Pharmacokinetic Analyses ...................................................................53 
11.3.7 
Interim Analysis ...................................................................................54 
11.3.8 
Safety Analyses ....................................................................................54 
11.3.9 
Exploratory Analyses ...........................................................................55 
12 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS ........................55 


 
 
 
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12.1 
Compliance Statement .....................................................................................55 
12.2 
Informed Consent.............................................................................................56 
12.3 
Ethics Committee .............................................................................................56 
13 
ADMINISTRATIVE PROCEDURES ..................................................................57 
13.1 
Sponsor’s Responsibilities ...............................................................................57 
13.1.1 
Subject Confidentiality ........................................................................57 
13.1.2 
Study Supplies .....................................................................................58 
13.1.3 
Investigator Training ............................................................................58 
13.1.4 
Ongoing Communication of Safety Information during the Study .....58 
13.1.5 
Study Monitoring .................................................................................59 
13.1.6 
Study Auditing and Inspecting.............................................................59 
13.2 
Investigator’s Responsibilities .........................................................................59 
13.2.1 
Screening Log ......................................................................................59 
13.2.2 
MYK-461 Accountability ....................................................................59 
13.2.3 
Reporting and Recording of Study Data ..............................................60 
13.2.4 
Source Data and Source Documents ....................................................60 
13.2.5 
Subject Identification Information .......................................................61 
13.2.6 
Records Retention ................................................................................61 
13.2.7 
Protocol Deviations ..............................................................................61 
13.2.8 
Blood Sample Collection/Storage ........................................................61 
13.3 
Clinical Trial Insurance....................................................................................62 
13.4 
Protocol Amendments and Study Administrative Letters ...............................62 
14 
DATA QUALITY ASSURANCE .........................................................................62 
15 
ADMINISTRATIVE CONSIDERATIONS ..........................................................63 
15.1 
Use of Computerized Systems .........................................................................63 
15.2 
Study Records ..................................................................................................63 
16 
PUBLICATION .....................................................................................................64 
17 
REFERENCE LIST ...............................................................................................65 
APPENDICES .........................................................................................................................67 
 


 
 
 
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LIST OF TABLES 
Table 1 
Part A Week 4 Dose Adjustment Criteria ..................................................24 
Table 2 
Part B Week 4 Dose Adjustment Criteria ..................................................25 
Table 3 
New York Heart Association Functional Classification of Heart 
Failure ........................................................................................................38 
Table 4 
Power for Detecting a Statistically Significant Within Group Change 
With 10 Subjectsa .......................................................................................51 
 
LIST OF FIGURES 
Figure 1 
Study Schema.............................................................................................23 
 
LIST OF APPENDICES 
APPENDIX 1 
SCHEDULE OF STUDY PROCEDURES ...............................................67 
APPENDIX 2 
LABORATORY ASSESSMENTS ...........................................................71 
APPENDIX 3 
POTENTIAL DRUG-INDUCED LIVER INJURY REPORTING 
AND ADDITIONAL ASSESSMENTS REPORTING .............................71 
APPENDIX 4 
INVESTIGATOR’S SIGNATURE ...........................................................73 
APPENDIX 5 
INVESTIGATOR’S SIGNATURE AMENDMENT 1 .............................74 
 


 
 
 
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LIST OF ABBREVIATIONS 
2D 
2-dimensional 
3D 
3-dimensional 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CHMP 
Committee for Medicinal Products for Human Use 
cGMP 
Current Good Manufacturing Practices 
CPET 
cardiopulmonary exercise testing 
CRF 
case report form 
DILI 
drug-induced liver injury 
DNA 
deoxyribonucleic acid 
EC 
ethics committee; refers to an IRB or IEC or equivalent. 
EOS 
End of Study 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EMA 
European Medicines Agency  
FSH 
follicle-stimulating hormone 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HCM 
hypertrophic cardiomyopathy 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation  
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 


 
 
 
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IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LS 
least-squares 
LV 
left ventricular 
LVEF 
left ventricular ejection fraction 
LVFS 
left ventricular fractional shortening 
LVOT 
left ventricular outflow tract 
MAD 
multiple ascending-dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed effect model with repeated measures 
NASH 
nonalcoholic steatohepatitis 
NRS 
numeric rating scale 
NT-proBNP 
N-terminal pro B-type natriuretic peptide 
NYHA 
New York Heart Association 
QD 
once daily 
QTc 
corrected QT interval 
QTcF 
QTc Fridericia 
OSS 
overall summary score 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
pVO2 
peak oxygen uptake 
RER 
respiratory exchange ratio 
SAD 
single ascending-dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SUSAR 
suspected unexpected serious adverse reactions 
TBL 
total bilirubin 
TTE 
transthoracic echocardiography, transthoracic echocardiogram 
ULN 
upper limit of normal 
US 
United States 
VCO2 
carbon dioxide production 
VE 
volume expired 
VO2 
oxygen uptake 
VTI  
velocity time integral 


 
 
 
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1 
INTRODUCTION 
1.1 
Background 
Hypertrophic cardiomyopathy (HCM), an autosomal dominant genetic disease, is defined 
clinically as unexplained left ventricular (LV) hypertrophy in the absence of known causes 
such as pressure overload, systemic diseases, or infiltrative processes (Gersh et al, 2011). The 
phenotypic hallmark of HCM is myocardial hypercontractility accompanied by reduced LV 
compliance, reflected clinically as reduced ventricular chamber size, often supranormal 
ejection fraction, and diastolic dysfunction. Mutations in cardiac myosin and other sarcomere 
proteins in patients with HCM appear to increase net power generation by the sarcomere 
(Chuan et al, 2012; Sommese et al, 2013; Sung et al, 2012), which is consistent with the 
generally hypercontractile state and impaired compliance of the myocardium observed 
clinically in patients with HCM. 
MYK-461 is a first-in-class small molecule allosteric modulator of striated muscle myosin 
that selectively targets cardiac myosin and reversibly inhibits its binding to actin. 
MYK-461’s profile of myosin modulation is predicted to reduce dynamic left ventricular 
outflow tract (LVOT) obstruction in patients with obstructive HCM by reducing systolic 
hypercontractility and dynamic obstruction in the near term, and reducing ventricular 
hypertrophy with chronic treatment. MyoKardia is developing MYK-461 for the treatment of 
adults with symptomatic obstructive HCM to relieve obstruction, improve symptoms, and 
increase exercise capacity. 
In nonclinical studies, MYK-461 was specific for striated muscle myosin and selective for 
the cardiac isoform (see the MYK-461 Investigator’s Brochure [IB]). Its targeted mechanism 
of action and high degree of specificity were reflected in its pharmacology in vitro and in 
vivo, as well as in the toxicology and safety pharmacology. In a feline model of HCM with 
LVOT obstruction, treatment with MYK-461 reduced contractility and relieved obstruction 
in an exposure-dependent manner (Stern et al, 2016). The totality of the pharmacodynamic 
(PD) and tolerability data observed to date can be interpreted as direct or indirect 
consequences of altered cardiac contractility. 
Please refer to the IB for more detailed information on MYK-461. 
1.2 
Clinical Studies 
Three clinical studies have investigated the safety and tolerability of MYK-461 to date. A 
double-blind, placebo-controlled, single ascending-dose study (SAD) (MYK-461-002) was 
conducted in healthy men. Subjects received single doses ranging from 1 mg to 48 mg. 
Conduct of an open-label sequential-group SAD study in subjects with clinically stable HCM 
(MYK-461-001) is also complete; single doses of up to 144 mg were administered. In 
addition, a double-blind, placebo-controlled, multiple ascending-dose (MAD) study 
(MYK-461-003) is being conducted in which healthy adult subjects have received multiple 
doses of MYK-461 up to 25 mg once daily (QD) for up to 28 days. 


 
 
 
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1.2.1 
MYK-461-002 
In Study MYK-461-002, single doses from 1 mg to 48 mg were administered as an oral 
suspension to healthy men. All dose levels were well tolerated, with no serious adverse 
events (SAEs), deaths, or withdrawals from study due to adverse events (AEs) reported. The 
incidence of treatment-emergent AEs did not appear to increase with dose. The 
pharmacokinetic (PK) profile of MYK-461 displayed rapid absorption and subsequent 
distribution followed by a long elimination phase, with a mean elimination half-life of 
approximately 8 days. Single doses of ≥ 12 mg of MYK-461 were associated with detectable 
reductions in LV contractility from baseline as assessed by 3 independent echocardiographic 
measures (left ventricular ejection fraction [LVEF], LV fractional shortening (LVFS), and 
LVOT velocity time integral [VTI]). At the highest dose studied in healthy subjects (48 mg), 
mean reduction in LVEF at any timepoint was -6% relative to baseline. No changes in 
systolic blood pressure (BP) or heart rate (HR) were detected at any of the dose levels tested 
in this study. 
1.2.2 
MYK-461-001 
In Study MYK-461-001, single doses of up to 144 mg were administered to 15 subjects with 
HCM. All dose levels were well tolerated without deaths, withdrawals due to AEs, or dose-
related treatment-emergent AEs, except for 1 of 5 subjects who received the 144 mg dose. 
This subject experienced an SAE described as a vasovagal reaction characterized by a period 
of asystole and hypotension that spontaneously resolved without sequelae. In terms of 
causality assessment, there are no nonclinical or other clinical data to implicate MYK-461 in 
cardiac ion channel current modulation, or cardiac impulse generation or conduction. 
MYK-461 has no documented vasoactive properties and is biochemically inactive against 
smooth muscle myosin. Other potential contributions to the event include chronic β-blockade 
with metoprolol succinate 150 mg QD, and the observation that the subject inadvertently 
performed the Valsalva maneuver during the handgrip strength assessment immediately prior 
to the event.  
Preliminary PK analysis in Study MYK-461-001 revealed a PK profile in subjects with HCM 
similar to that of healthy subjects. All subjects with HCM demonstrated proof of mechanism 
in terms of documenting reduced LV contractility by at least 1 of 3 independent 
echocardiographic measures. In 2 subjects, measurable LVOT gradients following Valsalva 
were reduced to < 10 mm Hg following a single 96 mg dose of MYK-461. 
1.2.3 
MYK-461-003 
In Study MYK-461-003, 4 cohorts of healthy adult subjects have been dosed, each scheduled 
to dose for 28 days. MYK-461 was well tolerated at multiple doses up to 25 mg QD. All AEs 
were mild or moderate in severity, and there were no SAEs. In cohort 3, 3 of 12 subjects who 
received blinded treatment (either MYK-461 12.5 mg or placebo QD) had diarrhea and/or 
abdominal cramps. One of these subjects was discontinued due to recurrence of diarrhea 
upon rechallenge, and the other 2 subjects were successfully restarted on study medication. 
The investigator considered these gastrointestinal AEs either mild or moderate in severity 


 
 
 
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and likely related to study medication. No gastrointestinal AEs were reported in cohort 4 
(MYK-461 25 mg or placebo). 
Dosing in cohort 4 was stopped on Day 25 by the investigator, because 5 of 12 subjects who 
received blinded treatment (either MYK-461 25 mg or placebo QD) achieved the predefined 
stopping criterion for dose ascension of ≥ 20% reduction in LVEF. All subjects remained 
asymptomatic.  
PD evidence of reduced contractility was apparent in the higher dose-level groups (12.5 mg 
QD and 25 mg QD). These data, along with the PK and PD data from all subjects in all 
studies to date, have been incorporated into a robust PK-PD model to help inform a safe 
dosing strategy for the current study that is also likely to be efficacious.  
1.3 
Known and Potential Benefits and Risks 
Potential clinical benefit for the subjects who participate in this study is unclear at this stage 
of development. 
Little is known regarding the risks of administering repeat daily doses of MYK-461 to 
humans. Of 3 clinical studies with MYK-461 (Section 1.2), conduct of 2 single-dose studies 
is complete (one in healthy subjects and one in subjects with HCM), and conduct of 
1 multiple-dose study in healthy subjects is complete. Doses higher than 25 mg QD are not 
planned in the current study, as this was the highest dose tested to date in the repeat-daily-
dose study in healthy subjects. In that study, 5 of 12 subjects who received blinded treatment 
(MYK-461 25 mg or placebo QD) for 25 days exceeded the prespecified 20% relative 
decrease from baseline in LVEF, which precluded further dose escalation in that healthy 
subject study. Single doses up to 48 mg were well tolerated in 36 healthy adult subjects. 
Single doses of up to 144 mg were administered to subjects with HCM; 1 of 5 subjects who 
received 144 mg experienced a vasovagal reaction characterized by a period of asystole and 
hypotension that spontaneously resolved in the setting of a reduction in LVEF that also 
satisfied the prespecified stopping rules (> 20% relative reduction) for further dose escalation 
in that study. 
Safety testing in other mammalian species has demonstrated that dose-limiting toxicity is 
related to exaggerated pharmacologic effect, and not to off-target adverse effects. 
Experiments with isolated adult rat ventricular myocytes in vitro and with anesthetized rats in 
vivo have established that the pharmacological effects of MYK-461 can be counteracted by 
β-adrenergic agonists (isoproterenol and dobutamine, respectively). 


 
 
 
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2 
RATIONALE FOR THE STUDY AND FOR DOSE AND DOSING 
SCHEDULE 
2.1 
Rationale for the Study 
MyoKardia has studied MYK-461 extensively across a variety of pharmacological activity 
and nonclinical safety evaluation platforms. In clinical studies (Section 1.2), single doses of 
MYK-461 up to 48 mg were well tolerated in healthy subjects (MYK-461-002), and single 
doses of up to 144 mg have been well tolerated (except for a vasovagal reaction with asystole 
and hypotension in 1 of 5 subjects at the 144 mg dose) in a study in subjects with HCM 
(MYK-461-001). Daily doses of 25 mg were well tolerated clinically in healthy subjects for a 
period of 25 days, after which time dosing was suspended by the investigator secondary to 
concerns regarding the degree of pharmacological activity observed (MYK-461-003). The 
predefined stopping criterion for dose escalation (reduction in LVEF by ≥ 20%) was satisfied 
in both the single-dose study (MYK-461-001) at 144 mg and in the 28-day multiple-dose 
study (MYK-461-003) at 25 mg QD. 
MyoKardia has designed the current study to generate multiple-dose (steady-state) data in 
subjects with obstructive, symptomatic HCM using an approach that conforms to established 
ethical standards of safe human experimentation and the requirements of Good Clinical 
Practice (GCP). 
2.2 
Rationale for Dose and Dosing Schedule 
Part A 
The starting dose of MYK-461 will be 10 mg for subjects who weigh ≤ 60 kg and 15 mg for 
subjects who weigh > 60 kg. Each subject will receive oral MYK-461 at the starting dose QD 
from Day 1 through Week 4. At Week 4, an individual subject’s daily dose may be decreased 
by 5 mg, increased by 5 to 10 mg, or remain the same based on predetermined criteria (see 
Section 4). The subject will subsequently receive that dose from Week 5 through Week 12. 
The dose selection was based on PK/PD modeling and analysis of PD and safety data from 
all 3 MYK-461 clinical studies (MYK-461-001, MYK-461-002, and MYK-461-003).   
Part B 
The starting dose of MYK-461 in Part B will be 2 mg. The dose selected for this part is 
intended to describe the dose and concentration response for gradient reduction and exercise 
tolerance at lower drug exposures than those achieved in Part A. An individual subject’s 
daily dose may be increased to 5 mg based on predetermined criteria (see Section 4).  The 
subject will subsequently receive that dose from Week 5 (day 29) through Week 12.  


 
 
 
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3 
STUDY OBJECTIVES 
3.1 
Primary Objective  
The primary objective of this study is: 
• To characterize the effect of 12 weeks of MYK-461 treatment on reducing post-exercise 
peak LVOT gradient in subjects with symptomatic HCM and LVOT obstruction 
 
3.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To assess the proportion of subjects achieving an LVOT gradient response of 
post-exercise peak gradient < 30 mm Hg in subjects with symptomatic HCM and LVOT 
obstruction 
• To assess the effects of 12 weeks of MYK-461 treatment on dyspnea symptom score, 
peak oxygen uptake (pVO2), and volume expired (VE)/carbon dioxide production 
(VCO2) slope in subjects with symptomatic HCM and LVOT obstruction 
• To evaluate the PK of MYK-461 in subjects with symptomatic HCM and LVOT 
obstruction 
• To evaluate the PD of MYK-461 in subjects with symptomatic HCM and LVOT 
obstruction as assessed by a variety of echocardiographic imaging parameters in subjects 
with symptomatic HCM and LVOT obstruction 
• To evaluate the safety and tolerability of MYK-461 in subjects with symptomatic HCM 
and LVOT obstruction 
• To evaluate the posttreatment reversibility of the effects of MYK-461 after 4 weeks of 
washout in subjects with symptomatic HCM and LVOT obstruction 
 
3.3 
Exploratory Objectives 
The exploratory objectives of this study are: 
• To assess the proportion of subjects achieving an LVOT gradient response of 
post-exercise peak gradient < 10 mm Hg in subjects with symptomatic HCM and LVOT 
obstruction 
• To assess the effects of 12 weeks of MYK-461 treatment on New York Heart Association 
(NYHA) functional class, N-terminal pro B-type natriuretic peptide (NT-proBNP), and 
the Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score (OSS) 
in subjects with symptomatic HCM and LVOT obstruction 


 
 
 
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• To assess the effects of MYK-461 treatment on arterial pulse wave morphology assessed 
using an optical biosensor in subjects with symptomatic HCM and LVOT obstruction 
• To assess the effect of MYK-461 treatment on heart rate and heart rhythm as assessed 
using a cardiac monitoring skin patch in subjects with symptomatic HCM and LVOT 
obstruction 
 
4 
OVERALL STUDY DESIGN AND PLAN 
This is a phase 2 open-label pilot study to evaluate the efficacy, PK, PD, safety, and 
tolerability of MYK-461 in subjects with symptomatic HCM and LVOT obstruction. 
Approximately 20 adult subjects with symptomatic HCM, a resting LVOT gradient 
≥ 30 mm Hg, and post-exercise peak LVOT gradient ≥ 50 mm Hg will be enrolled. 
Approximately 10 subjects will participate in Part A and approximately 10 subjects will 
participate in Part B. The study will have a 12-week treatment phase and a 4-week washout 
phase (Figure 1). 
Figure 1  
Study Schema 
  
CPET, cardiopulmonary exercise training; D, day; HSE, hemodynamic stress echocardiography; N, number PK, 
pharmacokinetic sample; RE/V, resting echocardiography/Valsalva; W, week 
 
At Screening, subjects will undergo transthoracic echocardiography (TTE) in the supine or 
left lateral decubitus position. In addition to a standardized complete TTE, both resting 
instantaneous peak LVOT gradient (baseline) and provoked peak LVOT gradient (Valsalva 
maneuver) will be collected. Subjects will then undergo a standard symptom-limited exercise 
test (hemodynamic stress echocardiography). Subjects will be assessed systematically for 
 
 
 
 
Dose Adjustment 
 
 
Scr 
PK 
MYK - 461 adjusted dose 
Study Drug  
N  ≅ 20 Subjects 
Washout 
MYK - 461 starting  
dose 
Screening 
D1 
W12 
W2 
W4 
W8 
W16 
W5 
W6 
W1 
HSE: 
CPET: 
RE/V 
W3 
W7 


 
 
 
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symptoms of dyspnea and/or angina. Instantaneous peak LVOT gradient will be assessed 
immediately post-exercise by TTE. 
On Day 1, resting TTE will be performed, blood samples will be drawn for PK, and subjects 
will have an assessment of pVO2, VE/VCO2, and other variables via cardiopulmonary 
exercise testing (CPET). After CPET, subjects will be dosed with open-label oral MYK-461 
at the investigational site and will be observed for at least 1 hour after dosing, with 
assessment of vital signs and ECGs at 1 hour postdose. Subjects will then be supplied with 
MYK-461 sufficient for QD dosing at home.  
Subjects will be evaluated at the investigational site at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, and 16. 
At each of these visits, resting TTE will be performed and blood samples will be drawn for 
PK. On study visit days, study medication will be administered at the investigational site in 
order to collect blood samples for PK ≤ 2 hours prior to dosing. At Weeks 4, 12, and 16, 
hemodynamic stress echocardiography will be performed and peak LVOT gradient will be 
assessed. CPET will be conducted between Weeks 10 and 12 (inclusive).  
Part A: 
The MYK-461 starting dose will be 10 mg for subjects who weigh ≤ 60 kg and 15 mg for 
subjects who weigh > 60 kg. At the end of Week 4 (Day 28), each subject’s LVEF will be 
evaluated, and the subject’s dose may be increased, decreased, or remain unchanged based on 
the predetermined criteria in Table 1, in consultation between the investigator and the 
medical monitor. If MYK-461 plasma concentration exceeds 750 ng/mL at Week 2, no dose 
increase is allowed, regardless of LVEF data at Week 4; however, dose decrease per LVEF 
data is allowed in this circumstance. The subject will subsequently receive that dose from 
Week 5 through Week 12. 
Table 1 
Part A Week 4 Dose Adjustment Criteria 
Percent Decrease From Baseline in LVEF at the 
End of Week 4 (Day 28)  
Action for MYK-461 Dose 
Week 5-Week 12a  
< 10 
increase dose by 10 mg 
≥ 10 and < 15 
increase dose by 5 mg 
≥15 and < 20 
no change in dose 
≥ 20 
decrease dose by 5 mg 
LVEF, left ventricular ejection fraction 
b 
No dose increase allowed if plasma concentration of MYK-461 > 750 ng/mL at Week 2. 
 


 
 
 
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Part B: 
The MYK-461 starting dose will be 2 mg. At the end of Week 4 (Day 28), each subject’s 
resting (non-provoked) peak instantaneous LVOT gradient and LVEF from the Week 4 TTE 
will be evaluated. The subject’s dose will be increased to 5 mg or remain unchanged based 
on the predetermined criteria in Table 2 below, in consultation between the investigator and 
the medical monitor. If MYK-461 plasma concentration exceeds 300 ng/mL at Week 2, no 
dose increase is allowed.  The subject will subsequently receive that dose from Week 5 (Day 
29) through Week 12. 
Table 2 
Part B Week 4 Dose Adjustment Criteria 
Percent Decrease From Day 1 in Resting TTE 
Instantaneous Peak LVOT gradient at the End of 
Week 4 (Day 28)  
Action for MYK-461 Dose Week 5-Week 12a  
< 50% 
increase dose to 5 mg 
≥ 50% 
no change in dose 
; LVOT, left ventricular outflow tract;  
a 
No dose increase allowed if plasma concentration of MYK-461 > 300 ng/mL at Week 2. 
 
