Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy

Research output: Contribution to journalArticle

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 Nagueh, Anjali Owens, Florian Rader, Sara Saberi, Amy J. Sehnert, Mark V. Sherrid, Scott D. Solomon, Andrew Wang & 3 others Omar Wever-Pinzon, Timothy C. Wong, Stephen B. Heitner

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. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764)

Original languageEnglish (US)
Pages (from-to)2649-2660
Number of pages12
JournalJournal of the American College of Cardiology
Volume75
Issue number21
DOIs
StatePublished - Jun 2 2020

PMID: 32466879

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

In: Journal of the American College of Cardiology, Vol. 75, No. 21, 02.06.2020, p. 2649-2660.

Research output: Contribution to journalArticle

Harvard

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, S, 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

APA

Ho, C. Y., Mealiffe, M. E., Bach, R. G., Bhattacharya, M., Choudhury, L., Edelberg, J. M., ... 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

Vancouver

Ho CY, Mealiffe ME, Bach RG, Bhattacharya M, Choudhury L, Edelberg JM et al. Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology. 2020 Jun 2;75(21):2649-2660. https://doi.org/10.1016/j.jacc.2020.03.064

Author

Ho, Carolyn Y. ; Mealiffe, Matthew E. ; Bach, Richard G. ; Bhattacharya, Mondira ; Choudhury, Lubna ; Edelberg, Jay M. ; Hegde, Sheila M. ; Jacoby, Daniel ; Lakdawala, Neal K. ; Lester, Steven J. ; Ma, Yanfei ; Marian, Ali J. ; Nagueh, Sherif ; Owens, Anjali ; Rader, Florian ; Saberi, Sara ; Sehnert, Amy J. ; Sherrid, Mark V. ; Solomon, Scott D. ; Wang, Andrew ; Wever-Pinzon, Omar ; Wong, Timothy C. ; Heitner, Stephen B. / Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy. In: Journal of the American College of Cardiology. 2020 ; Vol. 75, No. 21. pp. 2649-2660.

BibTeX

@article{fa9535c30b044c098700e6dd02a28d8e,
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. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764)",
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 Sherif Nagueh 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 = "Copyright {\circledC} 2020 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2020",
month = "6",
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",
number = "21",

}

RIS

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

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.

N1 - Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764)

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. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764)

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

KW - cardiac troponin I (cTnI)

KW - clinical study

KW - hypertrophic cardiomyopathy

KW - mavacamten

UR - http://www.scopus.com/inward/record.url?scp=85084654075&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85084654075&partnerID=8YFLogxK

U2 - 10.1016/j.jacc.2020.03.064

DO - 10.1016/j.jacc.2020.03.064

M3 - Article

VL - 75

SP - 2649

EP - 2660

JO - Journal of the American College of Cardiology.

T2 - Journal of the American College of Cardiology.

JF - Journal of the American College of Cardiology.

SN - 0735-1097

IS - 21

ER -

ID: 63478040