Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy

Carolyn Y. Ho; Matthew E. Mealiffe; Richard G. Bach; Mondira Bhattacharya; Lubna Choudhury; Jay M. Edelberg; Sheila M. Hegde; Daniel Jacoby; Neal K. Lakdawala; Steven J. Lester; Yanfei Ma; Ali J. Marian; Sherif F. Nagueh; Anjali Owens; Florian Rader; Sara Saberi; Amy J. Sehnert; Mark V. Sherrid; Scott D. Solomon; Andrew Wang; Omar Wever-Pinzon; Timothy C. Wong; Stephen B. Heitner

doi:10.1016/j.jacc.2020.03.064

Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy

Carolyn Y. Ho^*, Matthew E. Mealiffe, Richard G. Bach, Mondira Bhattacharya, Lubna Choudhury, Jay M. Edelberg, Sheila M. Hegde, Daniel Jacoby, Neal K. Lakdawala, Steven J. Lester, Yanfei Ma, Ali J. Marian, Sherif F. Nagueh, Anjali Owens, Florian Rader, Sara Saberi, Amy J. Sehnert, Mark V. Sherrid, Scott D. Solomon, Andrew WangOmar Wever-Pinzon, Timothy C. Wong, Stephen B. Heitner

^*Corresponding author for this work

Medicine, Cardiology Division

Research output: Contribution to journal › Article › peer-review

229 Scopus citations

Abstract

Background: Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM. Objectives: MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM. Methods: The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro−B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6. Results: Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of −435 and −6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of −0.008 and 0.001 ng/ml, respectively (p = 0.009). Conclusions: Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing.

Original language	English (US)
Pages (from-to)	2649-2660
Number of pages	12
Journal	Journal of the American College of Cardiology
Volume	75
Issue number	21
DOIs	https://doi.org/10.1016/j.jacc.2020.03.064
State	Published - Jun 2 2020

Funding

This study was supported by MyoKardia, Inc. MyoKardia, Inc. was involved in the study design and interpretation of the data, analysis, writing of the report, and in the decision to submit the manuscript for publication. Dr. Ho has been a consultant and a member of the EXPLORER study steering committee for MyoKardia, Inc.; and has served on an advisory board for Ambry Genetics. Drs. Mealiffe, Edelberg, Bhattacharya, Sehnert, and Ma hold stock in MyoKardia, Inc. Dr. Hegde has performed Core Imaging Lab services for MyoKardia, Inc. Dr. Bach has received an institutional grant from MyoKardia, Inc. Dr. Jacoby has received grants from and consulting fees/honorarium for serving on an Advisory Board for MyoKardia, Inc.; and has been a member of the Steering Committee for EXPLORER. Dr. Lakdawala has received consulting fees/honorarium from MyoKardia, Inc. Dr. Marian has received travel expense reimbursements from MyoKardia, Inc. Dr. Owens has received consulting fees/honorarium from MyoKardia, Inc. Dr. Rader has received consulting fees/honorarium and other support from MyoKardia, Inc. Dr. Saberi has received honorarium and travel expense reimbursement for serving on an Advisory Board for MyoKardia, Inc. Dr. Sherrid has received consulting fees/honorarium and other support from Celltrion, Inc. Dr. Solomon has received grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, Inc., National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has received consulting fees/honorarium from Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, MyoKardia, Inc., Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. Dr. Wang has received grants from, has been a primary investigator, and serves on the steering committee for the EXPLORER trial for MyoKardia, Inc.; and has served on an Advisory Board and received an educational grant for the HCM Care App. Dr. Wong has received support to attend an investigator’s meeting for MyoKardia, Inc. Dr. Heitner has received grants from MyoKardia, Inc. during the conduct of the study; and has received other support from MyoKardia, Inc. and Cytokinetics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The authors thank the site investigators (T. Abraham, K. Afshar, P. Alvarez, K. Ananthasubramaniam, R. Bach, R. Becker, L. Choudhury, R. Daggubati, S. Day, S. Heitner, D. Jacoby, C. Kramer, N. Lakdawala, S. Lester, A. Marian, J. Moses, S. Nagueh, A. Owens, D. Owens, E. Popjes, F. Rader, A. Ravichandran, S. Saberi, K. Shah, M. Sherrid, J. Shirani, J. Symanski, A. Turer, A. Wang, L. Wang, O. Wever-Pinzon, M. Wheeler, M. Wolff, T. Wong), study coordinators, cardiac sonographers, the MyoKardia study team, and especially the patients and their families. This study was supported by MyoKardia, Inc. MyoKardia, Inc. was involved in the study design and interpretation of the data, analysis, writing of the report, and in the decision to submit the manuscript for publication. Dr. Ho has been a consultant and a member of the EXPLORER study steering committee for MyoKardia, Inc.; and has served on an advisory board for Ambry Genetics. Drs. Mealiffe, Edelberg, Bhattacharya, Sehnert, and Ma hold stock in MyoKardia, Inc. Dr. Hegde has performed Core Imaging Lab services for MyoKardia, Inc. Dr. Bach has received an institutional grant from MyoKardia, Inc. Dr. Jacoby has received grants from and consulting fees/honorarium for serving on an Advisory Board for MyoKardia, Inc.; and has been a member of the Steering Committee for EXPLORER. Dr. Lakdawala has received consulting fees/honorarium from MyoKardia, Inc. Dr. Marian has received travel expense reimbursements from MyoKardia, Inc. Dr. Owens has received consulting fees/honorarium from MyoKardia, Inc. Dr. Rader has received consulting fees/honorarium and other support from MyoKardia, Inc. Dr. Saberi has received honorarium and travel expense reimbursement for serving on an Advisory Board for MyoKardia, Inc. Dr. Sherrid has received consulting fees/honorarium and other support from Celltrion, Inc. Dr. Solomon has received grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, Inc., National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has received consulting fees/honorarium from Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, MyoKardia, Inc., Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. Dr. Wang has received grants from, has been a primary investigator, and serves on the steering committee for the EXPLORER trial for MyoKardia, Inc.; and has served on an Advisory Board and received an educational grant for the HCM Care App. Dr. Wong has received support to attend an investigator's meeting for MyoKardia, Inc. Dr. Heitner has received grants from MyoKardia, Inc. during the conduct of the study; and has received other support from MyoKardia, Inc. and Cytokinetics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Keywords