 
For all subjects who provide consent, blood will be drawn prior to dosing on Day 1 for 
assessment of HCM genotype and potentially additional deoxyribonucleic acid (DNA) 
sequencing. 
In addition, subjects may consent separately to collection of pharmacogenetic samples that 
will be stored for potential future analysis of genetic biomarkers of efficacy, safety-related, 
PD, or PK parameters as determined by future studies using clinically meaningful endpoints, 
through DNA sequencing or other genetic testing. 
Blood samples will be collected from all subjects prior to dosing on Day 1 and at Week 12 
and stored for exploratory circulating biomarker analysis, e.g., proteomic analysis related to 
disease activity, metabolic pathways, efficacy measures, or safety measures. 
4.1 
Study Duration 
The expected study duration is approximately 8 months (4 months for recruitment and 
4 months for study conduct) for Part A and approximately 10 months for Part B (18 months 
in total). Each subject is expected to be in the study no more than 140 days: up to 28 days for 
screening and up to 112 days for study conduct. 
4.2 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will regularly review study data. The 
role of the IDMC will be to help identify and manage any emerging safety issues, advise the 
investigators and Sponsor on any important emerging study conduct issues, and serve in an 
advisory role concerning the evaluation procedures and methodologies being employed to 
survey and detect potential safety signals. 


 
 
 
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5 
SELECTION AND WITHDRAWAL OF STUDY POPULATION 
5.1 
General Study Population and Clinical Sites 
Approximately 20 subjects with symptomatic HCM and LVOT obstruction are expected to 
enroll in this study at 7 clinical sites in the United States (US). 
5.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study. 
1. Able to understand and comply with the study procedures, understand the risks involved 
in the study, and provide written informed consent according to federal, local, and 
institutional guidelines before the first study-specific procedure. 
2. Men or women 18 to 70 years of age at the Screening visit.  
3. 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. 
4. Body mass index (BMI) 18 to 37 kg/m2, inclusive, at the Screening visit, calculated using 
the institution’s standard formula. 
5. All safety laboratory parameters (chemistry, hematology, and urinalysis) within normal 
limits (laboratory reference range) at the Screening visit as assessed by the central 
laboratory, or if outside of the limits must meet both of the following criteria: 
- 
considered by the investigator to be clinically unimportant 
- 
if a liver function test result, must be < 1.5 × the upper limit of the laboratory 
reference range. 
6. Has documented LVEF ≥ 55% at the Screening visit as determined by the investigator 
and the investigational site’s echocardiography laboratory. 
7. Resting LVOT gradient ≥ 30 mmHg and post-exercise peak LVOT gradient ≥ 50 mm Hg 
at the Screening visit as determined by the investigator and the investigational site’s 
echocardiography laboratory. 
8. NYHA functional class II or higher, judged by the investigator to be due to LVOT 
obstruction. 
9. Has adequate acoustic windows, in the judgment of the investigator and the 
investigational site’s echocardiography laboratory, to enable accurate TTEs. 
10. Female subjects must not be pregnant or lactating and, if sexually active, must be using 
one of the following acceptable birth control methods from the Screening visit through 3 
months after the last dose of investigational medicinal product (IMP). Hormonal 
contraceptives are not considered highly effective contraception for this study because 
MYK-461 could reduce the effectiveness of hormonal contraceptives.  
- 
Double-barrier method (e.g., vasectomy or male using a condom and female using a 
diaphragm or cervical cap) 


 
 
 
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- 
Barrier (e.g. male using a condom) plus non-hormonal intrauterine device (IUD) or 
intrauterine system (IUS) 
- 
Female is surgically sterile for 6 months or postmenopausal for 2 years. Permanent 
sterilization includes hysterectomy, bilateral oophorectomy, bilateral salpingectomy, 
and/or documented bilateral tubal occlusion at least 6 months prior to Screening. 
Females are considered postmenopausal if they have had amenorrhea for at least 
2 years or more following cessation of all exogenous hormonal treatments and 
follicle-stimulating hormone (FSH) levels are in the postmenopausal range. 
11. Male subjects with female partners (including postmenopausal partners) must agree to 
use highly effective contraceptive measures from the Screening visit through 3 months 
after the last dose of study medication. Highly effective contraception includes 
documented vasectomy, abstaining from sexual intercourse, double-barrier method (e.g., 
male using a condom and female using a diaphragm or cervical cap), or barrier plus 
hormonal contraception (e.g., male using a condom and female using hormonal 
contraception). As there may be a risk of drug being secreted in the ejaculate, male 
subjects (including men who have had vasectomies) whose partners are currently 
pregnant should use barrier methods for the duration of the study and for 3 months after 
the last dose of study medication. In addition, male subjects with sexual partners should 
use condoms for the duration of the study and for 3 months after the last dose of study 
medication, even if the partner is not pregnant or capable of becoming pregnant, in order 
to prevent passing MYK-461 to the partner in the ejaculate. 
12. Must be able to complete the Dyspnea Numeric Rating Scale (NRS) and the KCCQ per 
established guidelines. 
 
5.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
1. Hypersensitivity to MYK-461 or any of the components of the MYK-461 formulation. 
2. Presence of any medical condition that precludes exercise stress testing. 
3. History of sustained ventricular tachyarrhythmia. 
4. History of syncope with exercise within past 6 months. 
5. Active infection. 
6. Persistent atrial fibrillation or atrial fibrillation at Screening or history of paroxysmal 
atrial fibrillation with resting rate documented >100 bpm within 1 year of screening. 
7. 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). 
8. Aortic stenosis or fixed subaortic obstruction.  
9. History of LV systolic dysfunction (LVEF < 45%) at any time during their clinical 
course. 


 
 
 
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10. History of obstructive coronary artery disease (stenosis of >70% of luminal diameter in 
one or more coronary arteries). 
11. History of malignancy of any type, with the following exceptions: in situ cervical cancer 
more than 5 years prior to Screening or surgically excised non-melanomatous skin 
cancers more than 2 years prior to Screening. 
12. Positive serologic test at Screening for infection with human immunodeficiency virus 
(HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV). 
13. Positive test for alcohol or drugs of abuse at Screening. 
14. History or evidence of any other clinically significant disorder, condition, or disease 
(with the exception of those outlined above) 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. 
15. Participated in a clinical trial where the subject received any investigational drug (or is 
currently using an investigational device) within 30 days prior to Screening, or at least 
5 times the respective elimination half-life (whichever is longer).  
16. Current use of tobacco- or nicotine-containing products exceeding 10 cigarettes per day 
or equivalent. 
17. Part A: Subjects who in the opinion of the investigator require ongoing therapy with 
β-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. 
18. Part B: Subjects who in the opinion of the investigator require 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. 
19. Unable to comply with the study restrictions/requirements, including the number of 
required visits to the clinical site. 
20. Is employed by, or is a relative of someone employed by MyoKardia, the investigator, or 
his/her staff or family. 
 
5.4 
Screening and Enrollment 
An informed consent form (ICF) must be signed and dated by the subject before the subject 
is asked to discontinue HCM background therapy and before any study-specific tests or 
procedures may be performed. 
Each subject will be assigned an identification number when informed consent has been 
obtained. This number will be used to identify the subject throughout the study and should 
appear on all study-related documentation. 


 
 
 
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Subjects that fail to meet all inclusion criteria or present with an exclusion criterion may be 
re-screened. Refer to Study Reference Manual for re-screening criteria. 
5.5 
Withdrawal and Replacement of Subjects 
5.5.1 
Withdrawal from the Study 
Study participants may withdraw from further participation in the study at any time and for 
any reason. The degree to which a study participant withdraws can vary, and efforts will be 
made to collect important safety data if feasible and the study participant agrees. Study 
participants can: 
• Withdraw from treatment and agree to participate in the Early Termination and End of 
Study (EOS) visits  
• Withdraw from treatment and agree to participate in the Early Termination visit  
• Withdraw from treatment and all follow-up 
 
The investigator or MyoKardia may withdraw a study participant from treatment in the study 
for any of the following (or other) reasons: 
• AE 
• Noncompliance with study procedures/restrictions 
• Study termination by MyoKardia 
 
In all cases, the reason(s) for study withdrawal will be recorded in the source document and 
on the appropriate electronic case report form (eCRF). 
5.5.2 
Replacement of Subjects 
Subjects who do not receive MYK-461 may be replaced. Subjects who drop out of the study 
for reasons other than AEs after receiving study medication may be replaced at the discretion 
of MyoKardia. 
All data from subjects who receive at least 1 dose of IMP will be documented and maintained 
in the clinical trial database. 
6 
RANDOMIZATION AND BLINDING PROCEDURES 
6.1 
Randomization 
Subjects will not be randomized to treatment in this study. 


 
 
 
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6.2 
Blinding 
Treatment will not be blinded in this study. 
7 
STUDY TREATMENT 
All subjects will receive MYK-461 in an open-label manner.  
IMP is defined as MYK-461. Study medication is used throughout this protocol to refer to 
IMP as well as any other protocol-required medications (note that for this protocol there are 
no other required study medications). 
7.1 
MYK-461, Administration, and Schedule 
Study medication will consist of MYK-461 immediate release oral tablets, supplied in 
4 strengths: 2 mg, 5 mg, 10 mg, and 20 mg. MYK-461 tablets are uncoated and plain and 
white in appearance. The 2 mg and 5 mg tablets are round-convex in shape and of different 
sizes, while the 10 mg and 20 mg tablets are oval shaped of different sizes. 
MYK-461 tablets are manufactured according to current Good Manufacturing Practice 
(cGMP) regulations. They will be supplied in high-density polyethylene bottles with 
induction seals and child resistant caps at 30 count per bottle. All study medication will be 
labeled according to applicable local regulatory guidelines.  
The MYK-461 tablets must be stored at controlled room temperature at 20°C to 25°C (68°F 
to 77°F) in the packaging supplied by MyoKardia. Study medication at the investigational 
site will be stored in a secure area with access limited to authorized study personnel.  
IMP will be supplied to subjects at least every 4 weeks in 30-count high-density polyethylene 
bottles that are appropriately labeled, with written instructions for daily dosing. The subjects 
will be instructed to store the MYK-461 tablets/bottles in a cool dry place. Drug should be 
taken with approximately 8 ounces of water.  
7.2 
Treatment Compliance 
All subjects will return their IMP dosing containers, including unused study medication, to 
the site for tablet counts. Refer to the Pharmacy Manual for details. 
Subjects should be instructed to take the study medication at approximately the same time 
every day (± 4 hours). If the dosing window is missed, the subject should not take study 
medication that day. Subjects should never receive 2 doses of MYK-461 within a 12-hour 
period. 
On study visit days, subjects should wait until they reach the clinic to take their study 
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7.3 
Dose Adjustment  
All subjects in Part A will be assigned to a starting dose of oral MYK-461 based on body 
weight for doses ≥ 10 mg, which they will receive QD for 4 weeks. Subjects in Part B will be 
assigned a starting dose of 2 mg. At the Week 4 visit, dose adjustment may be performed 
based on the predetermined criteria in Section 4, Table 1 (Part A) and Table 2 (Part B). The 
subject will subsequently receive that dose from Week 5 (Day 29) through Week 12. 
7.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (e.g., alkaline phosphatase [ALP], aspartate 
aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL], or 
international normalized ratio) or signs/symptoms of hepatitis may meet the criteria for 
withholding of study medication or other protocol-required therapies. Withholding is either 
permanent or conditional depending on the clinical circumstances discussed below (as 
specified in the US Food and Drug Administration (FDA) Guidance for Industry–Drug 
Induced Liver Injury: Premarketing Clinical Evaluation, July 2009. 
7.4.1 
Criteria for Permanent Withholding of MYK-461 Due to Potential 
Hepatotoxicity 
MYK-461 should be discontinued permanently and the subject should be followed according 
to the recommendations in Appendix 3 for possible drug-induced liver injury (DILI), if all of 
the criteria below are met: 
• TBL > 2 × upper limit of normal (ULN) or international normalized ratio > 1.5 
• AND increased AST or ALT, if the baseline value was < ULN and AST or ALT 
elevation is > 3 × ULN 
• AND no other cause for the combination of laboratory abnormalities is immediately 
apparent; important potential causes for abnormal AST/ALT or TBL values include, but 
are not limited to the following: 
- 
obstructive gall bladder or bile duct disease 
- 
viral or alcoholic hepatitis (e.g., hepatitis A/B/C/D/E, Epstein-Barr virus, 
cytomegalovirus, herpes simplex virus, varicella) 
- 
hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 
significant right sided heart failure 
- 
concomitant administration of other hepatotoxins, including drugs that inhibit 
bilirubin glucuronidation (e.g., indinavir, atazanavir, irinotecan) or herbal or dietary 
supplements 
- 
heritable disorders causing impaired glucuronidation (e.g., Gilbert syndrome); 
α-1 antitrypsin deficiency 
- 
autoimmune hepatitis  
- 
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If an alternative cause for hepatotoxicity is identified or less stringent conditions developed 
than what is noted above, determine whether study medication and other protocol-required 
therapies should be permanently or temporarily discontinued based on subject population 
and/or severity of the hepatotoxicity or event, as deemed appropriate for the safety of the 
subject. 
7.4.2 
Criteria for Conditional Withholding of MYK-461 Due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent withholding of study medication 
outlined above, MYK-461 should be withheld if ANY of the following criteria are met, and 
the subject should be evaluated for DILI: 
• Elevation of either AST or ALT, regardless of baseline AST or ALT value, if: 
- 
> 8 × ULN at any time 
- 
> 5 × ULN and < 8 × ULN for ≥ 2 weeks 
- 
> 5 × ULN and < 8 × ULN and unable to adhere to enhanced monitoring schedule 
• OR: clinical signs or symptoms that are, in the opinion of the investigator, consistent with 
hepatitis (such as right upper quadrant pain/tenderness, fever, nausea, vomiting, jaundice, 
rash or eosinophilia > 5%). If such signs or symptoms are coupled with ALT or AST 
elevations > 3× ULN, study medication should be withheld.  
• OR: TBL > 3× ULN at any time 
• OR: ALP > 8× ULN at any time 
 
MYK-461 should be withheld pending investigation into alternative causes of DILI. If study 
medication is withheld, the subject should be followed according to recommendations in 
Appendix 3 for possible DILI. Rechallenge may be considered if an alternative cause, such as 
acute hepatitis B infection, is discovered and the laboratory abnormalities resolve to normal 
or baseline (Section 7.4.3). 
7.4.3 
Criteria for Rechallenge of MYK-461 After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and unanimously agreed by the 
investigator, IDMC, and Sponsor. 
If signs or symptoms recur with rechallenge, then MYK-461 should be permanently 
discontinued. Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Section 7.4.1) should never be rechallenged. 
7.5 
Guidelines for the Management of an Exaggerated Pharmacologic Effect 
Beta-adrenergic agonists are known to counteract the pharmacologic activity of MYK-461 in 
nonclinical studies. If a subject experiences AEs potentially related to reduced cardiac output, 


 
 
 
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administration of therapeutic doses of a β-adrenergic agonist (e.g., 5 to 10 µg/kg/min 
dobutamine infusion) should be considered. Additional supportive measures, 
e.g., intravenous volume supplementation and/or the use of arterial vasoconstrictor agents 
(α-adrenergic agonists) may complement the use of a β-adrenergic agonist. Aside from this 
specific advice regarding the role of a β-adrenergic agonist, appropriate care will be 
determined by the treating medical personnel. 
7.6 
Overdose 
There is no human overdose experience with MYK-461. The consequences of higher 
exposures achieved in nonclinical species are directly related to the pharmacologic activity of 
MYK-461, and consideration of interventions that might ameliorate the effects of 
unintentionally high exposures in human subjects provide the available guidance in suspected 
overdose. 
Experiments with isolated adult rat ventricular myocytes in vitro and with anaesthetized rats 
in vivo have established that the pharmacologic effects of MYK-461 can be counteracted by 
β-adrenergic agonists (isoproterenol and dobutamine, respectively). The ability of 
dobutamine (10 µg/kg/min by continuous intravenous infusion) to counteract the effects of 
MYK-461 in the rat was fully effective up to exposures causing a 60% reduction in cardiac 
contractility. Beyond this level of effect, dobutamine was only partially effective in 
counteracting the effects of MYK-461.There are no known direct-acting antidotes. 
In the event of dosing resulting in suspected overexposures (subsequently documented based 
on PK sampling, which may be assessed at a scheduled or unscheduled visit) that do not 
appear to be well tolerated, the subject should be closely monitored clinically with supportive 
measures undertaken as indicated, including initiation of inotropic support with dobutamine 
and/or α-adrenergic agonists and other supportive measures, in a suitably well-monitored, 
acute-care environment. 
It is unknown whether MYK-461 can be safely removed by dialysis. Attempts to employ 
these measures should be avoided until more information is available. 


 
 
 
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7.7 
Prior and Concomitant Treatment 
7.7.1 
Prior Therapy 
At the time of signing the ICF, subjects will be asked about their medication history over the 
previous 30 days, including prescription and nonprescription medications, herbal 
medications, vitamins, and minerals.  
If subjects have not taken any prohibited medications in the past 14 days they may proceed to 
Screening. Subjects taking prohibited medications must discontinue treatment for 14 days 
before proceeding to the Screening assessments. 
7.7.2 
Concomitant Therapy 
Document all concomitant therapies on the appropriate eCRF, whether prescription or 
over-the-counter, vitamin and/or mineral supplements, herbs, and medications taken for an 
event or procedure (e.g., biopsy). Include start/stop dates, route and indication. 
7.7.3 
Prohibited Therapy 
Prior or concomitant treatment with cardiotoxic agents such as doxorubicin or similar is 
prohibited, as is prior or concomitant treatment with antiarrhythmic drugs with negative 
inotropic activity, e.g., flecainide or propafenone. 
Part A: Use of β-blockers, calcium channel blockers, and disopyramide are prohibited within 
14 days of the Screening visit and throughout the study. 
Part B: Use of calcium channel blockers and disopyramide are prohibited within 14 days of 
the Screening visit and throughout the study. Subjects enrolled in Part B may be on a stable 
dose of β-blockers (for at least 14 days before Screening) and should remain on a stable dose 
throughout the study. 
8 
RISKS AND PRECAUTIONS 
8.1 
General 
Little is known regarding the risks of administering repeat daily doses of MYK-461 to 
humans. Of 3 clinical studies with MYK-461 (Section 1.2), conduct of 2 single-dose studies 
is complete (one in healthy subjects and one in subjects with HCM), and 1 multiple-dose 
study is ongoing in healthy subjects. Doses higher than 25 mg QD are not planned in the 
current study, as this was the highest dose tested to date in the repeat-daily-dose study in 
healthy subjects. In that study, 3 of 10 subjects treated with 25 mg QD for 25 days exceeded 
the prespecified 20% relative decrease from baseline in LVEF, which precluded further dose 
escalation in that healthy subject study. Single doses up to 48 mg were well tolerated in 
36 healthy adult subjects. Single doses of up to 144 mg were administered to subjects with 
HCM; 1 of 5 subjects who received 144 mg experienced a vasovagal reaction characterized 
by a period of asystole and hypotension that spontaneously resolved in the setting of a 


 
 
 
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reduction in LVEF that also satisfied the prespecified stopping rules (> 20% relative 
reduction) for further dose escalation in that study. 
Safety testing in other mammalian species has demonstrated that dose-limiting toxicity is 
related to exaggerated pharmacological effect, and not to off-target adverse effects. 
Experiments with isolated adult rat ventricular myocytes in vitro and with anesthetized rats in 
vivo have established that the pharmacological effects of MYK-461 can be counteracted by 
β-adrenergic agonists (isoproterenol and dobutamine, respectively). 
8.2 
Pregnancy 
8.2.1 
Avoidance of Pregnancy 
Women of childbearing potential must use appropriate methods of birth control as listed in 
Section 8.2.3. Women of non-childbearing potential are defined as women who are 
permanently (surgically) sterilized or are postmenopausal. Permanent sterilization includes 
hysterectomy, bilateral oophorectomy, and bilateral tubal occlusion or ligation at least 
6 months prior. Women are considered postmenopausal if they have had amenorrhea for at 
least 2 years or more following cessation of all exogenous hormonal treatments and FSH 
levels are in the postmenopausal range. 
8.2.2 
Restrictions for Male Subjects 
There is no information about effects that MYK-461 could have on the development of the 
fetus in humans. Therefore, it is important that the partners of male subjects do not become 
pregnant during the study and for a total period of 3 months after the male subject has taken 
the last dose of study medication. As a precaution, all male subjects should avoid fathering a 
child by using appropriate methods of birth control, as listed in Section 8.2.3, for the duration 
of the study and for 3 months after the last dose of study medication. This is to ensure that 
the fetus is not potentially exposed to the study medication in the ejaculate.  
In addition, male subjects with partners should use condoms for the duration of the study and 
for 3 months after the last dose of study medication, even if the partner is not pregnant or 
capable of becoming pregnant, in order to prevent passing MYK-461 to the partner in the 
ejaculate.  
Male subjects should be advised not to donate sperm for 3 months after the last dose of study 
medication. 
8.2.3 
Acceptable Forms of Contraception 
Highly effective methods of birth control are defined as those that result in a low failure rate 
(< 1% per year) when used consistently and correctly. Hormonal contraceptives are not 
considered highly effective contraception for this study because MYK-461 could reduce the 
effectiveness of hormonal contraceptives. From the time of Screening through 3 months after 
the last dose of study medication, subjects should practice true abstinence or use effective 
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• Double-barrier method (e.g., vasectomy or male using a condom and female using a 
diaphragm or cervical cap) 
• Barrier (e.g. male using a condom) plus non-hormonal intrauterine device (IUD) or 
intrauterine system (IUS) 
• Female is surgically sterile or postmenopausal as defined in Section 8.2.1. 
 
For male subjects only (but not partners of female subjects), documented vasectomy is also 
an accepted method of birth control. 
8.2.4 
Reporting and Follow-up of Pregnancies 
All pregnancies in female subjects and female partners of male subjects receiving at least 
1 dose of study medication will be reported if they occur anytime from first dose to 3 months 
after the last dose of study medication. The investigator is responsible for informing 
MyoKardia of the pregnancy. The subject will be asked to provide information on the 
outcome of the pregnancy, including premature termination. Spontaneous miscarriage and 
congenital abnormalities will be reported as SAEs. 
9 
STUDY ASSESSMENTS AND PROCEDURES 
The investigator is responsible for ensuring that all staff involved in the study are familiar 
and comply with the content of this section. 
The following describes the study procedures to be performed during the study. Additional 
details are provided in Appendix 1 of this document. When several assessments are to be 
conducted at the same timepoint, the preferred order of assessments is ECG, vital signs, 
laboratory assessments (including PK), then TTE. The order of assessments may vary 
slightly at specific timepoints (e.g., 1 hour postdose) to facilitate the most contemporaneous 
performance of the required assessments. Unscheduled or additional safety assessments may 
be performed if necessary in the opinion of the investigator. 
For assessments that require the subjects to be in a semi-recumbent or supine position, 
assessments should be conducted with subjects in the same position at all timepoints. 
9.1 
Efficacy and Pharmacodynamic Assessments 
9.1.1 
Echocardiography and Cardiopulmonary Exercise Testing 
Details are provided in the Study Reference Manual. Echocardiography and CPET should be 
performed prior to dosing. All echocardiography data will be sent to a central imaging 
laboratory. CPET data will also be sent to a central laboratory. 


