Supplemental Figure 2: Percent Change in High-Sensitivity ...



Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic CardiomyopathySUPPLEMENTAL MATERIALSupplemental Figure 1: PK in Group 1 and Group 2 – ITT Population Legend: EOS, end of study; ITT, intent-to-treat; PD, post-dose; PrD, pre-dose; PK, pharmacokinetic.914400205298Supplemental Figure 2: Percent Change in High-Sensitivity Cardiac Troponin I (hs-cTnI) by Participant914400177473Supplemental Table 1: Inclusion and Exclusion CriteriaInclusion criteriaExclusion criteriaAble to understand and comply with the study procedures, including CPET, understand the risks involved in the study, and provide written informed consent according to federal, local, and institutional guidelines before the first study-specific procedureIs ≥18 years old at screeningBody weight is >45 kg at screeningDiagnosed with nHCM (hypertrophied and non-dilated left ventricle in absence of systemic or other known cause) consistent with current ACCF/AHA and ESC guidelines; ie, the participant must meet at least 1 of the 2 following criteria at the time of screening:LV wall thickness ≥15 mm, orLV wall thickness ≥13 mm with a positive family history of HCMHas documented LVEF ≥55% at the screening visit as determined by the echocardiography central laboratoryHas adequate acoustic windows to enable accurate TTEsLVOT peak gradient at rest AND during Valsalva AND post-exercise <30 mmHg as determined by the echocardiography central laboratoryIf intracavitary gradient is present and distinctly measurable from the LVOT gradient, then maximal intracavitary gradient at rest AND during Valsalva AND post-exercise <30 mmHg as determined by the echocardiography central laboratoryHas NYHA Class II or III symptoms at screeningHas an elevated NT-proBNP at rest (>300 pg/mL) at screeningHas safety laboratory parameters (chemistry, hematology, coagulation, and urinalysis) within normal limits (according to the central laboratory reference range) at screening; however, aPreviously participated in a clinical study with mavacamtenHypersensitivity to mavacamten or any of the components of the mavacamten formulationParticipated in a clinical trial where the participant received any investigational drug (or is currently using an investigational device) within 30 days prior to screening or 5 times the respective elimination half-life (whichever is longer)Has a known infiltrative or storage disorder causing cardiac hypertrophy that mimics nHCM, such as Fabry disease, amyloidosis, or Noonan syndrome with LV hypertrophyHas any medical condition that precludes upright exercise stress testingHas a history of syncope or a history of sustained ventricular tachyarrhythmia with exercise within the past 6 monthsHas a history of resuscitated sudden cardiac arrest at any time or known appropriate ICD discharge within 6 months prior to screeningHas paroxysmal, intermittent atrial fibrillation with atrial fibrillation present per the investigator’s evaluation of the participant’s ECG at the time of screeningHas persistent or permanent atrial fibrillation not on anticoagulation for≥4 weeks prior to screening and/or is not adequately rate-controlled within 6 months prior to screening (note: patients with persistent or permanent atrial fibrillation who are anticoagulated and adequately rate- controlled are allowed)Is currently treated with disopyramide or ranolazine (within 14 days prior to screening) or treatment with disopyramide or ranolazine is planned during the studyparticipant with safety laboratory parameters outside normal limits may be included if he/she meets all of the following criteria:The safety laboratory parameter outside normal limits is considered by the investigator to be clinically unimportantIf there is an ALT or AST result, the value must be <3 × the upper limit of the laboratory reference rangeThe body size–adjusted eGFR is ≥30 mL/min/1.73 m2Female participants 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 study drug (hormonal contraceptives are not considered highly effective contraception for this study because it is unknown if mavacamten reduces the effectiveness of hormonal contraceptives):Double-barrier method (eg, male using a condom and female using a diaphragm or cervical cap)Barrier plus nonhormonal contraception (eg, male using a condom and female using a nonhormonal IUD or nonhormonal IUSFemale 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 ≥6 months prior to screening. Females are considered postmenopausal if they have had amenorrhea for≥2 years following cessation of all exogenous hormonal treatments and FSH levels are in the postmenopausal rangeFor participants on beta blocker, verapamil, or diltiazem, any dose adjustment <14 days before screeningCurrently treated or planned treatment during the study with a combination of beta blocker and verapamil or a combination of beta blocker and diltiazemHas been treated with invasive septal reduction (surgical myectomy or percutaneous alcohol septal ablation) within 6 months prior to screening (note: if a participant has had prior septal reduction therapy, the diagnostic wall thickness criteria and all other eligibility criteria must be met at time of screening)Documented history of resting or post- exercise LVOT or intracavity gradient>30 mmHg unless subsequently treated by septal reduction therapyQTcF >480 ms or any other ECG abnormality considered by the investigator to pose a risk to participant safety (eg, second-degree atrioventricular block type II)Has documented obstructive coronary artery disease (>70% stenosis in one or more epicardial coronary arteries) or myocardial infarction within the past 6 monthsHas known moderate or severe (as per the investigator’s judgment) aortic valve stenosis at screeningHas any acute or serious comorbid condition (eg, major infection or hematologic, renal, metabolic, gastrointestinal, or endocrine dysfunction) that, in the judgment of the investigator, could lead to premature termination of study participation or interfere with the measurement or interpretation of the efficacy and safety assessments in the studyHas pulmonary disease that limits exercise capacity or systemic arterial oxygen saturationPositive serologic test at screening for infection with human immunodeficiency virus, hepatitis C virus, or hepatitis B virus13. Male participants with sexual partners must agree to use condoms for the duration of the study and for 3 months after the last dose of study medication in order to prevent passing mavacamten to the partner in the ejaculateHistory of clinically significant malignant disease within 10 years of screening:Participants who have been successfully treated for nonmetastatic cutaneous squamous cell or basal cell carcinoma or have been adequately treated for cervical carcinoma in situ can be included in the studyParticipants with other malignancies who are cancer-free for >10 years before screening can be included in the studyHistory 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 the medical monitor, would pose a risk to participant safety or interfere with the study evaluation, procedures, or completionCurrently taking, or has taken within 14 days prior to screening, a CYP2C19 inhibitor (eg, omeprazole), a strong CYP3A4 inhibitor, or St. John’s WortPrior treatment with cardiotoxic agents such as doxorubicin or similarUnable to comply with the study requirements, including the number of required visits to the clinical siteEmployed by, or a relative of someone employed by MyoKardia, the investigator, or his/her staff or familyALT, alanine aminotransferase; ACCF, American College of Cardiology Foundation; AHA, American Heart Association; AST, aspartate aminotransferase; CPET, cardiopulmonary exercise testing; CYP, cytochrome P450; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; ESC, European Society of Cardiology; FSH, follicle-stimulating hormone; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter defibrillator; IUD, intrauterine device; IUS, intrauterine system; LV, left ventricular; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; NYHA, New York Heart Association; nHCM, non-obstructive hypertrophic cardiomyopathy; NT-proBNP, N-terminal pro b-type natriuretic peptide; QTcF, QT corrected using Fridericia's method; TTEs, transthoracic echocardiograms.Supplemental Table 2: Individual Data for the 5 Participants with LVEF Reduction below 45%Participant 1 (Group 2): 70-year-old male, uptitrated from 5 to 10 mg at week 6.Past medical history remarkable for: paroxysmal atrial fibrillation, nonsustained ventricular tachycardia (NSVT), palpitations, fatigue, presyncope, prior VT ablation, and ICD implant. He experienced non-serious symptoms of heart failure (palpitation, fatigue, dyspnea from days 53- 98), adverse event of cardiac failure on day 73 and study drug was permanently