N-terminal pro-B-type natriuretic peptide (NT-proBNP)
cardiac troponin I (cTnI)
clinical study
hypertrophic cardiomyopathy
mavacamten

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1016/j.jacc.2020.03.064

Cite this

Ho, C. Y., Mealiffe, M. E., Bach, R. G., Bhattacharya, M., Choudhury, L., Edelberg, J. M., Hegde, S. M., Jacoby, D., Lakdawala, N. K., Lester, S. J., Ma, Y., Marian, A. J., Nagueh, S. F., Owens, A., Rader, F., Saberi, S., Sehnert, A. J., Sherrid, M. V., Solomon, S. D., ... Heitner, S. B. (2020). Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology, 75(21), 2649-2660. https://doi.org/10.1016/j.jacc.2020.03.064

@article{632d90a5fcfa4b70bbb34531cb4fdf5f,

title = "Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy",

abstract = "Background: Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM. Objectives: MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM. Methods: The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro−B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6. Results: Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of −435 and −6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of −0.008 and 0.001 ng/ml, respectively (p = 0.009). Conclusions: Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing.",

keywords = "N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac troponin I (cTnI), clinical study, hypertrophic cardiomyopathy, mavacamten",

author = "Ho, {Carolyn Y.} and Mealiffe, {Matthew E.} and Bach, {Richard G.} and Mondira Bhattacharya and Lubna Choudhury and Edelberg, {Jay M.} and Hegde, {Sheila M.} and Daniel Jacoby and Lakdawala, {Neal K.} and Lester, {Steven J.} and Yanfei Ma and Marian, {Ali J.} and Nagueh, {Sherif F.} and Anjali Owens and Florian Rader and Sara Saberi and Sehnert, {Amy J.} and Sherrid, {Mark V.} and Solomon, {Scott D.} and Andrew Wang and Omar Wever-Pinzon and Wong, {Timothy C.} and Heitner, {Stephen B.}",

note = "Publisher Copyright: {\textcopyright} 2020 The Authors",

year = "2020",

month = jun,

day = "2",

doi = "10.1016/j.jacc.2020.03.064",

language = "English (US)",

volume = "75",

pages = "2649--2660",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier Inc.",

number = "21",

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Ho, CY, Mealiffe, ME, Bach, RG, Bhattacharya, M, Choudhury, L, Edelberg, JM, Hegde, SM, Jacoby, D, Lakdawala, NK, Lester, SJ, Ma, Y, Marian, AJ, Nagueh, SF, Owens, A, Rader, F, Saberi, S, Sehnert, AJ, Sherrid, MV, Solomon, SD, Wang, A, Wever-Pinzon, O, Wong, TC & Heitner, SB 2020, 'Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy', Journal of the American College of Cardiology, vol. 75, no. 21, pp. 2649-2660. https://doi.org/10.1016/j.jacc.2020.03.064

TY - JOUR

T1 - Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy

AU - Ho, Carolyn Y.

AU - Mealiffe, Matthew E.

AU - Bach, Richard G.

AU - Bhattacharya, Mondira

AU - Choudhury, Lubna

AU - Edelberg, Jay M.

AU - Hegde, Sheila M.

AU - Jacoby, Daniel

AU - Lakdawala, Neal K.

AU - Lester, Steven J.

AU - Ma, Yanfei

AU - Marian, Ali J.

AU - Nagueh, Sherif F.

AU - Owens, Anjali

AU - Rader, Florian

AU - Saberi, Sara

AU - Sehnert, Amy J.

AU - Sherrid, Mark V.

AU - Solomon, Scott D.

AU - Wang, Andrew

AU - Wever-Pinzon, Omar

AU - Wong, Timothy C.

AU - Heitner, Stephen B.

PY - 2020/6/2

Y1 - 2020/6/2

N2 - Background: Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM. Objectives: MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM. Methods: The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro−B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6. Results: Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of −435 and −6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of −0.008 and 0.001 ng/ml, respectively (p = 0.009). Conclusions: Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing.

AB - Background: Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM. Objectives: MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM. Methods: The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro−B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6. Results: Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of −435 and −6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of −0.008 and 0.001 ng/ml, respectively (p = 0.009). Conclusions: Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing.

KW - N-terminal pro-B-type natriuretic peptide (NT-proBNP)

KW - cardiac troponin I (cTnI)

KW - clinical study

KW - hypertrophic cardiomyopathy

KW - mavacamten

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Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy

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