 
 
 
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9.1.1.1 
Resting Transthoracic Echocardiography 
Resting TTE will be assessed throughout the study. Instantaneous peak LVOT gradient 
(baseline) and provoked peak LVOT gradient (Valsalva maneuver) will be assessed. Ejection 
fraction (2-dimensional [2D] and 3-dimensional [3D]), LVFS, global longitudinal strain by 
speckle tracking, and LVOT VTI will be analyzed, along with a variety of other 
echocardiographic measures (see Study Reference Manual). 
Resting TTE should be performed prior to hemodynamic stress echocardiography or CPET. 
9.1.1.2 
Hemodynamic Stress Echocardiography 
Subjects will undergo a standard symptom-limited exercise test (hemodynamic stress echo) 
after a 4-hour fast (water is allowed) at designated visits (Appendix 1). Instantaneous peak 
LVOT gradient will be assessed immediately post-exercise by TTE. 
9.1.1.3 
Cardiopulmonary Exercise Testing 
CPET and exercise ECGs will be conducted using a treadmill at designated visits (Appendix 
1). Symptom-limited exercise tests will be performed after a 4-hour fast (water is allowed). 
Subjects will be encouraged to perform maximally to achieve their expected HR. The 
following will be assessed: oxygen uptake (VO2), VCO2, VE, VE/VO2, VE/VCO2, and 
respiratory exchange ratio (RER).  
9.1.2 
Dyspnea Numeric Rating Scale  
The Dyspnea NRS is a validated measure of present dyspnea (Gift and Narsavage, 1998). 
Patients rate their shortness of breath by designating a number from to 0 to 10, with 0 being 
“no shortness of breath” and 10 being “shortness of breath as bad as can be.” 
9.1.3 
Kansas City Cardiomyopathy Questionnaire 
The KCCQ is a self-administered 23-item questionnaire that quantifies physical limitation, 
symptoms, quality of life, social interference, and self-efficacy (Green et al, 2000). The OSS 
is derived from the physical limitation, symptom, quality of life, and social interference 
domains. Scores range from 0 to 100, with higher scores reflecting better health status.  
9.1.4 
New York Heart Association Class 
The NYHA functional classification of heart failure assigns patients to 1 of 4 categories 
based on the patient’s symptoms and objectives assessments (Table 3). 


 
 
 
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Table 3 
New York Heart Association (NYHA) Functional Classification of 
Heart Failure 
Class 
Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity 
causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at 
rest. If any physical activity is undertaken, discomfort increases. 
 
Objective Assessment 
A 
No objective evidence of cardiovascular disease. No symptoms and no limitation in 
ordinary physical activity. 
B 
Objective evidence of minimal cardiovascular disease. Mild symptoms and slight 
limitation during ordinary activity. Comfortable at rest. 
C 
Objective evidence of moderately severe cardiovascular disease. Marked limitation in 
activity due to symptoms, even during less-than-ordinary activity. Comfortable only at 
rest. 
D 
Objective evidence of severe cardiovascular disease. Severe limitations. Experiences 
symptoms even while at rest. 
Source: http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-
Failure_UCM_306328_Article.jsp#.VrtuzPkrKUl 
 
9.1.5 
Exploratory Assessments 
9.1.5.1 
Pulse Wave Optical Biosensor 
An experimental noninvasive optical biosensor resembling a wristwatch may be fastened to 
the subject’s wrist for several minutes to collect data on arterial pulse wave morphology. 
This assessment is optional and will be performed only if the subject provides consent. 
9.1.5.2 
Cardiac Monitoring Skin Patch 
Throughout the study, subjects will wear a small data collection device that is FDA-approved 
for collecting HR and rhythm data. The self-contained device attaches to the skin using 
medical adhesive and contains 2 surface electrodes, internal electronics to capture a 
continuous single-lead ECG waveform, an accelerometer to capture physical activity, 
sufficient solid-state memory to store up to 14 days’ data, and a battery to power the device. 
It has no external wires or other connections. Following a period of data collection, the 
device will be transported to a core laboratory where the continuous ECG waveforms and 
activity record stored on the device will be uploaded for analysis. The analysis will provide 
full disclosure capabilities for HR, heart rhythm, and physical activity over the period during 
which the device was properly applied and functioning. The device will be used to explore 
the pattern of HR, heart rhythm, and physical activity before, during, and after treatment with 
MYK-461. 


 
 
 
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9.2 
Pharmacokinetic, Pharmacogenetic, and Biomarker Assessments 
9.2.1 
Pharmacokinetic Assessments 
Blood samples will be collected for PK assessments at all post-Screening visits. Plasma 
concentrations of MYK-461 will be evaluated. Unscheduled or additional PK samples may 
be collected if appropriate in the opinion of the investigator and/or Sponsor. 
At all visits from Day 1 to Week 12 (inclusive), MYK-461 will be administered at the 
investigational site to facilitate collection of PK samples ≤ 2 hours prior to dosing.  
9.2.2 
Genotype/Pharmacogenetic/Biomarker Assessment 
For all subjects who provide consent, blood will be drawn on prior to dosing Day 1 for 
assessment of HCM genotype and potentially additional deoxyribonucleic acid (DNA) 
sequencing. 
In addition, subjects may consent separately to collection of pharmacogenetic samples that 
will be stored for potential future analysis of genetic biomarkers of efficacy, safety-related, 
PD, or PK parameters as determined by future studies using clinically meaningful endpoints, 
through DNA sequencing or other genetic testing. 
Blood samples will be collected from all subjects prior to dosing on Day 1 and at Week 12 
and stored for exploratory circulating biomarker analysis, e.g., proteomic analysis related to 
disease activity, metabolic pathways, efficacy measures, or safety measures. 
9.3 
Safety Assessments 
Safety will be assessed throughout the study. Safety assessments include medical history, 
physical examinations, ECGs, vital signs, observed and subject-reported AEs, and safety 
laboratory results. 
Any abnormal findings judged by the investigator to be clinically important will be recorded 
as an AE. 
9.3.1 
Medical History 
A complete medical history will be recorded at the Screening visit, which will include 
evaluation (past or present) of the following: general, head and neck, eyes, ears, nose, throat, 
chest/respiratory, heart/cardiovascular, gastrointestinal/liver, gynecological/urogenital, 
musculoskeletal/extremities, skin, neurological/psychiatric, endocrine/metabolic, 
hematologic/lymphatic, allergies/drug sensitivities, past surgeries, substance abuse, or any 
other diseases or disorders as well as participation in clinical studies (study medication 
and/or device or other therapy).  


 
 
 
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9.3.2 
Physical Examination 
At Screening, Day 1, Week 12, and Week 16, a complete physical examination will be 
conducted including a neurological examination (gross motor and deep tendon reflexes), 
height (Screening only) and weight, and assessment of the following: general appearance, 
skin, head and neck, mouth, lymph nodes, thyroid, abdomen, musculoskeletal, 
cardiovascular, neurological, and respiratory systems. At all other visits, an abbreviated 
cardiopulmonary physical examination will be conducted, with other systems assessed as 
directed by interval history. 
Height (cm) and body weight (kg) will be measured at Screening, and BMI (kg/m2) will be 
calculated. Subjects will be required to remove their shoes and wear clothing as specified by 
the clinical site.  
9.3.3 
12-Lead ECG 
Triplicate 12-lead ECG evaluations will be performed after 10 minutes of rest at Screening 
and at all study visits. All ECG data will be sent to a central cardiac laboratory. 
On Day 1, ECG will be performed within 2 hours predose and at 1 hour postdose. At all other 
visits, ECGs will be taken prior to dosing. 
The investigator will judge the overall interpretation as normal or abnormal with clinical 
significance. Only the overall evaluation (normal/abnormal) will be recorded in the eCRF. 
The investigator will review the ECG and correlate abnormal findings with any other clinical 
findings, subject’s medical history, and laboratory data to determine the clinical importance 
of the finding. 
The investigator may add extra 12-lead ECG safety assessments if there are any abnormal 
findings or if the investigator considers it is required for any other safety reason. These 
assessments should be recorded as an unscheduled assessment. 
9.3.4 
Vital Signs 
Vital signs, to be assessed at each study visit, include temperature, HR, respiratory rate, and 
BP after resting for at least 5 minutes. Vital signs will be obtained with the subject in the 
same position; BP and HR should be the mean of 3 measurements taken ≥ 5 minutes apart. 
BP should be taken via an automated recorder.  
On Day 1 of dosing, vital signs will be taken predose and at 1 hour postdose. At all other 
visits, vital signs will be taken prior to dosing. Alert values (Section 7.3) will be flagged. 
Refer to the Study Reference Manual for additional details. 
9.3.5 
Other Safety Assessments 
Refer to Section 10 for information on AE assessment and Section 7.7 for concomitant 
therapy assessments. 


 
 
 
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Safety laboratory results will be assessed in an ongoing manner. A central safety laboratory 
will be used. Laboratory parameters are provided in Appendix 2. 
9.4 
Subject Restrictions During This Study 
The following restrictions apply for the specified times during the study period. If a subject 
does not comply with these restrictions or tests positive in any laboratory tests (e.g., drug, 
alcohol, pregnancy), they may be excluded or withdrawn from the study. 
• Starting 72 hours prior to the first dose until the final follow-up visit, subjects should not 
engage in unaccustomed intensive exercise except during protocol-specified exercise 
tests. 
• Starting at Screening, subjects will be required to abstain from blood or plasma donation 
until 3 months after the final study visit. 
• Starting on Day 1 until the final follow-up visit, subjects will be asked to abstain from 
alcohol, grapefruit or grapefruit juice, Seville oranges, and quinine (e.g., tonic water). 
• Contraception requirements are discussed in Section 8.2. 
 
9.5 
Study Procedures by Visit 
This section lists study procedures by visit. Every effort should be made to avoid protocol 
deviations. 
After providing written informed consent, potential subjects will undergo screening 
procedures to confirm eligibility to participate in the study. The investigator or appropriately 
trained designee will perform the screening procedures within 28 days prior to Day 1 
(administration of MYK-461). All results from the screening procedures needed to evaluate 
study eligibility, including safety laboratory results, must be available prior to the 
administration of study medication. 
9.5.1 
Screening (Day -28 to Day -1) 
• Informed consent 
• Medical history; includes participation in prior investigational clinical studies (IMP 
and/or device or other therapy) 
• Withdraw subject from β-blockers (Part A Only), calcium channel blockers (Part A and 
B), or disopyramide (Part A and B) as necessary, at least 14 days prior to further 
Screening assessments. 
• Complete physical examination; includes neurological examination, height, and weight 
• 12-lead ECG (triplicate) 


 
 
 
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• Vital signs: temperature, HR, respiratory rate, and BP after resting for at least 5 minutes 
• Blood samples for  
- 
Hematology and serum chemistry 
- 
FSH testing for postmenopausal women to confirm FSH is in the postmenopausal 
range 
- 
Hepatitis panel and HIV test  
- 
Thyroid stimulating hormone (TSH) test 
- 
Testing for drugs of abuse 
• Urine sample for urinalysis 
• Alcohol test based on standard at institution 
• Pregnancy test (blood or urine) for women of childbearing potential, based on standard at 
institution 
• Full resting TTE 
• Hemodynamic stress echocardiography after 4 hour fast 
• Prior and concomitant therapy assessment 
• Assessment of NYHA class 
• AE assessment (pretreatment symptoms that are an ongoing medical condition are 
recorded with the medical history, and signs and/or symptoms associated with a study 
procedure are recorded as an AE) 
• Apply cardiac monitoring skin patch 
• Optical biosensor pulse wave analysis (consenting subjects) 
 
9.5.2 
Day 1 
Complete the following procedures before administering the oral dose of study medication. 
• Complete physical examination; includes neurological examination and weight 
• 12-lead ECG (triplicate) within 2 hours predose 
• Vital signs after resting for at least 5 minutes 
• Pregnancy test (blood or urine) for women of childbearing potential, based on standard at 
institution 
• Full resting TTE 


 
 
 
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• CPET after a 4-hour fast (water is allowed) 
• Blood samples for  
- 
Hematology and serum chemistry 
- 
HCM genotyping (consenting subjects) 
- 
Potential future exploratory pharmacogenetic analysis (consenting subjects) 
- 
Potential exploratory biomarker analysis 
- 
NT-proBNP 
- 
PK, within ≤ 2 hours prior to dosing 
• Urine sample for urinalysis 
• Concomitant therapy assessment 
• AE assessment (pretreatment symptoms that are an ongoing medical condition are 
recorded with the medical history and signs, and/or symptoms associated with a study 
procedure are recorded as an AE) 
• Dyspnea NRS 
• KCCQ 
• Verify subject remains eligible 
• Retrieve previous cardiac monitoring skin patch and apply a new one 
• Optical biosensor pulse wave analysis (consenting subjects) 
 
Open-label administration of MYK-461 at site. 
Complete the following procedures postdose (when indicated, timing of assessments is 
approximate): 
• Resting vital signs at 1 hour postdose 
• 12-lead ECG (triplicate) at 1 hour postdose 
• AE assessment 
 
9.5.3 
Day 4 
• Contact subject via telephone to determine the subject’s status and ascertain whether the 
subject is experiencing any AEs. Information on concomitant medications should also be 
collected. 


 
 
 
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9.5.4 
Weeks 1, 2, 3, 4, 5, 6, 7, and 8 
Complete the following procedures before administering the oral dose of study medication. 
• Abbreviated cardiopulmonary physical examination, with other systems assessed as 
directed by interval history 
• 12-lead ECG (triplicate) 
• Vital signs after resting for at least 5 minutes 
• Resting TTE 
• Hemodynamic stress echocardiography (Week 4 only) after 4 hour fast 
• Blood samples for  
- 
hematology, serum chemistry (Weeks 4 and 8 only) 
- 
NT-proBNP (Weeks 4 and 8 only) 
- 
PK, within ≤ 2 hours prior to dosing 
• Pregnancy test (blood or urine) for women of childbearing potential, based on standard at 
institution (Weeks 4 and 8 only) 
• Retrieve previously applied cardiac monitoring skin patch (Weeks 2, 4, 6, and 8 only) 
and apply a new patch. At Week 8 only, the subject should be provided with an additional 
patch to be applied at Week 10. 
• Optical biosensor pulse wave analysis (consenting subjects) (Weeks 1, 2, 4, and 8 only)  
• Concomitant therapy assessment 
• AE assessment 
• Dyspnea NRS 
• Study medication compliance 
• Potential dose adjustment (Week 4 only) 
• Open-label MYK-461 administration at site 
 
9.5.5 
Week 10 
• Contact subject via telephone to determine the subject’s status and ascertain whether the 
subject is experiencing any AEs. Information on concomitant medications should also be 
collected. 


 
 
 
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9.5.6 
Week 12/Early Termination 
• Complete physical examination; includes neurological examination and weight 
• 12-lead ECG (triplicate) 
• Vital signs after resting for at least 5 minutes 
• Resting TTE 
• Hemodynamic stress echocardiography after 4 hour fast 
• CPET after a 4-hour fast (water is allowed). CPET may be conducted at the Week 12 
visit or anytime between Weeks 10 and 12. If CPET and hemodynamic stress 
echocardiography are conducted at the same visit, the hemodynamic stress 
echocardiography should be conducted first, followed by the CPET. 
• Blood samples for  
- 
Hematology and serum chemistry 
- 
NT-proBNP 
- 
Potential exploratory biomarker analysis 
- 
PK (within ≤ 2 hours prior to dosing) 
• Pregnancy test (blood or urine) for women of childbearing potential, based on standard at 
institution 
• Urine sample for urinalysis 
• Retrieve previously applied cardiac monitoring skin patch and apply a new patch. The 
skin patch is only required for up to 2 weeks of wear time. 
• Optical biosensor pulse wave analysis (consenting subjects) 
• Concomitant therapy assessment 
• AE assessment 
• Study medication compliance 
• Dyspnea NRS 
• KCCQ 
• NYHA class 
• Open-label MYK-461 administration at site 
 


 
 
 
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9.5.7 
Week 16/End of Study 
• Complete physical examination; includes neurological examination and weight 
• 12-lead ECG (triplicate) 
• Vital signs after resting for at least 5 minutes 
• Resting TTE 
• Hemodynamic stress echocardiography after 4 hour fast 
• Blood samples for 
- 
Hematology and serum chemistry 
- 
NT-proBNP 
- 
PK 
• Urine sample for urinalysis 
• Pregnancy test (blood or urine) for women of childbearing potential, based on standard at 
institution 
• Retrieve cardiac monitoring skin patch 
• Optical biosensor pulse wave analysis (consenting subjects) 
• Concomitant therapy assessment 
• AE assessment 
• Dyspnea NRS 
• KCCQ 
• NYHA class 
 
9.5.8 
Unscheduled Visits 
At the investigator’s discretion, unscheduled visits may be conducted for the assessment of 
AEs, physical examinations, vital signs, laboratory tests, ECGs, and/or TTEs. All 
information collected from unscheduled visits will be recorded on the eCRF and included in 
the clinical database. 
9.6 
Visit Window and Missed Visits 
Weekly visits should occur within the visit window (± 1 day). If an evaluation is missed, 
reschedule and perform it as close as possible to the original date. If rescheduling becomes, 
in the investigator’s opinion, medically unnecessary because the evaluation would occur too 
close to the next scheduled evaluation, it may be omitted. 


 
 
 
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10 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE 
EVENTS  
10.1 
Definitions 
10.1.1 
Adverse Event 
An AE is any untoward medical occurrence, or the deterioration of a preexisting medical 
condition (other than the condition that is being treated by the study) associated with the use 
of a study medication in humans, whether or not it is considered related to the study 
medication. An AE (also referred to as an adverse experience) can therefore be any 
unfavorable and unintended sign (e.g., tachycardia, enlarged liver, clinically important 
abnormal laboratory result or diagnostic procedure), subject-reported symptom (e.g., nausea, 
chest pain), or evidence of any disease activity temporally associated with the use of a study 
medication, whether or not related to the study medication. 
In clinical studies, an AE can include an undesirable medical condition occurring at any time 
after the subject has signed informed consent, including run-in or washout periods, even if no 
specific treatment has been administered. 
Preexisting medical conditions (other than natural progression of the disease being studied) 
judged by the investigator or subject to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period will be reported as AEs or SAEs 
as appropriate. 
Imaging-based assessments of decrease in contractility are not considered AEs unless 
associated with symptoms or signs of clinical concern on the part of the investigator. Such 
events should be categorized as an AE defined in terms of those symptoms or signs. 
An AE or SAE can also be a complication that occurs as a result of protocol-mandated 
procedures (e.g., invasive procedures such as biopsies). 
For MyoKardia to collect additional information about clinically important laboratory results 
or diagnostic tests (e.g., blood, ECG, imaging), at a minimum, the following abnormalities 
should be captured on the AE eCRF: 
• Any test result that meets the definition of an SAE 
• Any clinically important test abnormality that suggests a disease and/or organ toxicity 
that has worsened or is new (e.g., >3× deviation from the upper or lower limit of the 
analyzing laboratory reference range, or as otherwise specified in the protocol) 
• Any test abnormality that required the subject to have study medication discontinued or 
interrupted or in the clinical judgment of the investigator. 
• Any test abnormality that required the subject to receive specific corrective therapy, close 
observation, more frequent follow-up assessment, or further diagnostic investigation. 
 


 
 
 
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The term AE is used generally to include any AE whether serious or non-serious. 
10.1.2 
Serious Adverse Event 
An SAE is an AE that fulfils one or more of the following criteria in the opinion of the 
investigator or MyoKardia: 
• Results in death 
• Is immediately life-threatening (places the subject at immediate risk of death from the 
event as it occurred) 
• Requires in-subject hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions 
• Results in a congenital abnormality or birth defect 
• Is an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may be considered an SAE when, based upon appropriate medical 
judgment, it may require medical or surgical intervention to prevent one of the outcomes 
listed above. 
 