discontinued on Day 85 (week 12), following core lab measurement of LVEF 41%.LVEFNT-proBNPNYHA ClassScreening56%8492Day 159%6282Week 450%7732Week 8ND7162Week 1241%30182Day 989672Week 1650%10782Week 2450%7762Participant 2 (Group 2): 67-year-old male, uptitrated from 5 to 10 mg at week 6.Past medical history remarkable for: paroxysmal atrial fibrillation, NSVT, embolic stroke, pulmonary hypertension, dyspnea, and multiple prior AF ablations. On study day 68, diagnosed with recurrent AF, started on amiodarone which he did not tolerate and was admitted on day 81 for cardioversion as well as for symptoms of heart failure. He was started on diuretics and was cardioverted with improvement of symptoms. He was also diagnosed with systolic dysfunction with core lab LVEF <45% (day 91 = 44%) and study drug was discontinued. Although his LVEF stabilized after drug discontinuation and treatment with diuretics, LVEF returned to baseline at week 24, only after cardiac ablation procedure on day 161/week 23.LVEFNT-proBNPNYHA ClassScreening70%8043Day 179%6802Week 450%4122Week 847%9693Day 9144%14993Week 1646%5902Week 2479%11872Participant 3 (Group 1): 50-year-old male, Group 1, uptitrated from 5 to 10 mg at week 6. Past medical history remarkable for: cardiac chest pain, palpitations, and dyspnea. He was doing well with an improvement in NYHA class and stable NT-proBNP from day 1 through week 12. Drug was permanently discontinued on Day 86 (wk 12) following core lab measurement of LVEF<45% (44.99%). Participant was asymptomatic at time of treatment discontinuation.LVEFNT-proBNPNYHA ClassScreening66%7632Day 162%11702Week 470%11252Week 860%10871Week 1245%11931Week 1661%9941Week 2463%7992Participant 4 (Group 2): 62-year-old female, uptitrated from 5 to 10 mg at week 6.Past medical history remarkable for: chronic diastolic heart failure, hypertension, fatigue, dyspnea, and sleep apnea. Drug was permanently discontinued on Day 84 (week 12) due to core lab measured LVEF of 42%. The participant did not have heart failure symptoms at time of treatment discontinuation.LVEFNT-proBNPNYHA ClassScreening64%5262Day 163%5542Week 461%1792Week 861%5432Week 1242%9992Week 1659%6803Week 2456%6982Participant 5 (Group 1): 72-year-old male, remained on 5mg until treatment discontinuation (no uptitration). Past medical history remarkable for: atrial fibrillation, NSVT, prior NSTEMI Type II, fatigue, dyspnea and ICD implant. On day 63, received medical evaluation at an outside hospital for mental status changes on a day he took extra doses of metoprolol. ECHO at hospital noted a low LVEF (45%). Event was communicated to site 8 days later, when study treatment was interrupted (day 73). At the subsequent site visit on day 79, core lab measured LVEF 38% and treatment was discontinued.LVEFNT-proBNPNYHA ClassScreening60%18282Day 161%15212Week 458%21632Week 856%9242Day 7938%Week 1211512Day 8652%Week 1656%13203Week 2474%19762Supplemental Table 3: Change in Efficacy and Pharmacodynamic Parameters in the ITT PopulationParameter, Mean (SD)Group 1 Mavacamten~200 ng/mL (n = 19)Group 2 Mavacamten~500 ng/mL (n = 21)Pooled mavacamten (n = 40)Placebo (n = 19)LVEF (%) 95% CIP value-2.30 (5.30)-5.03, 0.420.91-5.61 (9.65)-10.13, -1.090.42-4.09 (8.02)-6.77, -1.420.45-2.31 (4.94)-4.85, 0.23-Lateral e’ (cm/s) 95% CIP value0.34 (2.57)-0.99, 1.660.661.46 (3.55)-0.20, 3.120.100.94 (3.15)-0.11, 1.990.350.32 (2.37)-0.94, 1.59-Septal e’ (cm/s) 95% CIP value0.64 (1.63)-0.21, 1.480.791.60 (1.49)0.92, 2.270.021.17 (1.61)0.64, 1.690.140.41 (1.20)-0.23, 1.05-E/e’lat ratio 95% CIP value-0.71 (2.73)-2.12, 0.690.81-1.13 (4.85)-3.40, 1.140.41-0.94 (3.97)-2.26, 0.390.43-1.16 (6.37)-4.55, 2.24-E/e’sep ratio 95% CIP value-1.42 (3.56)-3.25, 0.410.74-5.45 (10.03)-10.0, -0.880.25-3.65 (8.00)-6.28, -1.020.46-1.96 (9.11)-6.81, 2.90-E/e’average ratio 95% CIP value-1.51 (2.44)-2.77, -0.260.72-3.45 (6.78)-6.54, -0.360.28-2.58 (5.33)-4.33, -0.830.50-1.56 (6.449)-4.993, 1.880-LVEDV (mL) 95% CIP value1.15 (10.9)-4.45, 6.750.466.50 (13.5)0.19, 12.80.124.04 (12.5)-0.12, 8.20.22-0.35 (10.4)-5.68, 4.97-LA vol (index) (mL/m2) 95% CIP value0.25 (7.23)-3.47, 3.970.852.40 (9.13)-2.00, 6.800.881.39 (8.25)-1.40, 4.180.90-0.82 (8.72)-5.30, 3.67-Peak VO2 (mL/kg/min) 95% CIP value0.36 (3.12)-1.44, 2.160.870.12 (3.76)-1.75, 1.990.670.22 (3.44)-1.02, 1.460.930.58 (2.39)-0.60, 1.77-NYHA Class 95% CIP value-0.6 (0.7)-1.0, -0.20.42-0.3 (0.6)-0.5, -0.30.51-0.4 (0.7)-0.7, -0.20.95-0.4 (0.6)-0.8, -0.1-NT-proBNP* (%) Geometric mean P value-47.10.01-57.90.001-53.20.0005-0.7-cTnI* (%) Geometric mean P value-23.40.09-41.00.003-34.00.0093.8-Overall KCCQ Summary Score95% CIP value0.35 (8.71)-4.68, 5.380.526.24 (10.73)1.22, 11.260.483.82 (10.24)0.24, 7.39>0.996.02 (17.63)-3.38, 15.42-Clinical KCCQ Summary Score95% CIP value0.11 (7.67)-4.32, 4.540.965.66 (10.01)0.97, 10.340.403.37 (9.41)0.09, 6.660.474.34 (16.05)-4.22, 12.89-*Percent change is presented.Supplemental Table 4: Composite Functional Endpoint in a Subgroup with Baseline Elevated cTnI or E/e’averageParametersGroup 1 mavacamten~200 ng/mL (n = 9)Group 2 mavacamten~500 ng/mL (n = 12)Pooled mavacamten (n = 21)Placebo (n = 12)Met endpoint, either type, n (%)3 (33.3)4 (33.3)7 (33.3)095% CI7.5, 70.19.9, 65.114.6, 57.00, 26.5P value0.04560.03360.0287-Type 1, n (%)1 (11.1)1 (8.3)2 (9.5)095% CI0.3, 48.30.2, 38.51.2, 30.40, 26.5Type 2, n (%)2 (22.2)3 (25.0)5 (23.8)095% CI2.8, 60.05.5, 57.28.2, 47.2-Composite endpoint is defined as either improvement from baseline to week 16 of at least 1.5 mL/kg/min in pVO2 and reduction of 1 or more NYHA Class (Type 1), or improvement of at least 3.0 mL/kg/min in pVO2 and no worsening in NYHA Class (Type 2) unless otherwise denoted.cTnI, cardiac-specific troponin-I; CI, confidence interval; E/e’, ratio between transmitral early peak velocity and mitral annular early diastolic velocity; NYHA, New York Heart Association; pVO2, peak oxygen consumption.SUPPLEMENTARY METHODSStudy EndpointsPrespecified safety analyses included the incidence of treatment-emergent adverse events (TEAEs), relatedness of TEAEs by the investigators’ assessment, adverse events (AEs) leading to treatment discontinuation, and change over time in vital signs, safety labs, and electrocardiograms (ECGs) summarized by treatment assignment. ECG was used to monitor QTcF throughout the study. The treatment-emergent period was defined as the time from the first administration of study drug to 56 days after the last dose. TEAEs were defined as any new or worsening occurrences that occurred within the treatment-emergent period.Exploratory efficacy analyses included: change from baseline to week 16 in peak oxygen consumption (pVO2) measured by cardiopulmonary exercise testing (CPET), echocardiographic measures of LVEF and parameters of diastolic function (eg, E/e’), serum biomarkers NT-proBNP and cardiac troponin I (cTnI), and proportion of patients who reported improvement in NYHA Functional Class. Change from baseline in echocardiography and biomarker assessments were also analyzed post-treatment at week 24.Study AssessmentsStandardized CPET-based pVO2 was determined at baseline and week 16 (Figure 1) by a core laboratory (Cardio-metabolic Diagnostic Research Institute, Palo Alto, CA). NT-proBNP (by Elecsys ProBNP II Immunoassay on Cobas platform) and cTnI (by Abbott Stat Architect platform) were measured at baseline (prior to exercise), every 4 weeks through week 16, and post-treatment at week 24.Resting transthoracic echocardiography (TTE) was assessed at every onsite visit, except week 6. Post-exercise stress echocardiography was performed at screening. All echocardiograms were acquired at each site by sonographers according to a detailed acquisition protocol that included comprehensive 2-dimensional imaging with Doppler. Principal investigators and other study site personnel remained blinded to TTEs. Quantitative measures on all echocardiograms were assessed by a core laboratory (Brigham and Women’s Hospital, Boston MA) with measurements made according to the American Society of Echocardiography recommendations.HCM GenotypingHCM genotyping was performed via the next generation sequencing Hypertrophic Cardiomyopathy Panel in a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory (Invitae, San Francisco, CA). The sequencing panel was broad and included 60 genes on either the laboratory’s defined primary HCM panel and additional panels with the laboratory-defined “Preliminary Evidence Genes for HCM,” RASopathy Genes, and Autosomal Recessive Syndromic Pediatric Cardiomyopathy Genes. The clinical laboratory’s in-house variant assessment methodology was utilized for variant pathogenicity classification.(1)References1. Nykamp K, Anderson M, Powers M, et al. Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med 2017;19:1105–17. ................
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