• Study objectives were restated for consistency and parity across objectives. • Kaplan-Meier analysis of safety was changed to a more customary analysis of incidence of safety endpoints, as the study was not powered for the former. • Type of ergometer used for exercise testing (treadmill or exercise bicycle) was included as a randomization stratification. • Pulmonary disease that limited exercise capacity or systemic arterial oxygen saturation was added as an exclusion criterion to avoid enrollment of subjects whose exercise tolerance was limited by pulmonary disease and not reflective of HCM. • Clarified that safety endpoints of CV death, atrial fibrillation that required intervention, CV hospitalization, heart failure requiring loop diuretics, syncope, and stroke would be adjudicated. • Removed reference to a separate cytochrome P450 (CYP)2C19 sampling, as CYP2C19 is included in the pharmacogenetics panel and does not require a separate sample. • Study visits were added at Weeks 16 and 20 to allow for pregnancy testing at those time points.

• The duration of treatment was extended from 24 to 30 weeks, and all endpoints were updated to be consistent with this change. • An additional opportunity for dose adjustment (dose increased, decreased, unchanged) was introduced at Week 14 (based on Week 12 assessments). • The primary efficacy endpoint was modified to include changes in NYHA class as follows: − (1) An improvement of 1.5 mL/kg/min or more in pVO2 as determined by cardiopulmonary exercise testing (CPET) and (2) a reduction of 1 or more class in NYHA class at the end of the Week 30 dosing period • The Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC), and Work Productivity and Activity Impairment-Specific Health Problem (WPAI-SHP) questionnaires were added as exploratory endpoints, and the Canadian Cardiovascular Society Chest Pain Grade Scale was removed. • Additional safety endpoints were specified, all based on safety data collected during the study. • A CMR substudy was added for a planned 60 to 80 subjects who provided additional, specific consent and did not have an implantable ICD device or pacemaker or atrial fibrillation at screening. The primary, secondary, and exploratory objectives of the substudy were defined. In addition to main study procedures, subjects in the CMR substudy were to undergo CMR at Day 1 and Week 30. • A study drug stopping rule was included specifying that if local QTcF > 500 ms was observed at any time, study drug would be withdrawn, and subject would have an unscheduled electrocardiogram (ECG) 2 weeks later. ECG-based criteria for rechallenge/restarting study drug and permanent discontinuation of study drug were specified. • Clarified that blood samples for exploratory circulating biomarker analysis were not optional and were to be collected on Day 1 and at Week 30. • Spirometry prior to CPET was removed.

• Study site sonographers were permitted to read transthoracic echocardiography (TTE) results (ie, measure LVEF), while keeping other site personnel blinded so that the investigator could be notified immediately in the event of LVEF ≤ 30%. • Exclusion criteria were added that prohibited the use of beta-blockers in combination with verapamil or beta-blockers in combination with diltiazem. • The requirements for triplicate ECGs and postdose ECGs were removed from the schedule of study procedures. • PK assessment was added at Week 8 visit to guide any necessary dose reduction, and PK assessments on Day 1 were removed from the schedule of study procedures. • LVEF ≤ 30% was included as an adverse event of special interest (AESI), requiring reporting to MyoKardia within 24 hours. • LVEF measurement by the site sonographer was added such that the investigator could be immediately notified at the study visit if LVEF ≤30% • Sham unscheduled visits were included to maintain the study blind. The study began enrolling on this Amendment.

• Based on FDA advice regarding the primary efficacy endpoint (09 April 2018), a second definition of clinical response for the primary endpoint was added and the endpoint was updated to: 1) An improvement of ≥ 1.5 mL/kg/min in pVO2 as determined by CPET and a reduction ≥ 1 NYHA class or 2) an improvement of 3.0 mL/kg/min or more in pVO2 with no worsening in NYHA class. • Screening period increased from 28 to 35 days to allow for potential repeat of key assessments. Rescreening requirements were added. • A list of appropriate contraceptive methods for female subjects of childbearing potential was included based on Clinical Trial Facilitation Group guidance. The statement warning that mavacamten may reduce effectiveness of hormonal contraceptives was removed based on results of the mavacamten and hormonal contraceptive drug-interaction study MYK-461-010. • Exclusion criteria were updated to allow a history of antitachycardia pacing and pulse generator changes during the trial. • Allowable QTcF interval at screening was increased from > 480 ms to > 500 ms. • Criteria for temporary study drug discontinuation based on QTcF were modified to account for QRS width and change from baseline in QTcF. These criteria are more reflective of the expected variances in QT interval and conduction abnormalities prevalent in HCM patients. • The cardiac monitoring skin patch (ie, SEEQ) was no longer available from the manufacturer, necessitating a change to a replacement continuous cardiac monitoring device (ie, Holter).

• Kansas City Cardiomyopathy Questionnaire 23-item version (KCCQ-23) was changed from an exploratory to a secondary endpoint based on FDA feedback (09 August 2019) and to enable inclusion in product labeling. • The secondary endpoint for NYHA class was updated from a continuous to a categorical endpoint as more appropriate for the noncontinuous variable. • The endpoints of proportion of subjects with postexercise LVOT peak gradient < 50 mmHg at Week 30 and proportion of subjects with postexercise LVOT peak gradient < 30 mmHg at Week 30 were changed from secondary to exploratory endpoints. • Change from baseline to Week 30 in the HCM risk prediction model and change from baseline to Week 30 in cardiac troponin-I (cTn-I) were included as exploratory endpoints.