10.2 
Adverse Event Reporting and Descriptions 
10.2.1 
Reporting Period and Follow-Up 
AEs will be assessed from the time the subject provides informed consent through the 
duration of the study. Preexisting medical conditions that increase in severity from the first 
dose of study medication will be reported as AEs. Preexisting medical conditions that 
increase in severity after providing informed consent but before the first dose of study 
medication will be reported as medical history. 
Any AEs that are unresolved at the subject’s last visit in the study are followed by the 
investigator until resolved, or stabilized and are considered irreversible, or the subject has 
died. 
MyoKardia retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
10.2.2 
Adverse Event Attributes 
The following attributes will be recorded for each AE. Additional attributes may be collected 
as required by MyoKardia  


 
 
 
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10.2.2.1 
Description 
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study personnel: “Have you had any health problems since you were last asked?”, 
or revealed by observation will be collected and recorded in the eCRF. 
When collecting AEs the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms (e.g., anemia, not low hemoglobin). However, if a diagnosis is 
known and there are other signs or symptoms that are not generally part of the diagnosis, the 
diagnosis and each sign or symptom will be recorded separately. 
Death is an outcome and not the name of the event. In this situation, the event that led to the 
death is the name of the event. If the cause of death is unknown, “found dead” is an 
acceptable description. 
10.2.2.2 
Start Date/Time and Stop Date/Time 
Record the date (and time during period of residency) the AE started and the date (and time 
during period of residency) the event ended. For events that continue for long periods of time, 
it is acceptable to record the end date as the day the event stabilized.  
10.2.2.3 
Relationship to Study Treatment (Suspected Adverse Reactions) 
The investigator should assess causality by answering either “yes” or “no” to the following 
question, “is there a reasonable possibility that the event may have been caused by the 
IMP/study medication?” 
10.2.2.4 
Intensity 
Record the intensity or severity of the event using the following guide: 
• mild (awareness of sign or symptom, but easily tolerated) 
• moderate (discomfort sufficient to cause interference with normal activities) 
• severe (incapacitating, with inability to perform normal activities) 
• life-threatening (urgent intervention indicated) 
• fatal (event lead to death) 
 
10.2.2.5 
Seriousness 
Record SAE criteria described in Section 10.1.2 or indicate that the AE is not serious. 


 
 
 
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It is important to distinguish between category (AE vs SAE) and intensity (mild, 
moderate or severe) of AEs. 
Severity is a measure of intensity (Section 10.2.2.4), whereas seriousness is defined by the 
criteria in Section 10.1.2. 
An AE of severe intensity need not necessarily be considered serious. For example, nausea 
that persists for several hours may be considered severe nausea, but not an SAE. On the other 
hand, a stroke that results in only a limited degree of disability may be considered a mild 
stroke but would be an SAE.  
10.2.2.6 
Outcome 
Record the outcome of the event based on the options provided on the eCRF. 
10.3 
Reporting and Evaluation of Serious Adverse Events 
All SAEs regardless of causality will be reported by the investigator or designee to 
MyoKardia/designee through the last visit or 30-day period after the last dose of study 
medication, whichever is longer, within 24 hours of knowledge of the event or sequelae. 
Deaths and SAEs occurring beyond this timepoint and considered related to study medication 
or study procedure must also be reported. SAE reporting instructions are provided in the 
Study Reference Manual. 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that qualify for 
mandatory expedited reporting to regulatory authorities where the SAE is suspected to be 
caused by the study treatment and is considered unexpected (i.e., not defined as expected in 
the current IB, clinical protocol, or approved labeling for marketed products). In this case, 
MyoKardia or designee will report to the relevant regulatory authority(ies) and forward a 
formal notification describing the SUSAR to investigators, according to regulatory 
requirement. Each investigator must then notify his/her ethics committee (EC) of the SUSAR 
as required by local regulatory authorities and in accordance with their EC policy. 
11 
STATISTICAL METHODS 
11.1 
Determination of Sample Size 
Approximately 10 subjects will be dosed in Part A and in Part B. The sample size is based on 
practical considerations and is consistent with this type of study. Ten subjects per group 
receiving MYK-461 will provide 80% power to detect a 30 mm Hg within-group change 
from baseline in post-exercise peak LVOT gradient and a > 99% power to detect a 
50 mm Hg change (Table 4). This assumes a 1-sided α = 0.05 and a common standard 
deviation of 35 mm Hg. The common standard deviation of 35 mm Hg is based on observed 
data in patients with HCM and provocable LVOT (Nistri et al, 2012). 


 
 
 
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Table 4 
Power for Detecting a Statistically Significant Within Group Change 
With 10 Subjectsa 
Difference Versus Baseline In Peak LVOT Gradient 
(mm Hg) 
Power (%) 
50 
> 99 
40 
95 
30 
80 
20 
50 
LVOT, left ventricular outflow tract 
a 
 Calculations were made using nQuery 7.0 Advisor software.  
 
11.2 
Study Endpoints 
11.2.1 
Primary Endpoint 
• Change in post-exercise peak LVOT gradient from baseline to Week 12  
 
11.2.2 
Secondary Endpoints 
• Proportion of subjects achieving an LVOT gradient response of post-exercise peak 
gradient < 30 mm Hg 
• Change in dyspnea symptom score from baseline to Week 12 
• Change in pVO2 and VE/VCO2 from baseline to Week 12 
• Change from baseline in LVEF (2D and 3D), global longitudinal strain, and LVFS from 
baseline to Week 12 
• Change from Week 12 to Week 16 in post-exercise peak LVOT gradient 
• Plasma PK profile of MYK-461 
 
11.2.3 
Exploratory Endpoints 
• Proportion of subjects achieving an LVOT gradient response of post-exercise peak 
gradient < 10 mm Hg 
• Change in NYHA functional classification from baseline to Week 12 
• Change in NT-proBNP from baseline to Week 12 
• Change in KCCQ OSS from baseline to Week 12 
• Change from baseline in arterial pulse wave morphology assessed using an optical 
biosensor 


 
 
 
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• Change from baseline in HR and heart rhythm assessed using a cardiac monitoring skin 
patch 
 
11.2.4 
Safety Endpoints 
• Treatment-emergent AEs and SAEs 
• Changes from baseline in laboratory values and vital signs 
• Changes from baseline in ECGs 
 
11.3 
Statistical Analysis 
Before database lock, a final statistical analysis plan (SAP) for clinical data and PK analyses 
will be prepared that will contain full details of all planned analyses. The analyses presented 
here represent an outline of the intended methodology. 
11.3.1 
Analysis Populations  
Three analysis populations are defined in this study. 
The Efficacy/PD Analysis Population is defined as all subjects who receive at least 1 dose of 
MYK-461 and have primary or secondary endpoint data, including a baseline value and at 
least one post baseline value. All efficacy and PD analyses will be performed on the 
Efficacy/PD Analysis Population.  
The Safety Analysis Population is defined as all subjects who receive at least 1 dose of 
MYK-461. Safety analyses will be performed on the Safety Analysis population. 
The PK Analysis Population is defined as all subjects who received at least 1 dose of 
MYK-461 and have detectable PK data. PK analyses will be performed on the PK Analysis 
Population. 
11.3.2 
General Considerations 
Descriptive summary statistics for continuous variables will include the number of subjects, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized using counts and percentages. Ninety-five percent confidence intervals will be 
presented, as appropriate. 
The two groups from Part A and Part B, respectively, will be analyzed separately and not 
statistically compared with one another for effect sizes.  They may be compared side-by-side 
with respect to demographic and baseline characteristics to evaluate whether they were 
drawn from the same overall population. 


 
 
 
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11.3.3 
Subject Disposition 
The number and percentage of subjects who complete and discontinue as well as reasons for 
early discontinuation will be presented. 
11.3.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively. 
11.3.5 
Efficacy/Pharmacodynamic Analyses 
All efficacy/PD analyses will be performed on the Efficacy/PD Analysis Population. 
11.3.5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline to Week 12 in post-exercise peak 
LVOT gradient. 
Post-exercise peak LVOT gradient will be analyzed using a mixed-effect model with 
repeated measures (MMRM). All data available from baseline (Screening) to Week 16 (EOS) 
will be included and missing data will be accounted for by the MMRM model. The model 
will include the fixed categorical effects of timepoint: baseline, Week 4, Week 12 (end of 
treatment), and Week 16 (EOS).  
This model will provide least-squares (LS) mean estimates with their corresponding standard 
errors at each time point. Comparison between baseline and Week 12 (end of treatment) will 
be based on the LS mean difference obtained from the MMRM, and will be presented with 
its associated 95% confidence interval. Statistical significance of the difference versus 
baseline will be evaluated at the 1-sided 0.05 level. 
11.3.5.2 
Secondary and Exploratory Efficacy Endpoints 
The proportion of subjects achieving LVOT gradient responses of < 30 mm Hg and 
< 10 mm Hg will be summarized at each post-baseline visit. In case of missing data at a 
given visit, it will be assumed that the subject had not achieved an LVOT gradient response. 
Quantitative endpoints, including the Dyspnea NRS, pVO2, VE/CO2, LVEF, NYHA 
functional classification, NT-proBNP, and KCCQ OSS will be analyzed using the same 
MMRM model as for the primary efficacy endpoint. The list of timepoints included in the 
MMRM will be adjusted according to the visits at which each endpoint will be measured. 
Data collected from the optical biosensor and cardiac monitoring skin patch will be analyzed 
descriptively.  
11.3.6 
Pharmacokinetic Analyses 
Plasma concentrations of MYK-461 will be determined and summarized descriptively. 
Population PK and PK/PD analyses will be conducted. 


 
 
 
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11.3.7 
Interim Analysis 
No formal interim analysis is planned. 
11.3.8 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis population.  
11.3.8.1 
Adverse Events 
AEs will be mapped to system organ classes and preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA). AEs will be monitored during the study and 
the data analyzed with respect to overall incidence as well as severity and potential 
relationship of AEs to study medication. AEs with onset on or after the first dose of study 
medication, or with an onset before the first dose of study medication that increase in severity 
on or after the first dose of study medication, will be considered treatment-emergent. 
Treatment-emergent AEs will be summarized for the Safety Analysis Population by system 
organ class and preferred term, and by severity and relationship to treatment. Severe and 
life-threatening AEs, SAEs, and AEs leading to study withdrawal, if any, will be presented in 
data listings. 
11.3.8.2 
12-lead Electrocardiogram 
The RR, PR, QRS, and QT intervals will be measured. HR will be calculated as 
60/(RR × 1000) (with RR expressed in msec) and rounded to the nearest integer. 
Correction for Heart Rate 
Corrected QT interval (QTc) will be calculated using the manually over-read QT values. 
Each individual ECG QT value will be corrected for HR. The measured QT data will be 
corrected for HR using the Fridericia method (QTcF) as per the following formulae/method 
(with QT, RR and QTc expressed in msec): 
Fridericia’s Correction: 
 
 
ECG Numeric Variables 
HR, PR, QRS, and QTcF will be summarized using descriptive statistics. The change from 
baseline of these ECG parameters at each timepoint will be listed for each subject. For each 
timepoint of measurement, the changes from baseline will be summarized using descriptive 
statistics. 
 


 
 
 
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Categorical Analysis 
The incidence count and percentage of subjects with any postdose QTcF values of > 
450 msec, > 480 msec, and > 500 msec will be tabulated for all subjects. Subjects with QTc 
values > 500 msec will be listed with corresponding baseline values, ∆QTcF, and baseline 
and treatment HR. The incidence count and percentage of subjects with ∆QTcF increase of 
> 30 msec and > 60 msec will be tabulated. 
Morphology Findings 
New ECG morphologies for each subject not present on any ECG at baseline for that subject 
will be summarized for all observation timepoints combined.  
The number and percentage of subjects having T-wave morphology changes and/or the 
occurrence of abnormal U-waves that represent the appearance or worsening of the 
morphological abnormality from baseline will be reported. 
Concentration-QTc Analyses 
A concentration-QTc regression analysis, based on data collected from the ECG recordings 
after drug administration and concentration values for each subject at each matching 
timepoint, will be performed. 
11.3.8.3 
Other Safety Analyses 
Safety laboratory data including hematology, chemistry, and vital signs will be evaluated by 
visit for the Safety Analysis Population using descriptive statistics. Changes from baseline at 
each post-Day 1 timepoint will also be assessed. Listings of subjects with laboratory, and/or 
vital sign values that are out of the reference range will be produced. Abnormal physical 
examination results will be listed. Concomitant medications will be summarized. 
11.3.9 
Exploratory Analyses 
Additional exploratory analyses may be performed. Detailed planned exploratory analyses 
will be specified in the SAP. 
12 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS 
12.1 
Compliance Statement 
This study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) GCP guidelines; US Title 21 Code of Federal Regulations (CFR) 
Parts 11, 50, 54, 56, and 312; European Union (EU) GCP; cGMP; the principles enunciated 
in the Declaration of Helsinki; and all human clinical research regulations in the countries 
where the study is to be conducted. 


 
 
 
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12.2 
Informed Consent 
The ICFs used for the study must comply with the Declaration of Helsinki, US 21 CFR 
Part 50, ICH GCP guidelines, and any other local regulations. The investigator, or a person 
delegated by the investigator, must explain the medical aspects of the study including the 
nature of the study and the treatment, orally and in writing, in such a manner that the 
potential subject is aware of potential benefits and risks. Potential subjects must be informed 
that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. Subjects, or a legal guardian if the subject is unable to, must give informed 
consent in writing. 
Prior to participation in any study-related procedures, subjects must sign and date an 
ethics-committee (EC)-approved written ICF in a language the subject can understand. The 
informed consent process must be conducted, documented in the source document (including 
the date), and the form must be signed before the subject undergoes any study-specific 
procedures. 
The language in the written information about the study should be as non-technical as 
practical and should be understandable to the potential subject. Before informed consent is 
obtained, the investigator should provide the potential subject ample time and opportunity to 
inquire about the study and to decide whether or not to participate. 
All questions about the study should be answered to the satisfaction of the subject. The 
written ICF should be signed and personally dated by the subject and by the person who 
conducted the informed consent discussion. All subjects will receive a copy of his/her signed 
and dated ICF. 
12.3 
Ethics Committee 
The term EC used in this document refers to an Institutional Review Board (IRB) or 
Independent Ethics Committee (EC) or equivalent. The EC must review and, if appropriate, 
approve the following documents, as applicable: 
• Study protocol and amendment(s) 
• Written ICF(s) and consent form updates 
• Subject recruitment procedures/documents (e.g., advertisements) 
• Written information to be provided to subjects 
• IB and available safety information (Note: ECs do not approve IBs but are responsible for 
acknowledging receipt) 
• Information about payments and compensation available to subjects 
 
The EC approval must be in writing, clearly identifying the study (by protocol date and/or 
version), the documents reviewed, including informed consent, and date of the review. The 


 
 
 
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investigator has the responsibility to provide MyoKardia with the written EC approval prior 
to initiating any study-related procedures.  
The investigator also has the responsibility to inform the EC of the following according to 
the EC’s policy: 
• All SUSARs (as described in Section 10.3) 
• Any new information that may affect adversely the safety of the subjects or the conduct 
of the trial 
• Protocol deviations 
• A synopsis of the study report upon study completion 
 
Documentation of subsequent reviews of the study must also be forwarded to MyoKardia. 
13 
ADMINISTRATIVE PROCEDURES 
13.1 
Sponsor’s Responsibilities 
MyoKardia reserves the right to terminate the study at any time. MyoKardia and the 
investigators will assure that adequate consideration is given to the protection of the subjects’ 
interests. MyoKardia retains the right to terminate the study and remove all study materials 
from a clinical site at any time. Specific circumstances that may precipitate such termination 
are: 
• Request by Health Authority to terminate the study 
• Unsatisfactory subject enrollment with regard to quality or quantity 
• Significant or numerous deviations from study protocol requirements, such as failures to 
perform required evaluations on subjects, maintain adequate study records or inaccurate, 
incomplete, or late data recording on a recurrent basis 
• The incident or severity of AEs in this or other studies indicating potential health hazard 
caused by the study treatment 
 
13.1.1 
Subject Confidentiality 
The processing of personal data in pursuit of this study will be limited to those data that are 
reasonably necessary to investigate the utility of the study medications used in this study. 
These data will be processed with adequate precautions to ensure confidentiality according to 
applicable laws. 
 
 


 
 
 
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MyoKardia ensures that the personal data are: 
• Collected for a specified and legitimate purpose 
• Processed fairly and lawfully 
• Accurate and up to date 
 
Explicit consent for the processing of personal data will be obtained prospectively from the 
participating subject. 
MyoKardia, whose responsibilities require access to personal data, agrees to keep the identity 
of subjects confidential. This confidentiality will be maintained throughout the complete data 
processing. 
Subjects will be entitled to request confirmation of the existence of personal data held by 
MyoKardia and will have the right to rectify erroneous or inaccurate data up until database 
lock. 
13.1.2 
Study Supplies 
MyoKardia will supply or ensure the coordination of sufficient quantities of the following 
materials to each clinical site: 
• MYK-461 tablets of 4 strengths in 30-count bottles 
• Cardiac monitoring skin patches 
• Optical biosensors 
• Supplies for laboratory assessments 
 
13.1.3 
Investigator Training 
All clinical sites will have a center-specific study initiation meeting to ensure the center staff 
understands the protocol, study requirements, and data capture processes. This training will 
take place before the first subject is enrolled. Each clinical site will be provided with 
information regarding GCP and regulations specific to the conduct of the clinical studies. 
Each clinical site will be responsible for ensuring that new team members are adequately 
trained and the training is documented. 
13.1.4 
Ongoing Communication of Safety Information during the Study 
MyoKardia will provide the investigator with documentation of SAEs from the study and 
other studies that are related to MyoKardia study medication and are unexpected (refer to 
Section 10.3), as appropriate. The investigator must forward this documentation to the EC as 
described in Section 10.3. 


 
 
 
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MyoKardia will also notify the investigator about any other significant safety findings that 
could alter the safety profile of the IMP from what is described in the protocol and 
significantly affect the safety of subjects, affect the conduct of the study, or alter the EC’s 
opinion about the continuation of the study.  
13.1.5 
Study Monitoring 
MyoKardia will monitor this clinical study through remote data checks and monitoring visits 
to check the adequacy of clinical site staff and facilities, and to ensure adherence to the 
protocol, study procedures, and applicable regulations. The clinical site monitor will also 
assess proper eCRF completion and source document retention. The investigator and clinical 
site staff are expected to provide adequate space for monitoring visits and to allocate 
sufficient time to permit adequate review of the study’s progress. The investigator will permit 
study-related monitoring, audits, EC review, and regulatory inspection(s), providing direct 
access to source data/documents and study-related facilities (e.g., pharmacy, diagnostic 
laboratories). 
13.1.6 
Study Auditing and Inspecting 
MyoKardia may audit the study conduct, compliance with the protocol, and accuracy of the 
data in 1 or more clinical sites. 
The investigator(s)/institution(s) will permit study-related monitoring, audits and inspections 
by MyoKardia, EC, government regulatory authority(ies), and MyoKardia’s quality 
assurance personnel or its designees by providing direct access to source data/documents 
after appropriate notification from MyoKardia. 
13.2 
Investigator’s Responsibilities 
13.2.1 
Screening Log 
The investigator must keep a record that lists all subjects who signed an informed consent 
and the reason for non-inclusion if the potential subject does not ultimately enroll and receive 
IMP. 
13.2.2 
MYK-461 Accountability 
The investigator must ensure that the study medications at the investigational site are kept 
secured and accounted for with access limited to only those individuals authorized by the 
investigator. The investigator, his/her designee, or pharmacist must also maintain adequate 
records of distribution, dispensing, and return of all study medication to be able to reconcile 
the study medication records (i.e., accountability or dispensing logs) at the end of the study. 
The study medication records must be readily available for inspection by the site monitor 
and/or auditor. In general, no study medication can be returned to MyoKardia/clinical site or 
disposed of at the clinical site until the clinical site monitor has verified the accuracy of the 
study medication records at the clinical site and indicated whether the medication should be 
destroyed at the clinical site or returned to MyoKardia/designee. 


 
 
 
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13.2.3 
Reporting and Recording of Study Data 
Data will be captured and compiled using procedures developed by MyoKardia or designee. 
Electronic data capture (EDC) technology will be used for this study. Clearly record all 
requested study data on the eCRF and other forms as required. Whenever possible, record the 
reason for missing data in the source document. Only individuals who are identified on the 
study personnel responsibility/signature log and who have received appropriate training on 
the EDC system may enter or correct data in the eCRF. Incomplete or inconsistent data on 
the eCRF will result in data queries that require resolution by the investigator or designee. 
Corrections to the eCRF, including the reason for change, will be automatically documented 
through the EDC system’s audit trail. 
Subject source data must be maintained as original records or a certified copy (i.e., copy of 
original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original). The investigator and 
affiliated institution should take measures to prevent accidental or premature destruction of 
documents. Data collected on the eCRF must match the source documents. 
An eCRF must be completed for each subject who receives at least 1 dose of IMP. All entries 
into the eCRF are ultimately the responsibility of the investigator before approving them via 
an electronic signature. The investigator is responsible for ensuring accurate, authentic and 
complete records for each subject. 
An electronic copy of the eCRF casebooks will be sent to the clinical site for retention with 
other study documents after full completion of the study. 
13.2.4 
Source Data and Source Documents 
The nature and location of all source documents will be identified to ensure that all sources 
of original data required to complete the eCRF are known to the company and clinical site 
staff. The source documents are to be accessible for verification by the clinical site monitor. 
Source documents should at minimum include the following information for each subject: 
• Subject identification and contact information (name, date of birth, sex, address, phone) 
• Documentation verifying subject eligibility (i.e., medical history, physical examination) 
• Informed consent process documentation and ICF 
• Record of all visits and other contacts 
• Record of all AEs and other safety parameters and all event attributes 
• Record of all concomitant therapy (including start/stop dates, indication for use, dose) 
• Date of study completion and reason for early discontinuation, if applicable 
 


 
 
 
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The author of an entry in the source documents should be identifiable as well as the date of 
the entry. Direct access to source documentation (medical records) must be allowed for the 
purpose of verifying that the data recorded in the eCRF are consistent with the original 
source data. The investigator will provide certified copies of the subject’s medical records in 
the event that clinical site’s policy does not permit direct access to the electronic medical 
records. 
13.2.5 
Subject Identification Information 
To permit easy identification of the individual subject during and after the study, the 
investigator is responsible for keeping an updated log that contains the subject identification 
information. This document will be reviewed by the clinical site monitor for completeness. 
However, to ensure the subject’s confidentiality, the document will be maintained at the 
clinical site and no copy will be made. 
13.2.6 
Records Retention 
MyoKardia will inform the investigator in writing when it is acceptable to dispose of any 
study records. To enable evaluation and/or audits from regulatory authorities or MyoKardia, 
the investigator agrees to keep records, including the identity of all subjects (e.g., subject 
identification code list and all source documents), all original signed ICFs, copies of all 
eCRFs, original laboratory reports, detailed records of study medication disposition, and all 
essential documents for the conduct of a clinical study. To comply with international 
regulations, the records should be retained by the investigator for at last 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing application in an ICH region, or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the IMP. However, the 
investigator may need to retain these documents for a longer period if required by the local 
regulatory requirements or by an agreement with MyoKardia. 
13.2.7 
Protocol Deviations 
Protocol waivers will not be allowed. 
Unless there is a safety concern, there should be no deviations or violations of the study 
protocol. In the event of a safety concern, the investigator or designee must document and 
explain the reason for any deviation from the approved protocol. The investigator or the 
medical monitor may implement a deviation from, or a change to, the protocol to eliminate 
an immediate hazard to subjects without prior EC approval. Immediately after the 
implemented deviation or change, the investigator must submit a report explaining the 
reasons for the protocol deviation to the EC and MyoKardia, if required. If a protocol 
deviation may result in inadequate subject data, MyoKardia may determine that the subject 
should be replaced. The medical monitor will notify the study monitor(s) of the decision. 
13.2.8 
Blood Sample Collection/Storage 
Blood samples that are collected as part of routine medical care or as part of protocol 
procedures may be stored and analyzed for PK or PD analyses. 


 
 
 
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After the study, samples may be used for additional investigation to help identify factors that 
may influence response to therapy. Such samples will be used in compliance with guidelines 
defined by US FDA Guidance on Informed Consent for In Vitro Dialogistic Device Studies 
Using Leftover Human Specimens That are Not Individually Identifiable (issued 25Apr2006) 
and European Medicines Agency’s (EMA’s) Reflection Paper on Pharmacogenomic 
Samples, Testing and Data Handling (EMA/Committee for Medicinal Products for Human 
Use [CHMP] 2007). 
13.3 
Clinical Trial Insurance 
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted. An insurance certificate will be made available to the participating 
clinical sites upon request. 
13.4 
Protocol Amendments and Study Administrative Letters 
Study procedures will not be changed without the mutual agreement of the investigator and 
MyoKardia. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and, where required, in a new version of the 
study protocol. 
The amendment should be approved by the EC and the appropriate regulatory authority(ies), 
before implementation, as appropriate. Local requirements should be followed for revised 
protocols. 
If a protocol amendment requires a change to the ICF, the EC will need to approve the 
revised ICF before the revised form is used. 
If there are nonsubstantial changes such as clarification of statement or corrections to 
obvious errors/typos/inconsistencies in the protocol, or change to logistical or administrative 
aspects, then MyoKardia may issue an Administrative Letter. If local regulations require, any 
administrative change will be communicated to or approved by the EC. 
14 
DATA QUALITY ASSURANCE 
Quality assurance and quality control systems will be implemented and maintained with 
Standard Operating Procedures by MyoKardia, as appropriate, to ensure that this clinical 
study is conducted and data are generated, documented (recorded), and reported in 
compliance with the protocol, ICH E6 GCP: Consolidated Guidance and the applicable 
regulatory requirements. 


 
 
 
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15 
ADMINISTRATIVE CONSIDERATIONS 
15.1 
Use of Computerized Systems 
This study will require the use of the following electronic data collection methods: 
• EDC system to capture protocol-required subject data: clinical sites will enter data from 
source documents onto eCRFs for each study visit using a web-based interface. Study 
monitors and data management personnel will use this system to review data and 
generate queries and reports as needed. 
• Cardiac clinical data management systems will be used to analyze ECG, CPET, and 
echocardiographic data from digital equipment used by clinical site personnel to collect 
subject data. 
In addition, other central data management systems/databases and software may be used to 
collect and analyze study data: 
• Laboratory Information Systems or proprietary systems will be used by laboratories for 
storing and/or analyzing bioanalytical laboratory data collected throughout the study. 
• Statistical software will be used for the statistical analysis of the study data as outlined in 
the SAP. 
 
Information on the above systems will be provided to the investigator, clinical site personnel, 
and other personnel as appropriate. Measures will be taken to ensure data security and 
accuracy, including but not limited to user training, granting of user accounts and privileges 
to trained and authorized personnel in a role-based manner, username/password/electronic 
signature requirements enforcement, programmed and manual edit checks as outlined in data 
validation specifications, computer generated audit trails, centralized data management, and 
routine study monitoring. The systems used will be compliant with US 21 CFR Part 11 and 
Annex 11 to the Rule Governing Medicinal Products in the European Union and the data 
collected will be archived (at minimum) for the period specified by applicable regulatory 
requirements. 
15.2 
Study Records 
The investigator and affiliated institution shall maintain the study documents and records as 
specified in “Essential Documents for the Conduct of a Clinical Trial” (ICH E6 Section 8), 
and as required by the applicable regulatory requirement(s). This includes, but is not limited 
to, the protocol, eCRFs, AE reports, subject source data (original records or certified copies), 
correspondence with health authorities and EC, consent forms, investigator’s curriculum 
vitae, monitor visit logs, laboratory reference ranges and laboratory certification or quality 
control procedures, and laboratory director curriculum vitae. 
The eCRF must be completed at the time of, or shortly after the subject’s visit or upon receipt 
of test results. Information will be provided to clinical site staff on the proper way to 
complete the eCRF. 
A copy of each subject’s eCRF will be maintained by the investigator. 


 
 
 
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16 
PUBLICATION 
The data and results of the study will be owned solely by MyoKardia and shall be 
confidential information of MyoKardia, subject to the investigator’s publication rights, all as 
outlined in the agreement between the investigator/institution and MyoKardia regarding the 
conduct of the clinical study (the “Clinical Study Agreement”). It is understood by the 
investigator that MyoKardia may use the information developed in this study in connection 
with the development of MyoKardia’s proprietary IMP and, therefore, may disclose such 
information as necessary or useful to other clinical investigators or regulatory agencies. To 
allow for the use of the information derived from the study, the investigator understands that 
he/she has an obligation to provide and disclose all study results and all data developed 
during this study to MyoKardia. 
Any publication or presentation of the results or data of this clinical study by the investigator 
may only be made in strict compliance with the provision of the Clinical Study Agreement. 
The investigator understands that it is not MyoKardia’s intention to prevent publication of 
the data generated in the study; rather, MyoKardia reserves the right to control the form and 
timing of such publication for commercial reasons and desires to confirm the scientific 
accuracy of such information prior to such publication or presentation. 


 
 
 
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17 
REFERENCE LIST 
Chuan P, Sivaramakrishnan S, Ashely EA, Spudich JA. Cell-intrinsic functional effects of 
the α-cardiac myosin Arg-403-Gln mutation in familial hypertrophic cardiomyopathy. 
Biophys J. 2012;102:2782-2790.  
EMA/CHMP (European Medicines Agency/Committee for Medicinal Products for Human 
Use). Guideline on Strategies to Identify and Mitigate Risks for First-In-Human Clinical 
Trials with Investigational Medicinal Products. 01 September 2007. Available at 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC 
500002988.pdf. 
EMA/CHMP (European Medicines Agency/Committee for Medicinal Products for Human 
Use). Reflection Paper on Pharmacogenomic Samples, Testing and Data Handling. 
15 November 2007. Available at 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC 
500003864.pdf. 
Frey N, Luedde M, Katus HA. Mechanisms of disease: hypertrophic cardiomyopathy. Nat 
Rev Cardiol. 2012; 9:91–100. 
Gift AG, Narsavage G. Validity of the Numeric Rating Scale as a measure of dyspnea. Am J 
Critical Care 1998;7(3):200-204. 
Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA Guideline for the diagnosis and 
treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines. Developed in 
collaboration with the American Association for Thoracic Surgery, American Society of 
Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of 
America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, 
and Society of Thoracic Surgeons. J Am Coll Cardiol. 2011;58:e212-260. 
Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas 
City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll 
Cardiol. 2000;35:1245-1255. 
Green EM, Wakimoto H, Anderson R L, et al. A small-molecule inhibitor of sarcomere 
contractility suppresses hypertrophic cardiomyopathy in mice. Science. 2016;351(6273):617-
621. 
Hershberger RE, Cowan J, et al. Progress with genetic cardiomyopathies: screening, 
counseling, and testing in dilated, hypertrophic, and arrhythmogenic right ventricular 
dysplasia/cardiomyopathy. Circ Heart Fail. 2009;2:253-261. 
Ho CY. Hypertrophic cardiomyopathy in 2012. Circulation. 2012;125:1432-1438. 


 
 
 
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Ho CY, Sweitzer NK, McDonough B, et al. Assessment of diastolic function with Doppler 
tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation. 
2002;105:2992-2997. 
International Conference on Harmonisation (ICH). E6 Good Clinical Practice (GCP): 
Consolidated Guidance. April 1996. Available at 
http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf. 
Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 
years. J Am Coll Cardiol. 2012;60:705-715. 
Nistri S, Olivotto I, Maron MS, et al. β Blockers for prevention of exercise-induced left 
ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy. Am J 
Cardiol. 2012;110:715–719. 
Sommese RF, Sung J, Nag S, et al. Molecular consequences of the R453C hypertrophic 
cardiomyopathy mutation on human beta-cardiac myosin motor function. Proc Natl Acad Sci 
USA. 2013;110:12607-12612. 
Stern, JA, Markova S, Ueda Y, et al. A small molecule modulator of sarcomere contractility 
relieves left ventricular outflow tract obstruction in feline hypertrophic cardiomyopathy. 
PLOS One. 2016 Dec 14;11(12):e0168407. 
Sung J, Choe E,  Elting M, Nag S, Sutton S, Deacon J, Leinwand L, Ruppel K, Spudich J, 
Single Molecule Studies of Recombinant Human α- and β-Cardiac Myosin to Elucidate 
Molecular Mechanism of Familial Hypertrophic and Dilated Cardiomyopathies. Biophysical 
Journal, Volume 102, Issue 3, 613a - 614a, January 2012. 
DOI: http://dx.doi.org/10.1016/j.bpj.2011.11.3345 
US Department of Health and Human Services. Guidance for Industry. Informed Consent for 
in Vitro Diagnostic Device Studies Using Leftover Human Specimens That Are Not 
Individually Identifiable. April 2006. Available at 
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cuments/ucm071265.pdf.2012;60:705.


 
 
 
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APPENDICES 
APPENDIX 1 
SCHEDULE OF STUDY PROCEDURES 
Timepoint (Day/Week)a 
Screen 
D -28 to 
D -1 
D1 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W12/ 
ET 
W16/ 
EOS or 
ET + 
4W 
General Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical historyb 
X 
 
 
 
 
 
 
 
 
 
 
 
Telephone call to subjectc 
 
 
  
 
 
 
 
 
 
 
 
 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs/SAEse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body height 
X 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
ECGg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Resting TTEh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CPETi 
 
X 
 
 
 
 
 
 
 
 
Xj 
 
Hemodynamic stress echocardiographyk 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
Optional pulse wave optical biosensorl 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
X 
Apply cardiac monitoring skin patchm 
X 
X 
 
X 
 
X 
 
X 
 
Xn 
X 
 
Retrieve previously applied cardiac 
monitoring skin patchm 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Laboratory 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis panel, HIV test, TSH, and 
drug/alcohol testing 
X 
 
 
 
 
 
 
 
 
 
 
 
PK sampleso 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Hematology 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
X 
X 


 
 
 
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Footnotes and abbreviations defined on last page of table. 


 
 
 
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APPENDIX 1 
SCHEDULE OF STUDY PROCEDURES (continued) 
Timepoint (Day/Week)a 
Screen 
D -28 
to D -1 
D1 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W12/ 
ET 
W16/ 
EOS or 
ET + 
4W 
Laboratory (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
NT-proBNP 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
FSHp 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (women)q 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
HCM genotypingr 
 
X 
 
 
 
 
 
 
 
 
 
 
Pharmacogenetics 
 
X 
 
 
 
 
 
 
 
 
 
 
Biomarkers (blood)t 
 
X 
 
 
 
 
 
 
 
 
X 
 
Symptom Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
Dyspnea NRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
KCCQ 
 
X 
 
 
 
 
 
 
 
 
X 
X 
NYHA class 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Investigational Medical Product 
 
 
 
 
 
 
 
 
 
 
 
 
Open-label MYK-461 administration at site 
 
X 
X 
X 
X 
Xu 
X 
X 
X 
X 
X 
 
Open-label MYK-461 QD 
 
 
 
 
 
 
 
 
 
 
 
 
Study medication compliancev 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE, adverse event; BP, blood pressure; CPET, cardiopulmonary exercise testing; D, day; ECG, electrocardiogram; eCRF, electronic case report form; EOS, end 
of study; ET, early termination; FSH, follicle-stimulating hormone; HCM, hypertrophic cardiomyopathy; HIV, human immunodeficiency virus; HR, heart rate; 
ICF, informed consent form; IMP, investigational product; KCCQ, Kansas City cardiomyopathy questionnaire; LVFS, left ventricular fractional shortening; 
LVOT, left ventricular outflow tract; NRS, numerical rating scale; NT-proBNP, N-terminal of the prohormone brain natriuretic peptide; NYHA, New York Heart 
Association; PK, pharmacokinetic; QD, once daily; SAE, serious adverse event; TSH, thyroid-stimulating hormone; TTE, transthoracic echocardiography; 
VCO2, carbon dioxide production; VE, volume expired; VO2, oxygen uptake; VIT, velocity time integral; W, week. 
a 
At the investigator’s discretion, unscheduled visits may be conducted at the investigational site for the assessment of AEs, physical examinations, vital signs, 
laboratory tests, ECGs, and/or TTEs. All information collected from unscheduled visits will be recorded on the eCRF and included in the clinical database. 
b 
A complete medical history will be recorded at the Screening visit, which will include evaluation (past or present) of the following: general, head and neck, 
eyes, ears, nose, throat, chest/respiratory, heart/cardiovascular, gastrointestinal/liver, gynecological/urogenital, musculoskeletal/extremities, skin, 
neurological/psychiatric, endocrine/metabolic, hematologic/lymphatic, allergies/drug sensitivities, past surgeries, substance abuse, or any other diseases or 
disorders as well as participation in clinical studies (study medication and/or device or other therapy). 
c 
Approximately on Day 4 and approximately at Week 10, subjects will be contacted via telephone to determine the subject’s status and whether the subject is 
experiencing any AEs. Information on concomitant medications will also be collected. 


 
 
 
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d 
Vital signs include temperature, HR, respiratory rate, and BP after resting for at least 5 minutes. Obtain vital signs with subject in the same position; BP and 
HR should be the mean of 3 measurements taken ≥ 5 min apart. BP should be taken via an automated recorder. On Day 1, vital signs will be taken predose 
and at 1 hour postdose. At all other visits, vital signs will be taken predose. 
e 
Any changes in baseline conditions that occur after the ICF is signed are recorded on the medical history eCRF, unless the change is related to a study 
procedure, in which case it is considered an AE. All changes that occur after the administration of the study medication are recorded as AEs. 
f 
At Screening, Day 1, Week 12, and Week 16, a complete physical examination will be conducted including a neurological examination (gross motor and 
deep tendon reflexes), height (Screening only) and weight, and assessment of the following: general appearance, skin, head and neck, mouth, lymph nodes, 
thyroid, abdomen, musculoskeletal, cardiovascular, neurological, and respiratory systems. At all other visits, an abbreviated cardiopulmonary physical 
examination will be conducted, with other systems assessed as directed by interval history. 
g 
A 12-lead ECG (triplicate) will be performed after 10 minutes of rest at Screening and at all study visits. On Day 1, ECG will be performed within 2 hours 
predose and at 1 hour postdose. At all other visits, ECGs will be taken predose.  
h 
Instantaneous peak LVOT gradient (baseline) and provoked peak LVOT gradient (Valsalva maneuver) will be assessed. Ejection fraction (2-dimensional 
and 3-dimensional), LVFS, global longitudinal strain by speckle tracking, and VTI will be analyzed. Resting TTE should be performed prior to 
hemodynamic stress echocardiography or CPET. 
i 
CPET after a 4-hour fast (water is allowed) by standardized treadmill with assessment of LVOT peak gradient. CPET should be conducted prior to dosing 
with study medication. The following will be assessed: VO2, VCO2, VE, VE/VO2, VE/VCO2, and respiratory exchange ratio (RER).  
j 
CPET may be conducted at the Week 12 visit or anytime between Weeks 10 and 12. If CPET and hemodynamic stress echocardiography are conducted at 
the same visit, the hemodynamic stress echocardiography should be conducted first, followed by the CPET. 
k 
Subjects will undergo a standard symptom-limited exercise test. Instantaneous peak LVOT gradient will be assessed immediately post-exercise by TTE. Post 
Screening, hemodynamic stress echocardiography should be conducted prior to dosing with study medication and after a 4 hour fast.  
l 
For participating sites, an optical biosensor may be fastened to the subject’s wrist for several minutes to collect data on pulse wave morphology. This 
assessment is optional and will be conducted only if the subject provides consent. 
m 
The cardiac monitoring adhesive skin patch is to be applied at Screening visit and removed at the Day 1 visit. Additional patches should be applied and 
retrieved at the timepoints shown. Each subject should be trained on applying the patch and should be provided with an additional patch for the subject to 
apply if a patch comes off after less than 14 days. 
n 
At Week 8, the subject should be provided with an additional cardiac monitoring skin patch. At Week 10, the subject is to remove the patch applied at 
Week 8 and mail the patch using a preaddressed, postage-paid envelope. The subject will then apply the additional patch that was supplied at Week 8. 
o 
Collect PK samples ≤ 2 hours prior to dosing. 
p 
FSH testing at Screening for postmenopausal women to confirm postmenopausal status. 
q 
Pregnancy test (serum or urine) for women of childbearing potential, based on standard at institution. 
r 
For subjects who consent, blood will be drawn on Day 1 (predose) for assessment of HCM genotype. 
s 
For subjects who consent, blood sample will be drawn for potential future exploratory pharmacogenetic analysis on Day 1 (predose). 
t 
Blood samples for potential exploratory biomarker analysis predose on Day 1 and Week 12. 
u 
At the end of Week 4, each subject’s dose may be adjusted based on predetermined criteria.  
v 
All subjects will return their IMP dosing containers to the site for tablet counts. Refer to the Pharmacy Manual for details. 


 
 
 
 
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APPENDIX 2 
LABORATORY ASSESSMENTS 
The following safety laboratory parameters will be measured by the central laboratory: 
Hematology 
Serum Chemistry 
Urinalysisa 
CBC, including differential count 
• Sodium 
• Specific gravity 
• Potassium 
• pH 
Platelet count 
• Chloride 
• Protein 
 
• Bicarbonate 
• Glucose 
 
• Calcium 
• Leukocyte esterase 
 
• Magnesium 
• Blood 
 
• BUN 
 
 
• Creatinine 
 
 
• ALP 
 
 
• ALT 
 
 
• AST 
 
 
• Total bilirubin 
 
 
• CPKb 
 
 
• Glucose 
 
 
• Protein 
 
 
• Albumin 
 
ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; BUN, blood urea 
nitrogen; CBC, complete blood count; CPK, creatine phosphokinase. 
w 
Urine microscopy will be performed if there is a significant abnormality in the dipstick. 
x 
If CPK is high, troponin I will be performed and reported. 
 
At the investigator’s discretion, safety laboratory assessments may be repeated on Day -1 to 
confirm study eligibility before dosing of study medication. 
The following non-safety laboratory parameters will be measured at Screening:  
• Hepatitis panel (HVB and HVC) 
• HIV test 
• FSH 
• TSH 
• Testing for alcohol and drugs of abuse 
APPENDIX 3 
POTENTIAL DRUG-INDUCED LIVER INJURY REPORTING 
AND ADDITIONAL ASSESSMENTS REPORTING 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent aspartate 
AST/ALT and TBL elevation according to the criteria specified in Section 7.4 (3 × ULN for 
AST/ALT and 2 × ULN for TBL in subjects with no underlying liver disease and eligibility 
criteria requiring normal liver function at baseline) require the following: 


 
 
 
 
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• The event is to be reported to MyoKardia as an SAE within 24 hours of discovery or 
notification of the event (i.e., before additional etiologic investigations have been 
concluded). 
• The appropriate case report form (CRF) (e.g., Adverse Event CRF) that captures 
information necessary to facilitate the evaluation of treatment-emergent liver 
abnormalities are to be completed and sent to MyoKardia. 
 
Other events of hepatotoxicity and potential DILI are to be reported as SAEs if they meet the 
criteria for an SAE defined in Section 10.1.2. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are withheld 
(either permanently or conditionally) due to potential DILI or who experience AST/ALT 
elevations > 3 × ULN are to undergo a period of “close observation” until abnormalities 
return to normal or to the subject’s baseline levels. Assessments that are to be performed 
during this period include the following:  
• Repeat liver chemistries within 24-48 hours (ALT, AST, ALP, TBL); in cases of TBL 
> 2 × ULN or AST/ALT much greater than 3 × ULN, retesting is to be performed within 
24 hours. 
- 
Subjects are to be monitored at least twice weekly; testing frequency may decrease to 
once per week or less if laboratory abnormalities stabilize or the investigational 
product(s) or protocol-required therapies have been discontinued AND the subject is 
asymptomatic. 
• Obtain prothrombin time/international normalized ratio, fractionated bilirubin, and any 
other potentially relevant laboratory evaluations of liver function or disease. 
• Obtain complete blood count with differential to assess for eosinophilia. 
• Obtain appropriate blood sampling for PK analysis if this has not already been collected. 
• Obtain a more detailed history of the following: 
- 
prior and/or concurrent diseases or illness 
- 
exposure to environmental and/or industrial chemical agents 
- 
symptoms (if applicable) including right upper quadrant pain, hypersensitivity-type 
reactions, fatigue, nausea, vomiting, and fever 
- 
prior and/or concurrent use of alcohol, recreational drugs, and special diets 
- 
concomitant medications (including nonprescription medicines and herbal and dietary 
supplements)  
• Initiate full viral and autoimmune hepatitis evaluation (serologies for hepatitis A, B, C, 
D, E, Epstein-Barr virus, herpes simplex virus, etc.); evaluate for other potential causes of 


 
 
 
 
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DILI, including but not limited to: NASH, hypoxic/ischemic hepatopathy, and biliary 
tract disease. 
• Obtain gastroenterology or hepatology consult. 
• Perform appropriate liver imaging or biopsy if clinically indicated; strongly consider 
these tests in cases of concurrent transaminase and TBL elevation as specified in 
Section 7.4. 
• Follow the subject until all laboratory abnormalities return to baseline or normal. The 
“close observation period” is to continue for a minimum of 4 weeks after investigational 
product(s) or protocol-required therapies discontinuation. 
 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 
APPENDIX 4 
INVESTIGATOR’S SIGNATURE 
I have read and understand the contents of the clinical protocol, MYK-461-004, A Phase 2 
Open-label Pilot Study to Evaluate Efficacy, Pharmacokinetics, Pharmacodynamics, Safety, 
and Tolerability of MYK-461 in Subjects with Symptomatic Hypertrophic Cardiomyopathy 
and Left Ventricular Outflow Tract Obstruction (Pioneer-HCM), and I agree to the 
following: 
• To assume responsibility for the proper conduct of this clinical study at this clinical site 
and to conduct the study in compliance with this protocol, any future amendments and 
with any other study conduct procedures provided by MyoKardia/designee. 
• That I am aware of, and will comply with, the internationally recognized code of Good 
Clinical Practices (GCP) and all other applicable regulatory requirement to obtain written 
and dated approval for the Ethics Committee (e.g., Institutional or Central Review Board 
[IRB] or Independent Ethics Committee [IEC]) for the study protocol, written informed 
consents, consent form updates, study participant recruitment procedures and any other 
written information to be provided to the study participants before initiating this clinical 
study. 
• Not to implement any changes to, or deviations from the protocol without prior 
agreement from MyoKardia and review and documented approval from the EC, except to 
eliminate an immediate hazard to the study participants, or when change(s) involves only 
logistical or administrative aspect of the clinical study. 
• To permit direct monitoring and auditing by MyoKardia or MyoKardia’s representatives 
and inspection by the appropriate regulatory authority(ies). 
• That I am thoroughly familiar with the appropriate use of the Investigational Medicinal 
Product (IMP) and other study medication(s) (if applicable), as described in this protocol, 
and any other information provided by MyoKardia or designee, including, but not limited 


 
 
 
 
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to the current Investigator’s Brochure (IB) or equivalent document and marketed 
prescription information (if applicable). 
• To provide sufficient time and adequate numbers of qualified staff and facilities for the 
foreseen duration of the clinical study to conduct the study properly, ethically and safely. 
• To ensure that all persons assisting in this study are adequately informed about the 
protocol, IMP/study medication(s) and their clinical study-related duties and functions. 
 
 
Signed: ____________________________________ 
Date: ___________________ 
(sign name with credentials) 
Printed Name: ______________________________ 
APPENDIX 5 
INVESTIGATOR’S SIGNATURE AMENDMENT 1 
I have read and understand the contents of the clinical protocol, MYK-461-004 Amendment 
1, A Phase 2 Open-label Pilot Study to Evaluate Efficacy, Pharmacokinetics, 
Pharmacodynamics, Safety, and Tolerability of MYK-461 in Subjects with Symptomatic 
Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction (Pioneer-
HCM), and I agree to the following: 
• To assume responsibility for the proper conduct of this clinical study at this clinical site 
and to conduct the study in compliance with this protocol, any future amendments and 
with any other study conduct procedures provided by MyoKardia/designee. 
• That I am aware of, and will comply with, the internationally recognized code of Good 
Clinical Practices (GCP) and all other applicable regulatory requirement to obtain written 
and dated approval for the Ethics Committee (e.g., Institutional or Central Review Board 
[IRB] or Independent Ethics Committee [IEC]) for the study protocol, written informed 
consents, consent form updates, study participant recruitment procedures and any other 
written information to be provided to the study participants before initiating this clinical 
study. 
• Not to implement any changes to, or deviations from the protocol without prior 
agreement from MyoKardia and review and documented approval from the EC, except to 
eliminate an immediate hazard to the study participants, or when change(s) involves only 
logistical or administrative aspect of the clinical study. 
• To permit direct monitoring and auditing by MyoKardia or MyoKardia’s representatives 
and inspection by the appropriate regulatory authority(ies). 
• That I am thoroughly familiar with the appropriate use of the Investigational Medicinal 
Product (IMP) and other study medication(s) (if applicable), as described in this protocol, 
and any other information provided by MyoKardia or designee, including, but not limited 
to the current Investigator’s Brochure (IB) or equivalent document and marketed 
prescription information (if applicable). 


 
 
 
 
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• To provide sufficient time and adequate numbers of qualified staff and facilities for the 
foreseen duration of the clinical study to conduct the study properly, ethically and safely. 
• To ensure that all persons assisting in this study are adequately informed about the 
protocol, IMP/study medication(s) and their clinical study-related duties and functions. 
 
 
Signed: ____________________________________ 
Date: ___________________ 
(sign name with credentials) 
Printed Name: ______________________________ 
 

SAP_001.pdf: 
 
Confidential 
 
 
 
 
PROTOCOL NUMBER: MYK-461-004 
 
A Phase 2 Open-label Pilot Study to Evaluate Efficacy, Pharmacokinetics, 
Pharmacodynamics, Safety, and Tolerability of MYK-461 in Subjects With 
Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow 
Tract Obstruction (PIONEER-HCM) 
 
24 OCTOBER 2017 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Prepared by: 
 
PPD, Inc. 
929 North Front Street 
Wilmington, NC 28401 
 
 
Issued by: 
____________________________  
 
Date:  _________ 
 
 
Nicole M. Wedick, ScD 
 
 
Biostatistics Team Leader, Biostatistics 
PPD, Inc. 
             
 
Upon review of this document, including table, listing, and figure shells, the undersigned 
approves the statistical analysis plan. The analysis methods and data presentation are acceptable, 
and the table, listing, and figure production can begin. 
 
 
Approved by: ____________________________  
 
Date:  _________ 
 
            ____________________________  
 
Date:  _________ 
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... IV 
1. 
INTRODUCTION ............................................................................................................ 1 
2. 
OBJECTIVES ................................................................................................................... 1 
2.1. PRIMARY OBJECTIVE .......................................................................................................... 1 
2.2. SECONDARY OBJECTIVES ................................................................................................... 1 
2.3. EXPLORATORY OBJECTIVES ............................................................................................... 2 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 2 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 2 
3.2. STUDY ENDPOINTS ............................................................................................................. 5 
3.2.1 
Primary Endpoint........................................................................................................ 5 
3.2.2 
Secondary Endpoints .................................................................................................. 5 
3.2.3 
Exploratory Endpoints ................................................................................................ 5 
3.2.4 
Safety Endpoints.......................................................................................................... 5 
3.3. TREATMENTS ...................................................................................................................... 6 
3.4. DOSE ADJUSTMENT/MODIFICATIONS ................................................................................. 6 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 6 
4.1. SAMPLE SIZE ...................................................................................................................... 7 
4.2. RANDOMIZATION, STRATIFICATION, AND BLINDING .......................................................... 8 
4.3. ANALYSIS SET .................................................................................................................... 8 
4.3.1. 
All Enrolled ................................................................................................................. 8 
4.3.2. 
Efficacy Analysis Population ...................................................................................... 8 
4.3.3. 
Safety Analysis Population ......................................................................................... 8 
4.3.4. 
Pharmacokinetic (PK) Analysis Population ............................................................... 8 
4.3.5. 
PK/ECG Analysis Population ..................................................................................... 8 
5. 
SUBJECT DISPOSITION ............................................................................................... 8 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................... 9 
6.1. DEMOGRAPHICS .................................................................................................................. 9 
6.2. MEDICAL HISTORY ............................................................................................................. 9 
6.3. INCLUSION AND EXCLUSION CRITERIA ............................................................................... 9 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 10 
7.1. PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 10 
7.1.1. 
Prior Medications ..................................................................................................... 11 
7.1.2. 
Concomitant Medications and Procedures ............................................................... 11 
7.2. STUDY TREATMENTS ........................................................................................................ 11 
7.2.1. 
Extent of Exposure .................................................................................................... 11 
7.2.2. 
Treatment Compliance .............................................................................................. 12 
8. 
EFFICACY ANALYSIS................................................................................................. 12 


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8.1. PRIMARY EFFICACY ENDPOINT ......................................................................................... 12 
8.2. SECONDARY AND EXPLORATORY EFFICACY ENDPOINT ................................................... 13 
9. 
SAFETY ANALYSIS ..................................................................................................... 13 
9.1. ADVERSE EVENTS ............................................................................................................. 13 
9.1.1. 
Incidence of Adverse Events ..................................................................................... 14 
9.1.2. 
Relationship of Adverse Events to Study Drug ......................................................... 14 
9.1.3. 
Severity of Adverse Event.......................................................................................... 15 
9.1.4. 
Serious Adverse Events ............................................................................................. 15 
9.1.5. 
Adverse Events Leading to Treatment Discontinuation............................................ 15 
9.1.6. 
Adverse Events Leading to Study Discontinuation ................................................... 15 
9.1.7. 
Death ......................................................................................................................... 15 
9.2. CLINICAL LABORATORY EVALUATIONS ........................................................................... 16 
9.2.1. 
Hematology ............................................................................................................... 16 
9.2.2. 
Serum Chemistry ....................................................................................................... 16 
9.2.3. 
Urinalysis .................................................................................................................. 16 
9.3. VITAL SIGN MEASUREMENTS ........................................................................................... 17 
9.4. PHYSICAL EXAMINATION ................................................................................................. 17 
9.5. ELECTROCARDIOGRAM ..................................................................................................... 17 
10. 
PHARMACOKINETICS ............................................................................................... 18 
11. 
PK-QTC ANALYSES ..................................................................................................... 18 
12. 
PHARMACOGENOMIC/HCM GENOTYPE ............................................................ 19 
13. 
INTERIM ANALYSIS ................................................................................................... 19 
14. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 19 
14.1.1. 
References .............................................................................................................. 20 
APPENDICES ............................................................................................................................. 21 


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List of Abbreviations 
2D  
2-dimensional 
 
3D  
3-dimensional 
 
AE  
adverse event 
 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST  
aspartate aminotransferase 
BLQ 
Below the limit of quantitation 
 
BMI  
body mass index 
 
BP  
blood pressure 
 
CPET  
cardiopulmonary exercise testing 
CRF  
case report form 
 
CV 
coefficient of variation 
 
DILI  
drug-induced liver injury 
DNA  
deoxyribonucleic acid 
ECHO 
echocardiogram 
EOS 
End of Study 
 
ECG  
Electrocardiogram 
 
HCM  
hypertrophic cardiomyopathy 
HR  
heart rate 
 
HSE 
Hemodynamic stress echocardiography  
IB  
Investigator’s Brochure 
ICH  
International Council for Harmonisation 
IMP 
investigational medicinal product 
KCCQ  
Kansas City Cardiomyopathy Questionnaire 
LME 
linear mixed effects 
LS  
least squares 
 
LVEF  
left ventricular ejection fraction 
LVFS  
left ventricular fractional shortening 
LVOT  
left ventricular outflow tract 
MedDRA  
Medical Dictionary for Regulatory Activities 
MMRM  
mixed effect model with repeated measures 
NRS  
numeric rating scale 
NT-proBNP  
N-terminal pro B-type natriuretic peptide 
NYHA  
New York Heart Association 
OSS  
overall summary score 
PD  
pharmacodynamic(s) 
PK  
pharmacokinetic(s) 
 
PT 
preferred term 
pVO2  
peak oxygen uptake 


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QTc  
corrected QT interval 
QTcB  
QTc Bazett 
 
QTcF  
QTc Fridericia 
 
RR 
respiratory rate 
SAE  
serious adverse event 
SE 
standard error 
SD 
standard deviation 
SOC 
system organ class 
 
TBL  
total bilirubin 
 
TEAE 
treatment-emergent adverse event 
TTE  
transthoracic echocardiography, transthoracic echocardiogram 
VCO2 
carbon dioxide production 
VE  
volume expired 
 
WHO 
World Health Organization 
 
 
 
 
 


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1. Introduction 
 
Hypertrophic cardiomyopathy (HCM), an autosomal dominant genetic disease, is defined 
clinically as unexplained left ventricular (LV) hypertrophy in the absence of known causes such 
as pressure overload, systemic diseases, or infiltrative processes (Gersh et al., 2011). The 
phenotypic hallmark of HCM is myocardial hypercontractility accompanied by reduced LV 
compliance, reflected clinically as reduced ventricular chamber size, often supranormal ejection 
fraction, and diastolic dysfunction. Mutations in cardiac myosin and other sarcomere proteins in 
patients with HCM appear to increase net power generation by the sarcomere (Chuan et al., 
2012; Sommese et al., 2013; Sung et al., 2012), which is consistent with the generally 
hypercontractile state and impaired compliance of the myocardium observed clinically in 
patients with HCM. 
MYK-461 is a first-in-class small molecule allosteric modulator of striated muscle myosin that 
selectively targets cardiac myosin and reversibly inhibits its binding to actin. MYK-461’s profile 
of myosin modulation is predicted to reduce dynamic left ventricular outflow tract (LVOT) 
obstruction in patients with obstructive HCM by reducing systolic hypercontractility and 
dynamic obstruction in the near term, and reducing ventricular hypertrophy with chronic 
treatment. MyoKardia is developing MYK-461 for the treatment of adults with symptomatic 
obstructive HCM to relieve obstruction, improve symptoms, and increase exercise capacity. 
In nonclinical studies, MYK-461 was specific for striated muscle myosin and selective for the 
cardiac isoform (see the MYK-461 Investigator’s Brochure [IB]). Its targeted mechanism of 
action and high degree of specificity were reflected in its pharmacology in vitro and in vivo, as 
well as in the toxicology and safety pharmacology. In a feline model of HCM with LVOT 
obstruction, treatment with MYK-461 reduced contractility and relieved obstruction in an 
exposure-dependent manner (Stern et al., under review). The totality of the pharmacodynamic 
(PD) and tolerability data observed to date can be interpreted as direct or indirect consequences 
of altered cardiac contractility. 
Please refer to the IB for more detailed information on MYK-461. 
2. Objectives 
 
2.1. Primary Objective 
The primary objective of this study is: 
• 
To characterize the effect of 12 weeks of MYK-461 treatment on reducing post-exercise 
peak LVOT gradient in subjects with symptomatic HCM and LVOT obstruction. 
 
2.2. Secondary Objectives 
The secondary objectives of this study are: 


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• 
To assess the proportion of subjects achieving an LVOT gradient response of post-
exercise peak gradient < 30 mm Hg 
• 
To assess the effects of 12 weeks of MYK-461 treatment on dyspnea symptom score, 
peak oxygen uptake (pVO2), and volume expired (VE)/carbon dioxide production 
(VCO2) slope 
• 
To evaluate the pharmacokinetic (PK) of MYK-461 
• 
To evaluate the PD of MYK-461 as assessed by a variety of echocardiographic imaging 
parameters 
• 
To evaluate the safety and tolerability of MYK-461 
• 
To evaluate the posttreatment reversibility of the effects of MYK-461 after 4 weeks of 
washout  
in subjects with symptomatic HCM and LVOT obstruction. 
 
2.3. Exploratory Objectives 
The exploratory objectives of this study are: 
• 
To assess the proportion of subjects achieving an LVOT gradient response of post-
exercise peak gradient < 10 mm Hg 
• 
To assess the effects of 12 weeks of MYK-461 treatment on New York Heart Association 
(NYHA) functional class, N-terminal pro B-type natriuretic peptide (NT-proBNP), and 
the Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score (OSS)  
• 
To assess the effects of MYK-461 treatment on arterial pulse wave morphology assessed 
using an optical biosensor 
• 
To assess the effect of MYK-461 treatment on heart rate (HR) and heart rhythm as 
assessed using a cardiac monitoring skin patch 
 in subjects with symptomatic HCM and LVOT obstruction. 
 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
This is a non-randomized, phase 2 open-label pilot study to evaluate the efficacy, PK, PD, safety, 
and tolerability of MYK-461 in subjects with symptomatic HCM and LVOT obstruction. 
Approximately 20 adult subjects with symptomatic HCM, a resting LVOT gradient ≥ 30 mm Hg, 
and post-exercise peak LVOT gradient ≥ 50 mm Hg will be enrolled. Approximately 10 subjects 
will participate in Part A and approximately 10 subjects will participate in Part B. The study will 
have a 12-week treatment phase and a 4-week washout phase (Figure 1). 


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At Screening, subjects will undergo transthoracic echocardiography (TTE) in the supine or left 
lateral decubitus position. In addition to a standardized complete TTE, both resting instantaneous 
peak LVOT gradient (baseline) and provoked peak LVOT gradient (Valsalva maneuver) will be 
collected. Subjects will then undergo a standard symptom-limited exercise test (hemodynamic 
stress echocardiography). Subjects will be assessed systematically for symptoms of dyspnea 
and/or angina. Instantaneous peak LVOT gradient will be assessed immediately post-exercise by 
TTE. 
On Day 1, resting TTE will be performed, blood samples will be drawn for PK, and subjects will 
have an assessment of pVO2, VE/VCO2, and other variables via cardiopulmonary exercise 
testing (CPET). After CPET, subjects will be dosed with open-label oral MYK-461 at the 
investigational site and will be observed for at least 1 hour after dosing, with assessment of vital 
signs and electrocardiograms (ECGs) at 1 hour postdose. Subjects will then be supplied with 
MYK-461 sufficient for once daily (QD) dosing at home. 
Subjects will be evaluated at the investigational site at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, and 16. At 
each of these visits, resting TTE will be performed and blood samples will be drawn for PK. On 
study visit days, study medication will be administered at the investigational site in order to 
collect blood samples for PK ≤ 2 hours prior to dosing. At Weeks 4, 12, and 16, hemodynamic 
stress echocardiography will be performed and peak LVOT gradient will be assessed. CPET will 
be conducted between Weeks 10 and 12 (inclusive).  
 
 


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Part A: 
The MYK-461 starting dose will be 10 mg for subjects who weigh ≤ 60 kg and 15 mg for 
subjects who weigh > 60 kg. At the end of Week 4 (Day 28), each subject’s left ventricular 
ejection fraction (LVEF) will be evaluated, and the subject’s dose may be increased, decreased, 
or remain unchanged based on the predetermined criteria in Table 1, in consultation between the 
investigator and the medical monitor. If MYK-461 plasma concentration exceeds 750 ng/mL at 
Week 2, no dose increase is allowed, regardless of LVEF data at Week 4; however, dose 
decrease per LVEF data is allowed in this circumstance. The subject will subsequently receive 
that dose from Week 5 through Week 12. 
 
 
Part B: 
The MYK-461 starting dose will be 2 mg. At the end of Week 4 (Day 28), each subject’s resting 
(non-provoked) peak instantaneous LVOT gradient and LVEF from the Week 4 TTE will be 
evaluated. The subject’s dose will be increased to 5 mg or remain unchanged based on the 
predetermined criteria in Table 2 below, in consultation between the investigator and the medical 
monitor. If MYK-461 plasma concentration exceeds 300 ng/mL at Week 2, no dose increase is 
allowed. The subject will subsequently receive that dose from Week 5 (Day 29) through 
Week 12. 
For all subjects who provide consent, blood will be drawn prior to dosing on Day 1 for 
assessment of HCM genotype and potentially additional deoxyribonucleic acid (DNA) 
sequencing. 
In addition, subjects may consent separately to collection of pharmacogenetic samples that will 
be stored for potential future analysis of genetic biomarkers of efficacy, safety-related, PD, or 
PK parameters as determined by future studies using clinically meaningful endpoints, through 
DNA sequencing or other genetic testing. 
Blood samples will be collected from all subjects prior to dosing on Day 1 and at Week 12 and 
stored for exploratory circulating biomarker analysis, e.g., proteomic analysis related to disease 
activity, metabolic pathways, efficacy measures, or safety measures. 
The expected study duration is approximately 8 months (4 months for recruitment and 4 months 
for study conduct) for Part A and approximately 10 months for Part B (18 months in total). Each 
subject is expected to be in the study no more than 140 days: up to 28 days for screening and up 
to 112 days for study conduct. 
a 


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Table 2: Part B Week 4 Dose Adjustment Criteria 
 
3.2. Study Endpoints 
3.2.1 Primary Endpoint 
 
• 
Change in post-exercise peak LVOT gradient from baseline to Week 12 
3.2.2 Secondary Endpoints 
• 
Proportion of subjects achieving an LVOT gradient response of post-exercise peak 
gradient < 30 mm Hg 
• 
Change in dyspnea symptom score from baseline to Week 12 
• 
Change in pVO2 and VE/VCO2 from baseline to Week 12 
• 
Change from baseline in LVEF 2-dimensional (2D) and 3-dimensional (3D), global 
longitudinal strain, and left ventricular fractional shortening (LVFS) from baseline to 
Week 12 
• 
Change from Week 12 to Week 16 in post-exercise peak LVOT gradient  
• 
Plasma PK profile of MYK-461 treatment 
3.2.3 Exploratory Endpoints 
• 
Proportion of subjects achieving an LVOT gradient response of post-exercise peak 
gradient < 10 mm Hg 
• 
Change in NYHA functional classification from baseline to Week 12 
• 
Change in NT-proBNP from baseline to Week 12 
• 
Change in KCCQ OSS from baseline to Week 12 
• 
Change from baseline in arterial pulse wave morphology assessed using an optical 
biosensor 
• 
Change from baseline in HR and heart rhythm assessed using a cardiac monitoring skin 
patch 
3.2.4 Safety Endpoints 
• 
Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) 
• 
Changes from baseline in laboratory values and vital signs 


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• 
Changes from baseline in ECGs 
3.3. Treatments 
All subjects will receive MYK-461 in an open-label manner. 
Investigational medicinal product (IMP) is defined as MYK-461. Study medication is used 
throughout this protocol to refer to IMP as well as any other protocol-required medications (note 
that for this protocol there are no other required study medications). 
3.4. Dose Adjustment/Modifications 
All subjects in Part A will be assigned to a starting dose of oral MYK-461 based on body weight 
for doses ≥ 10 mg, which they will receive QD for 4 weeks. Subjects in Part B will be assigned a 
starting dose of 2 mg. At the Week 4 visit, dose adjustment may be performed based on the 
predetermined criteria in Section 3.1, Table 1 (Part A) and Table 2 (Part B). The subject will 
subsequently receive that dose from Week 5 (Day 29) through Week 12. 
Subjects with abnormal hepatic laboratory values (e.g., alkaline phosphatase [ALP], aspartate 
aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL], or international 
normalized ratio) or signs/symptoms of hepatitis may meet the criteria for withholding of study 
medication or other protocol-required therapies. Withholding is either permanent or conditional 
depending on the clinical circumstances discussed in the protocol.  
4. General Statistical Considerations 
All statistical analyses and programming of tables, figures, and listings will be performed by 
PPD using the SAS® Version 9.2 or higher (SAS Institute Inc., Cary, North Carolina, USA). 
Unless otherwise specified, all tables will be presented with the columns labeled with the 
combination of ‘initial dose’/’adjusted dose’.   
Descriptive summaries will consist of the number and percentage of subjects in each category for 
discrete variables, and the sample size, mean, median, standard deviation (STDEV), first and 
third quartiles, minimum and maximum for continuous variables.  For the analysis of primary 
endpoint using a mixed-effect model with repeated measures (MMRM), LS mean with standard 
error (SE) will also be provided. Standard error formatting should be presented to 4 more 
decimal places than the measured value.  
P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be presented as 
‘< 0.0001’ and p-values that round to 1.000 will be presented as ‘> 0.9999’. Confidence intervals 
(CIs) will be estimated based on the MMRM for the analysis of the primary endpoint, a two-
sided 90% significance level. 
All mean and quartile values will be formatted to one more decimal place than the measured 
value. Standard deviation values will be formatted to 2 more decimal places than the measured 
value. All percentages will be rounded to 1 decimal point. The number and percentage of 
responses will be presented in the form XX (XX.X), where the percentage is in the parentheses. 
All analysis and summary tables will have the analysis population sample size (i.e., number of 
subjects) in the column heading. All listings will be sorted for presentation in order of study site, 
subject identification and date of procedure or event. 


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The day of the first dose of study drug will be defined as Day 1.  
Baseline value will be defined as the last non-missing value in date/time before the first dose of 
study drug is administered.  
Missing data handling will be described in Section 7, 8, 9 and 10.  
All laboratory data will be reported using International System of Units (SI).  
The planned analysis visit window for weekly visits will consider +/- 3 days of the scheduled 
visit date based on the date of first exposure to the study drug. For a missed visit, the evaluation 
will be rescheduled as close as possible to the original planned visit, thus analysis windows have 
been designed to be all-inclusive. If more than one result is available for a particular visit 
window and results are equidistant from the analysis target date, the later result will be selected 
to break the tie. The associated visit window with corresponding visit is tabulated below. 
Visit 
Scheduled Visit Day 
 Visit Window 
Day 1 
Day 1 
[1, 4] 
Week 1 
Day 8 
[5, 11] 
Week 2 
Day 15 
[12, 18] 
Week 3 
Day 22 
[19, 25] 
Week 4 
Day 29 
[26, 32] 
Week 5 
Day 36 
[33, 39] 
Week 6 
Day 43 
[40, 46] 
Week 7 
Day 50 
[47, 53] 
Week 8 
Day 57 
[54, 64] 
Week 10* 
Day 71 
[65, 78] 
Week 12* 
Day 85 
[79, 99] 
Week 16 
Day 113 
[100, 116] 
*CPET may be conducted between study visits 10 and 12, therefore the planned analysis window ranges from 
Day 65 to Day 99 with Day 85 set to the scheduled visit day.  Note: The window is adjusted for visit 12; visit 10 will 
not be presented. 
For any subjects who discontinued treatment prior to Week 4 dose adjustment, the subjects will 
not be presented in the treatment columns (initial dose/adjusted dose), however will be presented 
in the total column in the table. 
If the “seconds” portion of the date/time variable is missing or not collected, it will be imputed as 
“:00”, as needed.   
 
4.1. Sample Size 
Approximately 10 subjects will be dosed in Part A and in Part B. The sample size is based on 
practical considerations and is consistent with this type of study. Ten subjects per group receiving 
MYK-461 will provide 80% power to detect a 30 mm Hg within-group change from baseline in post-
exercise peak LVOT gradient and a > 99% power to detect a 50 mm Hg change (Table 3). This 
assumes a 1-sided α = 0.05 and a common standard deviation of 35 mm Hg. The common standard 


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deviation of 35 mm Hg is based on observed data in patients with HCM and provocable LVOT 
(Nistri et al., 2012).  
 
4.2. Randomization, Stratification, and Blinding 
Subjects will not be randomized to treatment in this study, and treatment will not be blinded. 
4.3. Analysis Set 
4.3.1. 
All Enrolled 
The All Enrolled Population includes every subject who signed informed consent. Subjects in the 
all enrolled population will be analyzed according to the planned dose combination. 
4.3.2. 
Efficacy Analysis Population 
The Efficacy Analysis Population is defined as all subjects who receive at least 1 dose of MYK-
461 and have primary or secondary endpoint data, including a baseline value and at least one 
post baseline value. All efficacy analyses will be performed on the Efficacy Analysis Population. 
Subjects in the efficacy population will be analyzed according to the planned dose combination.  
4.3.3. 
Safety Analysis Population 
The Safety Analysis Population is defined as all subjects who receive at least 1 dose of MYK-
461. Safety analyses will be performed on the Safety Analysis population. Subjects in the safety 
population will be analyzed according to the actual dose combination.  
4.3.4. 
Pharmacokinetic (PK) Analysis Population 
The PK Analysis Population is defined as all subjects who received at least 1 dose of MYK-461 
and have at least one detectable PK concentration. PK analyses will be performed on the PK 
Analysis Population. 
4.3.5. 
PK/ECG Analysis Population 
The PK/ECG Analysis Population is defined as all subjects who received at least 1 dose of 
MYK-461 and have detectable PK concentration and ECG data pre-dose.  
 
5. Subject Disposition 
Subject disposition will be summarized for the all enrolled population. A disposition of subjects 
includes the number and percentage of subjects for the following categories: subjects who were 
enrolled, subjects who failed screening, subjects who completed the study, subjects who 
discontinued from the study, will be summarized.  Besides, number of subjects in safety set, 


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efficacy set, PK set and in PK/ECG set will be summarized as well. All percentages will be 
based on the number of subjects enrolled. 
 
The reasons for study discontinuation will also be summarized in this table. The reason for study 
discontinuation includes the following: adverse event, death, lost to follow-up, non-compliance 
with study procedures/restrictions, pregnancy, study terminated by sponsor, withdrawal by 
subject and other. 
 
Subject disposition data will be presented in a listing.  
 
All protocol deviations, extracted from the clinical trial management system, will be presented in 
a listing. Significant protocol deviations will be further subset in a separate listing.  
 
6. Demographics and Baseline Characteristics 
6.1. Demographics 
A summary of demographics and baseline information will be presented. The demographic 
characteristics consist of age (years), sex, race, and ethnicity. The baseline characteristics consist 
of baseline height (cm), baseline weight (kg), and baseline body mass index (BMI) (kg/m^2). 
Age is calculated as (date of informed consent – date of birth)/365.25.  
 
Age (years), baseline height (cm), baseline weight (kg), and baseline BMI (kg/m^2) will be 
summarized using descriptive statistics. The number and percentage of subjects by age category 
(<=65, >65), sex (Male, Female), BMI category (<25.0, 25.0-29.9, ≥30.0 kg/m^2), race (White, 
Black or African American, Asian, American Indian or Alaska Native, Native Hawaiian or Other 
Pacific Islander, and Other) and ethnicity (Hispanic or Latino, Not Hispanic or Latino), will also 
be reported. Percentages will be based on the total number of subjects in the enrolled set. In 
addition, reproductive status and Pregnancy test will be also summarized. 
 
Subject demographic and baseline characteristics will be presented in a listing. 
 
6.2. Medical History 
 
Medical History will be mapped to system organ classes (SOCs) and preferred terms (PTs) using 
the Medical Dictionary for Regulatory Activities (MedDRA Version 19 or higher).  The number 
and percentage of subjects with any medical history will be summarized overall and by 
decreasing frequency of MedDRA SOC. Within each SOC, PT will be sorted by alphabetical 
order. Percentages will be calculated based on number of subjects in the safety population.  
 
Subject medical history data including specific details will be presented in a listing. 
 
6.3. Inclusion and Exclusion Criteria 
 


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Subjects who failed inclusion and exclusion criteria will be presented in a listing.  
 
7. Treatments and Medications 
7.1. Prior and Concomitant Medications 
 
All medications used within 30 days prior to the date of informed consent through the end of 
study (EOS) will be collected on the case report form (CRF). All medications will be coded 
according to the World Health Organization drug dictionary (WHODRUG June 2016 or later). 
 
A prior medication is defined as any medication that is taken within 30 days prior to the first 
dose of study drug. A concomitant medication is defined as any medication that has a stop date 
that is on or after the date of first dose of study drug. 
 
For the purpose of inclusion in prior and/or concomitant medication tables, incomplete 
medication start and stop dates will be imputed as follows: 
Missing start dates (where UK, UKN and UNKN indicate unknown or missing day, month and 
year respectively):  
 UK-MMM-YYYY: If the month and year are different from the month and year of the first 
dose of study drug, assume 01-MMM-YYYY. If the month and year are the same as the 
first dose of study drug month and year and the end date (after any imputation) is on or 
after the first dose of study drug, then assume the date of the first dose of study drug. If the 
month and year are the same as the first dose of study drug month and year and the end 
date (after any imputation) is prior to the first dose of study drug, then assume the end date 
for the start date; 
 DD-UKN-YYYY/UK-UKN-YYYY: If the year is different from the year of the first dose 
of study drug, assume 01-JAN-YYYY of the collected year. If the year is the same as the 
first dose of study drug year and the end date (after any imputation) is on or after the first 
dose of study drug, then assume the date of the first dose of study drug. If the year is the 
same as the first dose of study drug and the end date (after any imputation) is prior to the 
first dose of study drug, then assume the end date for the start date. 
 
Missing stop dates (where UK, UKN and UNKN indicate unknown or missing day, month and 
year respectively):  
 UK-MMM-YYYY: Assume the last day of the month; 
 DD-UKN-YYYY/UK-UKN-YYYY: Assume 31-DEC-YYYY. 
 
If start date is completely missing and end date is not prior to the first dose, then the medication 
will be classified as both prior and concomitant. If the start date is completely missing and the 
end date is prior to the first dose of study drug, then the medication will be classified as prior. If 
the end date is missing, then the medication will be classified as ongoing. Medications for which 
the start and end dates are missing will be classified as prior and concomitant. 
 


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7.1.1. 
Prior Medications 
The total number of prior medications and the number and percentages of subjects with at least 
one prior medication will be summarized by preferred term and by alphabetical order. All 
summaries will be performed using the safety set. 
 
7.1.2. 
Concomitant Medications and Procedures 
The total number of concomitant medications and the number and percentages of subjects with at 
least one concomitant medication will be summarized and presented by preferred term and will 
be sorted in alphabetical order. All summaries will be performed using the safety set. 
 
Concomitant procedures will be mapped to SOCs and PTs using the MedDRA Version 19 or 
later and will be presented in a listing. 
 
7.2. Study Treatments 
Study medication will consist of MYK-461 immediate-release oral tablets, 2mg, 5mg, 10mg, and 
20mg. All subjects in Part A will be assigned to a starting dose of oral MYK-461 based on body 
weight for doses ≥ 10 mg. Subjects who weigh ≤ 60 kg will start at 10 mg and subjects who weigh 
> 60 kg will start at 15 mg. Subjects in Part B will be assigned a starting dose of 2 mg. Each subject 
will receive oral MYK-461 at their determined starting dose QD beginning on Day 1 and 
continuing through Week 4. At Week 4, and individual subject’s daily dose may be adjusted 
based on predetermined criteria. The subject will subsequently receive that dose from Week 5 
through Week 12. 
7.2.1. 
Extent of Exposure 
Duration of treatment (days) is defined as the total number of days a subject is exposed to any 
study drug and will be presented as the total number of days from the first dose date (Day 1) to 
the last dose date (date of last dose minus the date of first dose + 1) as recorded on the Study 
Completion/Termination page on the CRF. If the last dose date on the Study 
Completion/Termination page is missing, or if a subject is lost to follow-up, but the study drug 
exposure at investigation site form confirms that the subject has taken study drug at a visit, the 
latest date of the exposure at investigation site on the CRF will be used.  
 
Because study drug reduction may occur during the study, the exposure to study drug will also 
be characterized by cumulative dose (mg), which is defined as the cumulative number of dose 
taken by subjects.  
 
The duration of treatment to study drug will be summarized for all subjects in the Safety set and 
will be presented in a table by summary statistics. The duration of treatment will then be 
classified into the following categories: > 0 week, ≥ 2 weeks, ≥ 4 weeks, ≥ 6 weeks, ≥ 8 weeks, ≥ 
10 weeks, and ≥ 12 weeks and will be presented as the number and percentage of subjects in 
each duration category. Percentages will be computed from the number of subjects in the Safety 
set.  
 


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The total cumulative dose (mg) will be defined as the sum of the actual dose taken across all 
study days. Average daily dose is cumulative dose divided by total days on study drug. The 
average daily dose and cumulative dose will be summarized by descriptive summary statistics.  
 
A summary of each subject’s exposure will be presented in a listing.  
 
7.2.2. 
Treatment Compliance  
Study drug compliance will be calculated for each subject by taking into account whether a 
subject takes all doses of study drug as instructed. The number of tablets taken will be calculated 
by subtracting the number of tablets returned from the number of tablets dispensed.  
 
The overall study drug compliance (%) will be calculated by dividing the actual cumulative dose 
taken at all visits by the planned cumulative dose prescribed for all visits and then multiplying by 
100. The overall study drug compliance will be summarized.  
 
Summary statistics on percentage of treatment compliance as well as the number and percentage 
of subjects in each compliance category (<75%, 75-85%, and greater than 85% compliant) will 
be presented overall. Percentages will be calculated out of the number of subjects who were 
dosed in the Safety set. A subject is considered compliant if overall study drug compliance is 
greater than or equal to 80%. 
 
8. Efficacy Analysis 
 
All efficacy analyses will be performed on the Efficacy Analysis Population. 
8.1. Primary Efficacy Endpoint 
 
The primary efficacy endpoint is the change from baseline to Week 12 in post-exercise peak 
LVOT gradient. Baseline is defined as the last non-missing measurement of post-exercise LVOT 
gradient prior to the first dose. Post-exercise peak LVOT gradient will be analyzed using a 
mixed-effect model with repeated measures (MMRM). All data available from baseline 
(Screening) to Week 16 (EOS) will be included and missing data will be accounted for by the 
MMRM model. The model will include the fixed categorical effects of timepoint: baseline, 
Week 4, Week 12 (end of treatment), and Week 16 (EOS). An unstructured covariance structure 
will be assumed unless model diagnostics suggest otherwise. 
 
This model will provide least-squares (LS) mean estimates with their corresponding standard 
errors at each time point. Comparison between baseline and Week 12 (end of treatment) will be 
based on the LS mean difference obtained from the MMRM, and will be presented with its 
associated two-sided 90% confidence interval. Statistical significance of the difference versus 
baseline will be evaluated at the two-sided 0.10 level. The primary efficacy endpoint will also be 
descriptively summarized by each timepoint.  
 


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8.2. Secondary and Exploratory Efficacy Endpoint 
 
The proportion of subjects achieving LVOT gradient responses of < 30 mm Hg and < 10 mm Hg 
will be summarized at each post-baseline visit as well as across all post-baseline visits. In case of 
missing data at a given visit, it will be assumed that the subject had not achieved an LVOT 
gradient response.   
 
Figures presenting mean +/- SE of resting, post-exercise and provoked LVOT gradient by 
timepoint will be included in the analyses. 
 
Quantitative endpoints, including the Dyspnea numeric rating scale (NRS), pVO2, VE/CO2, 
LVEF, NYHA functional classification, NT-proBNP, and KCCQ OSS will be analyzed using the 
same MMRM model as for the primary efficacy endpoint. The list of timepoints included in the 
MMRM will be adjusted according to the visits at which each endpoint will be measured. All 
efficacy endpoint will also be descriptively summarized by each timepoint.  
 
Change from baseline in heart rate and heart rhythm using a cardiac monitoring skin patch will 
be analyzed descriptively. Resting echocardiogram (ECHO) and hemodynamic stress 
echocardiography (HSE) parameters will be presented in a listing. 
 
9. Safety Analysis 
All safety analyses will be performed on the Safety Analysis population. 
 
9.1. Adverse Events 
 
AEs will be mapped to SOCs and PTs using the MedDRA Version 19 or later. AEs will be 
monitored during the study and the data analyzed with respect to overall incidence as well as 
severity and potential relationship of AEs to study medication.  
 
A treatment-emergent AE (TEAE) is defined as an AE that meets any of the following 
conditions: 
 begins on or after the first dose of study drug and before the stop of study drug + 28 days; 
 begins before the first dose of study drug and worsens in severity on or after the first dose of 
study drug and before the stop of study drug + 28 days; 
 is completely missing an onset date and end date; 
 is completely missing an onset date and the end date is on or after the first dose of study 
drug. 
 
For the purpose of inclusion in TEAE tables, incomplete AE onset and end dates will be imputed 
as follows: 
Missing onset dates (where UK and UKN indicate unknown or missing day and month 
respectively):  


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 
UK-MMM-YYYY: If the month and year are different from the month and year of the 
first dose of study drug, assume 01-MMM-YYYY. If the month and year are the same as 
the first dose of study drug month and year, and the end date (after any imputation) is on 
or after the first dose of study drug, then assume the date of the first dose of study drug. If 
the month and year are the same as the first dose of study drug month, and year and the 
end date (after any imputation) is prior to the first dose of study drug, then assume the 
end date for the onset date.  
 
DD-UKN-YYYY/UK-UKN-YYYY: If the year is different from the year of first dose of 
study drug, assume 01-JAN-YYYY of the collected year. If the year is the same as the 
first dose of study drug year, and the end date (after any imputation) is on or after the first 
dose of study drug, then assume the date of the first dose of study drug. If the year is the 
same as the first dose of study drug, and the end date (after any imputation) is prior to the 
first dose of study drug, then assume the end date for the onset date.  
 
Missing end dates (where UK and UKN indicate unknown or missing day and month 
respectively):  
 UK-MMM-YYYY: Assume the last day of the month; 
 DD-UKN-YYYY/UK-UKN-YYYY: Assume 31-DEC-YYYY. 
 
An overview summary of the number and percentage of subjects with any TEAE, serious TEAE, 
study drug-related TEAE, study drug-related serious TEAE, TEAE leading to treatment 
discontinuation, TEAE leading to study termination, TEAE leading to treatment interruption and 
AE leading to death will be provided. 
 
9.1.1. 
Incidence of Adverse Events 
 
Summaries of the total number of TEAEs and the number and percentage of subjects with at 
least one TEAE will be provided. Treatment-emergent AEs will be presented by SOC and PT. At 
each level of subject summarization, a subject is counted once if the subject reported one or more 
events. Percentages will be calculated out of the number of subjects in the Safety set.  
 
A summary of TEAEs will also be presented in descending order from the SOC with the highest 
total incidence (that is, summed across all treatment groups) to the SOC with the lowest total 
incidence. If the total incidence for any two or more SOCs is equal, the SOCs will be presented 
in alphabetical order. Within each SOC, the PTs will be presented in alphabetical order.  
 
All AEs will be presented in a listing. 
 
9.1.2. 
Relationship of Adverse Events to Study Drug 
A summary of TEAEs by relationship to study drug will be presented in a table by incidence of 
occurrence. The investigator will provide an assessment of the relationship of the event to the 
study drug. The possible relationships are “Not Related”, “Unlikely”, “Possible”, “Probable”, 
and “Definite”. In the TEAE relationship table, if a subject reports multiple occurrences of the 


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same TEAE, only the most closely related occurrence will be presented. Treatment –emergent 
AEs that are missing a relationship will be presented in the summary table as “Definite” but will 
be presented in the data listing with a missing relationship or the actual relationship respectively. 
Percentages will be calculated out of the number of subjects in the Safety set. 
 
The TEAE data will be categorized and presented by SOC, PT, and relationship in a manner 
similar to that described in Section 9.1.1. 
 
9.1.3. 
Severity of Adverse Event 
A summary of TEAEs by severity will be presented in a table. The severity that will be presented 
represents the most extreme severity captured on the CRF page. The possible severities are 
“Mild,” “Moderate,” and “Severe.”  In the TEAE severity table, if a subject reported multiple 
occurrences of the same TEAE, only the most severe will be presented. Treatment-emergent AEs 
that are missing severity will be presented in tables as “Severe” but will be presented in the data 
listing with a missing severity. Percentages will be calculated out of the number of subjects in 
the Safety set. 
 
The TEAE data will be categorized and presented by SOC, PT, and severity in a manner similar 
to that described in Section 9.1.1. 
 
9.1.4. 
Serious Adverse Events 
The seriousness of an AE should be assessed by the Investigator independently from the severity 
of the AE. A serious AE (SAE) is defined as any untoward medical occurrence that at any dose 
results in death, is life-threatening, is a congenital anomaly/birth defect, requires in-patient 
hospitalization or prolongation, or results in significant disability/incapacity. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
 
All SAEs will be summarized by MedDRA SOC and PT in a table. 
9.1.5. 
Adverse Events Leading to Treatment Discontinuation 
All TEAEs with a study drug action taken of “Drug Withdrawn” will be presented in a data 
listing.  
9.1.6. 
Adverse Events Leading to Study Discontinuation 
A summary of TEAEs where the answer to “Caused Study Discontinuation” is “Yes” will be 
presented in a data listing.  
9.1.7. 
Death 
All subjects who have an AE with an outcome of “Death Related to Adverse Event” will be 
presented in a listing.  


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9.2. Clinical Laboratory Evaluations 
 
Safety laboratory data including hematology, chemistry, and urinalysis will be evaluated by visit 
for the Safety Analysis Population using descriptive statistics.  
 
Laboratory assessments will be performed by a PPD central laboratory.  All summaries will be 
based on the standard units provided by the central laboratory, no conversions will be attempted.  
Drug-induced liver injury (DILI) will be identified, according to the criteria in the protocol 
Section 7.4, and summarized.  Subjects who met each of the DILI criteria, TBL > 2 X ULN or   
> 3 X ULN for AST/ALT with baseline < ULN will be summarized descriptively.  
 
9.2.1. 
Hematology 
The following laboratory tests will be included: red blood cell count (RBC), hemoglobin, 
hematocrit (HCT), platelet count, mean corpuscular hemoglobin (MCH), mean corpuscular 
hemoglobin concentration (MCHC), mean corpuscular volume (MCV), red blood cell 
distribution width (RDW), WBC count, total neutrophils, lymphocytes, monocytes, eosinophils, 
and basophils. 
 
Baseline values and change from baseline at each scheduled post-baseline timepoint will be 
descriptively summarized.  All hematology data by subject will be presented in a listing, with the 
measurements outside of the reference range flagged. 
 
For the schedule of hematology laboratory tests, please refer to Appendix 1. 
 
9.2.2. 
Serum Chemistry 
The following laboratory tests will be included: blood urea nitrogen (BUN), calcium, creatinine, 
sodium, potassium, chloride, magnesium, bicarbonate, protein, albumin, bilirubin (TBL), 
alkaline phosphatase (ALP), aspartate aminotransferase (AST), creatinine phosphokinase (CPK), 
and alanine aminotransferase (ALT).  
 
Baseline values and change from baseline at each scheduled post-baseline timepoint will be 
descriptively summarized. All chemistry data by subject will be presented in a listing, with the 
measurements outside of the reference range flagged. 
 
For the schedule of serum chemistry laboratory tests, please refer to Appendix 1. 
 
9.2.3. 
Urinalysis 
The following laboratory tests will be included: specific gravity, pH, protein, glucose, leukocyte 
esterase, and blood.  
 
Baseline values and change from baseline at each scheduled post-baseline timepoint will be 
descriptively summarized. All urinalysis data by subject will be presented in a listing. 
 


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For the schedule of urinalysis laboratory tests, please refer to Appendix 1. 
 
9.3. Vital Sign Measurements 
 
Vital signs, to be assessed at each study visit, include temperature, HR, respiratory rate, and 
blood pressure (BP) after resting for at least 5 minutes. Vital signs will be obtained with the 
subject in the same position; BP and HR should be the mean of 3 measurements taken ≥ 5 
minutes apart. BP should be taken via an automated recorder. 
 
On Day 1 of dosing, vital signs will be taken predose and at 1 hour postdose. At all other visits, 
vital signs will be taken prior to dosing.  
 
Summary tables presenting observed values and changes from baseline will be presented for vital 
sign data, including systolic BP (mmHg), diastolic BP (mmHg), temperature (C), pulse (bpm), 
and respiration (breaths/minute) for subjects in the Safety set.  
 
Changes from baseline at each scheduled post-baseline visit will be presented. All vital sign data 
by subject will be presented in a listing. 
 
9.4. Physical Examination 
At Screening, Day 1, Week 12, and Week 16, a complete physical examination will be 
conducted including a neurological examination (gross motor and deep tendon reflexes), height 
(Screening only) and weight, and assessment of the following: general appearance, skin, head 
and neck, mouth, lymph nodes, thyroid, abdomen, musculoskeletal, cardiovascular, neurological, 
and respiratory systems. At all other visits, an abbreviated cardiopulmonary physical 
examination will be conducted, with other systems assessed as directed by interval history. 
 
Physical examination results will be presented in a listing. 
 
9.5. Electrocardiogram 
 
Triplicate ECG recordings will be obtained at each scheduled timepoint and the average of the 
three readings will be used to determine ECG intervals, including QRS, heart rate, PR, QT, 
Corrected QT interval using Fridericia’s formula (QTcF), Corrected QT interval using Bazett’s 
formula (QTcB) and RR. Missing ECG data will not be imputed. If one or two replicates are 
missing, the average will be calculated on the available replicates. 
 
ECG Numeric Variables 
HR, PR, QRS, QT, QTcF, QTcB, and RR will be summarized using descriptive statistics. The 
change from baseline of these ECG parameters at each timepoint will be listed for each subject. 
For each timepoint of measurement, the changes from baseline will be summarized using 
descriptive statistics. 
 


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MYK-461-004 
                                               Date Issued: 24 OCTOBER 2017 
 
  
Confidential 
 
 
 
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Categorical Analysis 
The cumulative incidence count and percentage of subjects with any postdose QTcF values of > 
450 msec, > 480 msec, and > 500 msec will be tabulated for all subjects. Subjects will be listed 
with corresponding baseline values, ∆QTcF, and baseline and treatment HR. The cumulative 
incidence count and percentage of subjects with ∆QTcF increase of > 30 msec and > 60 msec 
will be tabulated. Also subjects with QTcB/QTcF >480 ms and/or change from baseline in 
QTcB/QTcF >60 ms will also be listed in a separate listing. 
 
Morphology Findings 
New ECG morphologies for each subject not present on any ECG at baseline for that subject will 
be summarized for all observation timepoints combined. 
 
The number and percentage of subjects having new morphology changes from baseline will be 
reported, and summarized as QTc Prolongation, ST depression, ST elevation, T-waves biphasic, 
T-waves flat, T-wave inversion, or U-wave abnormality.  
 
ECG overall interpretation by visit will be presented in a listing. 
 
For the schedule of ECG test, please refer to Appendix 1. 
 
10. Pharmacokinetics 
Blood samples for plasma PK analysis of MYK-461 will be collected within 2 hours prior to 
dosing at the following timepoints: Day 1, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, 
Week 7, Week 8, Week12 and Week 16 or End of Study (End of Treatment + 4 Week) for Part A 
and Part B. 
 
Concentrations that are BLQ will be treated as zero for descriptive statistics. All missing 
concentrations will be treated as missing for descriptive statistics.  
 
Plasma concentration data of MYK-461 will be listed by subject and summarized by MYK-461 
dose level and nominal time point using descriptive statistics (number of subjects (n), arithmetic 
mean, standard deviation (SD), coefficient of variation (CV%), geometric mean, geometric 
CV%, median, minimum, and maximum).  
 
Arithmetic mean plasma concentration data of MYK-461 versus nominal time (days) will be 
plotted by MYK-461 dose level on linear and semi-logarithmic scales. Individual plasma 
concentration data of MYK-461 versus actual times will also be presented on linear and semi-
logarithmic scales. Overlay plot of individual plasma concentration data of MYK-461 versus 
actual times will also be presented on linear and semi-logarithmic scales.  
 
11. PK-QTc Analyses 
A concentration-QTc regression analysis, based on data collected from the ECG recordings after 
drug administration and MYK-461 concentration values for each subject at each matching 
timepoint will be performed.  A linear mixed effects (LME) model will be fitted on change from 


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                                         Statistical Analysis Plan, Version 2.0 
MYK-461-004 
                                               Date Issued: 24 OCTOBER 2017 
 
  
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baseline QTcF, with baseline QTcF, MYK-461 concentration as an independent variable and 
subject as a random effect. Baseline QTcF is defined as the average of the last assessment prior 
to start of study treatment. A corresponding scatter plot will be provided. The analyses will be 
performed on PK/ECG set.  
 
12.  Pharmacogenomic/HCM Genotype 
For all subjects who provide consent, blood will be drawn on prior to dosing Day 1 for 
assessment of HCM genotype and potentially additional deoxyribonucleic acid (DNA) 
sequencing.  
 
In addition, subjects may consent separately to collection of pharmacogenetic samples that will 
be stored for potential future analysis of genetic biomarkers of efficacy, safety-related, PD, or 
PK parameters as determined by future studies using clinically meaningful endpoints, through 
DNA sequencing or other genetic testing.  
 
Data collected for Pharmacogenomic and HCM Genotype will be listed and summarized as 
requested by the sponsor.  
13. Interim Analysis 
There will be an interim analysis for Part A subjects, when the last subject for Part A completes 
the study. The Part A interim analysis will include: demographics, disposition, adverse events, 
drug exposure, vital signs, laboratory evaluations, ECG, PK, primary and secondary efficacy 
endpoints.  
 
14. Changes in the Planned Analysis 
 
 
 


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                                         Statistical Analysis Plan, Version 2.0 
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14.1.1. References 
Chuan P, Sivaramakrishnan S, Ashely EA, Spudich JA. Cell-intrinsic functional effects of the α-
cardiac myosin Arg-403-Gln mutation in familial hypertrophic cardiomyopathy. Biophys J. 
2012;102:2782-2790.  
 
Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA Guideline for the diagnosis and 
treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines. Developed in 
collaboration with the American Association for Thoracic Surgery, American Society of 
Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, 
Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society 
of Thoracic Surgeons. J Am Coll Cardiol. 2011; 58:e212-260. 
 
Nistri S, Olivotto I, Maron MS, et al. β Blockers for prevention of exercise-induced left 
ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy. Am J 
Cardiol. 2012;110:715–719. 
 
Sommese RF, Sung J, Nag S, et al. Molecular consequences of the R453C hypertrophic 
cardiomyopathy mutation on human beta-cardiac myosin motor function. Proc Natl Acad Sci 
USA. 2013;110:12607-12612. 
 
Stern, JA, Markova S, Ueda Y, et al. A small molecule modulator of sarcomere contractility 
relieves left ventricular outflow tract obstruction in feline hypertrophic cardiomyopathy. 
JACC: Basic to Translational Science (under review). 
 
Sung J, Choe E, Elting M, et al. Single molecule studies of recombinant human α- and β-cardiac 
myosin to elucidate molecular mechanism of familial hypertrophic and dilated cardiomyopathies 
[Abstract]. Presented at the 56th Annual Meeting of the Biophysical Society. San Diego, CA, 25-
29 February 2012. Available at: 
http://www.biophysics.org/2012meeting/Abstracts/AbstractCD/tabid/2429/Default.aspx. 


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                                         Statistical Analysis Plan, Version 2.0 
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Appendices 
 


MyoKardia, Inc. 
                                                                                               Statistical Analysis Plan, Version 2.0 
MYK-461-004 
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MyoKardia, Inc. 
                                                                                               Statistical Analysis Plan, Version 2.0 
MYK-461-004 
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Confidential                                               
 
 
23 
 


MyoKardia, Inc. 
                                                                                               Statistical Analysis Plan, Version 2.0 
MYK-461-004 
                                                                                                     Date Issued: 24 OCTOBER 2017 
  
Confidential                                               
 
 
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MyoKardia, Inc.                                                                                      Statistical Analysis Plan, Version 2.0 
MYK-461-004                                                                                               Date Issued: 24 OCTOBER 2017 
  
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Table of Contents 
 
Table 14.1.1.A Disposition Enrolled Set 
 
Table 14.1.1.B Disposition Enrolled Set 
 
Table 14.1.2.A Demographics Safety Set 
 
Table 14.1.2.B Demographics Safety Set 
 
Table 14.1.3.A Medical History Safety Set  
Table 14.1.3.B Medical History Safety Set  
Table 14.1.4.A Prior Medications Safety Set 
Table 14.1.4.B Prior Medications Safety Set 
Table 14.1.5.A Drug Exposure Safety Set 
Table 14.1.5.B Drug Exposure Safety Set 
Table 14.1.6.A Drug Compliance Safety Set 
Table 14.1.6.B Drug Compliance Safety Set 
Table 14.1.7.A Concomitant Medications Safety Set 
Table 14.1.7.B Concomitant Medications Safety Set  
Table 14.2.1.1.A Post-exercise Peak LVOT Gradient (mmHg): Change from Baseline by 
Time Points (MMRM)  Efficacy Set  
Table 14.2.1.1.B Post-exercise Peak LVOT Gradient (mmHg): Change from Baseline by 
Time Points (MMRM)  Efficacy Set  
Table 14.2.1.2.A Resting Peak LVOT Gradient (mmHg): Change from Baseline by Time 
Points (MMRM)  Efficacy Set 
 
Table 14.2.1.2.B Resting Peak LVOT Gradient (mmHg): Change from Baseline by Time 
Points (MMRM)  Efficacy Set 
 
Table 14.2.1.3.A Post-exercise Peak LVOT Gradient (mmHg): Secondary Endpoints  
Efficacy Set 
 
Table 14.2.1.3.B Post-exercise Peak LVOT Gradient (mmHg): Secondary Endpoints  
Efficacy Set 
 
Table 14.2.1.4.A Dyspnea NRS: Change from Baseline by Time Points (MMRM)  
Efficacy Set 
 
Table 14.2.1.4.B Dyspnea NRS: Change from Baseline by Time Points (MMRM)  
Efficacy Set 
 
Table 14.2.1.5.A pVO2 (mL/kg/min): Change from Baseline by Time Points (MMRM)  
Efficacy Set 
 
Table 14.2.1.5.B pVO2 (mL/kg/min): Change from Baseline by Time Points (MMRM)  
Efficacy Set 
 
Table 14.2.1.6.A VE/CO2: Change from Baseline by Time Points (MMRM)  Efficacy Set 
Table 14.2.1.6.B VE/CO2: Change from Baseline by Time Points (MMRM)  Efficacy Set 
Table 14.2.1.7.A LVEF (%): Change from Baseline by Time Points (MMRM)  Efficacy 
Set 
 
Table 14.2.1.7.B LVEF (%): Change from Baseline by Time Points (MMRM)  Efficacy 
Set 
 
Table 14.2.1.8.A LVFS (%): Change from Baseline by Time Points  Efficacy Set  


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Table 14.2.1.8.B LVFS (%): Change from Baseline by Time Points  Efficacy Set  
Table 14.2.1.9.A Global Longitudinal Strain (%): Change from Baseline by Time Points  
Efficacy Set 
 
Table 14.2.1.9.B Global Longitudinal Strain (%): Change from Baseline by Time Points  
Efficacy Set 
 
Table 14.2.1.10.A NYHA Functional Classification: Change from Baseline by Time Points 
(MMRM)  Efficacy Set 
Table 14.2.1.10.B NYHA Functional Classification: Change from Baseline by Time Points 
(MMRM)  Efficacy Set 
Table 14.2.1.11.A NT-proBNP (pg/mL): Change from Baseline by Time Points (MMRM)  
Efficacy Set 
 
Table 14.2.1.11.B NT-proBNP (pg/mL): Change from Baseline by Time Points (MMRM)  
Efficacy Set 
 
Table 14.2.1.12.A KCCQ OSS: Change from Baseline by Time Points (MMRM)  Efficacy 
Set 
 
Table 14.2.1.12.B KCCQ OSS: Change from Baseline by Time Points (MMRM)  Efficacy 
Set 
 
Table 14.2.1.13.A HR and Heart Rhythm (Cardiac Monitoring Skin Patch): Change from 
Baseline by Time Points Efficacy Set 
Table 14.2.1.13.B HR and Heart Rhythm (Cardiac Monitoring Skin Patch): Change from 
Baseline by Time Points Efficacy Set 
Table 14.2.2.1.A Summary of Plasma Concentrations of MYK-461 PK Analysis 
Population 
 
Table 14.2.2.1.B Summary of Plasma Concentrations of MYK-461 PK Analysis 
Population 
 
Table 14.2.2.2.A Summary of Linear Regression Model Results PK-ECG PK/ECG 
Analysis Population  
Table 14.2.2.2.B Summary of Linear Regression Model Results PK-ECG PK/ECG 
Analysis Population  
Table 14.2.2.3 Summary of Linear Regression Model Results PK-ECG – All Subjects 
PK/ECG Analysis Population  
Table 14.3.1.1.A Overall Treatment-Emergent Adverse Events Safety Set  
Table 14.3.1.1.B Overall Treatment-Emergent Adverse Events Safety Set  
Table 14.3.1.2.1.A Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term by Subject Safety Set 
Table 14.3.1.2.2.A Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term by Events Safety Set  
Table 14.3.1.2.1.B Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term by Subject Safety Set 
Table 14.3.1.2.2.B Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term by Events Safety Set  
Table 14.3.1.3.1.A  Treatment-Emergent Adverse Events by Relationship to Study Drug 
by Subject Safety Set  


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Table 14.3.1.3.2.A  Treatment-Emergent Adverse Events by Relationship to Study Drug 
by Events Safety Set  
Table 14.3.1.3.1.B  Treatment-Emergent Adverse Events by Relationship to Study Drug by 
Subject Safety Set 
 
Table 14.3.1.3.2.B  Treatment-Emergent Adverse Events by Relationship to Study Drug by 
Events Safety Set 
 
Table 14.3.1.4.A  Treatment-Emergent Adverse Events by Severity Safety Set 
 
Table 14.3.1.4.B  Treatment-Emergent Adverse Events by Severity Safety Set 
 
Table 14.3.1.5.1.A Serious Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term by Subject Safety Set 
 
Table 14.3.1.5.2.A Serious Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term by Events Safety Set 
 
Table 14.3.1.5.1.B Serious Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term by Subject Safety Set 
 
Table 14.3.1.5.2.B Serious Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term by Events Safety Set 
 
Table 14.3.4.1.A Change from Baseline in Hematology Safety Set  
Table 14.3.4.1.B Change from Baseline in Hematology Safety Set  
Table 14.3.4.2.A Change from Baseline in Serum Chemistry Safety Set 
Table 14.3.4.2.B Change from Baseline in Serum Chemistry Safety Set 
 
Table 14.3.4.3.A Summary of Drug-induced Liver Injury Safety Set 
 
Table 14.3.4.3.B Summary of Drug-induced Liver Injury Safety Set 
 
Table 14.3.4.4.A Change from Baseline in Urinalysis Safety Set 
 
Table 14.3.4.4.B Change from Baseline in Urinalysis Safety Set 
 
Table 14.3.5.1.A Change from Baseline in Electrocardiogram Results (ERT) Safety Set  
Table 14.3.5.1.B Change from Baseline in Electrocardiogram Results (ERT) Safety Set 
 
Table 14.3.5.2.A Summary of QTcF Intervals Safety Set 
 
Table 14.3.5.2.B Summary of QTcF Intervals Safety Set 
 
Table 14.3.5.3.A Summary of New ECG morphologies Safety Set  
Table 14.3.5.3.B Summary of New ECG morphologies Safety Set  
Table 14.3.5.4.A Change from Baseline in Electrocardiogram Results (HBPRI) Safety Set
 
 
Table 14.3.5.4.B Change from Baseline in Electrocardiogram Results (HBPRI) Safety Set 
Table 14.3.6.A Change from Baseline in Vital Signs Safety Set 
 
Table 14.3.6.B Change from Baseline in Vital Signs Safety Set 
 
Table 14.3.7 HCM Genotype  
Listing 16.1.1.A Visit Schedule Safety Set  
Listing 16.1.1.B Visit Schedule Safety Set 
 
Listing 16.2.1.A Subject Disposition Enrolled Set 
 
Listing 16.2.1.B Subject Disposition Enrolled Set 
 
Listing 16.2.2.A Inclusion/Exclusion Criteria Screen Failures 
Listing 16.2.2.B Inclusion/Exclusion Criteria Screen Failures 
Listing 16.2.2.1.1.A Non-Significant Protocol Deviations Safety Set 
 


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Listing 16.2.2.1.2.A Significant Protocol Deviations Safety Set 
Listing 16.2.2.1.1.B Non-Significant Protocol Deviations Safety Set 
 
Listing 16.2.2.1.2.B Significant Protocol Deviations Safety Set 
 
Listing 16.2.3.A Demographics Safety Set  
Listing 16.2.3.B Demographics Safety Set 
 
Listing 16.2.4.1.A Prior and Concomitant Medications Safety Set  
Listing 16.2.4.1.B Prior and Concomitant Medications Safety Set  
Listing 16.2.4.2.A Medical History Safety Set 
 
Listing 16.2.4.2.B Medical History Safety Set 
 
Listing 16.2.5.1.1.A Dose Exposure  Safety Set 
 
Listing 16.2.5.1.1.B Dose Exposure  Safety Set 
 
Listing 16.2.5.1.2.A Drug Accountability  Safety Set 
 
Listing 16.2.5.1.2.B Drug Accountability  Safety Set 
 
Listing 16.2.5.2.A Dose Adjustment  Safety Set 
 
Listing 16.2.5.2.B Dose Adjustment  Safety Set 
 
Listing 16.2.5.3.A Concomitant Procedure Safety Set 
 
Listing 16.2.5.3.B Concomitant Procedure Safety Set 
 
Listing 16.2.6.1.A CPET (Cardiopulmonary Exercise Testing) Results Efficacy Set 
 
Listing 16.2.6.1.B CPET (Cardiopulmonary Exercise Testing) Results Efficacy Set 
 
Listing 16.2.6.2.A Electrocardiogram Results during CPET Procedure Efficacy Set 
 
Listing 16.2.6.2.B Electrocardiogram Results during CPET Procedure Efficacy Set 
 
Listing 16.2.6.3.A Resting Echocardiography Results Efficacy Set  
Listing 16.2.6.3.B Resting Echocardiography Results Efficacy Set  
Listing 16.2.6.4.A Hemodynamic Stress Echocardiography Results Efficacy Set  
Listing 16.2.6.4.B Hemodynamic Stress Echocardiography Results Efficacy Set  
Listing 16.2.6.5.A NYHA Functional Classification Results Efficacy Set  
Listing 16.2.6.5.B NYHA Functional Classification Results Efficacy Set  
Listing 16.2.6.6.A Kansas City Cardiomyopathy Questionnaire Results Efficacy Set 
 
Listing 16.2.6.6.B Kansas City Cardiomyopathy Questionnaire Results Efficacy Set 
 
Listing 16.2.6.7.A Dyspnea Numeric Rating Scale (NRS) Results Efficacy Set 
 
Listing 16.2.6.7.B Dyspnea Numeric Rating Scale (NRS) Results Efficacy Set 
 
Listing 16.2.6.8.A Cardiac Monitoring Skin Patch Efficacy Set 
 
Listing 16.2.6.8.B Cardiac Monitoring Skin Patch Efficacy Set 
 
Listing 16.2.7.1.A Individual Plasma Concentrations of MYK-461  PK Analysis 
Population 
 
Listing 16.2.7.1.B Individual Plasma Concentrations of MYK-461  PK Analysis 
Population 
 
Listing 16.2.8.1.A Adverse Events Safety Set 
 
Listing 16.2.8.1.B Adverse Events Safety Set 
 
Listing 16.2.8.2.A Adverse Events Leading to Treatment Discontinuation Safety Set 
 
Listing 16.2.8.2.B Adverse Events Leading to Treatment Discontinuation Safety Set 
 
Listing 16.2.8.3.A Adverse Events Leading to Study Discontinuation Safety Set  
Listing 16.2.8.3.B Adverse Events Leading to Study Discontinuation Safety Set 


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Listing 16.2.8.4.A Adverse Events Leading to Death Safety Set 
 
Listing 16.2.8.4.B Adverse Events Leading to Death Safety Set 
 
Listing 16.2.9.1.A Laboratory Results - Chemistry Safety Set 
 
Listing 16.2.9.1.B Laboratory Results - Chemistry Safety Set 
 
Listing 16.2.9.2.A Laboratory Results - Hematology Safety Set 
 
Listing 16.2.9.2.B Laboratory Results - Hematology Safety Set 
 
Listing 16.2.9.3.A Laboratory Results – Urinalysis Safety Set 
 
Listing 16.2.9.3.B Laboratory Results – Urinalysis Safety Set 
 
Listing 16.2.10.A Vital Sign Results Safety Set 
 
Listing 16.2.10.B Vital Sign Results Safety Set 
 
Listing 16.2.11.A Physical Exam Safety Set  
Listing 16.2.11.B Physical Exam Safety Set  
Listing 16.2.12.1.A Electrocardiogram Results Efficacy Set  
Listing 16.2.12.1.B Electrocardiogram Results Efficacy Set  
Listing 16.2.12.2.A Electrocardiogram Results with QTcB/QTcF >480 ms and/or Change 
from Baseline >60 ms Efficacy Set  
Listing 16.2.12.2.B Electrocardiogram Results with QTcB/QTcF >480 ms and/or Change 
from Baseline >60 ms Efficacy Set  
Listing 16.2.13.A CYP 2C19 and CYP 2C9 Genotyping Results 
 
Listing 16.2.13.B CYP 2C19 and CYP 2C9 Genotyping Results 
 
Listing 16.2.14.A HCM Genotype 
 
Listing 16.2.14.B HCM Genotype 
 
Figure 14.2.1.1.A Mean (±SD) Plasma Concentrations of MYK-461 versus Time by Dose 
Level PK Analysis Population 
 
Figure 14.2.1.2.A Individual Plasma Concentrations of MYK-461 versus Time PK 
Analysis Population  
Figure 14.2.1.3.A Regression of MYK-461 Concentration versus QTc Interval 
 
Figure 14.2.1.4.A Overlay of Individual Plasma Concentrations of MYK-461 versus Time 
PK Analysis Population 
 
Figure 14.2.1.1.B Mean (±SD) Plasma Concentrations of MYK-461 versus Time by Dose 
Level  
Figure 14.2.1.2.B Individual Plasma Concentrations of MYK-461 versus Time 
 
Figure 14.2.1.3.B Regression of MYK-461 Concentration versus QTc Interval 
 
Figure 14.2.1.4.B Overlay of Individual Plasma Concentrations of MYK-461 versus Time 
PK Analysis Population 
 
Figure 14.2.1.5 Regression of MYK-461 Concentration versus QTc Interval – All Subjects