TY - JOUR
T1 - Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM)
T2 - a randomised, double-blind, placebo-controlled, phase 3 trial
AU - Olivotto, Iacopo
AU - Oreziak, Artur
AU - Barriales-Villa, Roberto
AU - Abraham, Theodore P.
AU - Masri, Ahmad
AU - Garcia-Pavia, Pablo
AU - Saberi, Sara
AU - Lakdawala, Neal K.
AU - Wheeler, Matthew T.
AU - Owens, Anjali
AU - Kubanek, Milos
AU - Wojakowski, Wojciech
AU - Jensen, Morten K.
AU - Gimeno-Blanes, Juan
AU - Afshar, Kia
AU - Myers, Jonathan
AU - Hegde, Sheila M.
AU - Solomon, Scott D.
AU - Sehnert, Amy J.
AU - Zhang, David
AU - Li, Wanying
AU - Bhattacharya, Mondira
AU - Edelberg, Jay M.
AU - Waldman, Cynthia Burstein
AU - Lester, Steven J.
AU - Wang, Andrew
AU - Ho, Carolyn Y.
AU - Jacoby, Daniel
AU - EXPLORER-HCM study investigators
AU - Brunner-La Rocca, Hans peter
N1 - Funding Information:
IO has received grants from MyoKardia, Sanofi-Genzyme, Shire, and Bayer; personal fees from Sanofi-Genzyme, Shire, and Bayer; and payments as a consultant from MyoKardia. AM has received grants from Pfizer and Akcea. SS, NKL, AOw, and SMH report personal fees from MyoKardia during the conduct of the study. SDS has received grants from MyoKardia, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and personal fees from MyoKardia, Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cytokinetics, Gilead, GlaxoSmithKline, Novartis, Theracos, Akros, Arena, Cardior, Corvia, Daiichi-Sankyo, Ironwood, Merck, Roche, Takeda, Quantum Genetics, Cardurion, AOBiome, Janssen, Tenaya, and Cardiac Dimensions. AJS, DZ, WL, MB, and JME are employees of MyoKardia and report stocks or stock options from MyoKardia. CBW has received payments for serving on the EXPLORER-HCM steering committee and a patient advisory board for MyoKardia and has received unrestricted educational grants from MyoKardia. AW has received grants from MyoKardia; personal fees from Cytokinetics; and payments as a consultant from MyoKardia. CYH has received payments as a consultant from MyoKardia and Ambry Genetics. DJ has received personal fees from MyoKardia. All other authors declare no competing interests.
Funding Information:
We thank study coordinators, cardiac sonographers, exercise physiologists, the MyoKardia study team, and especially the patients and their families. Medical writing and editorial support were provided by Kim Fuller (SciFluent Communications), financially supported by MyoKardia.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/9/12
Y1 - 2020/9/12
N2 - Background Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy.Methods In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1.5 mL/kg per min or greater increase in peak oxygen consumption (pVO 2) and at least one NYHA class reduction or a 3.0 mL/kg per min or greater pVO 2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO(2), NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545.Findings Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19.4%, 95% CI 8.7 to 30.1; p=0.0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43.2 to -28.1; pInterpretation Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. Copyright (C) 2020 Elsevier Ltd. All rights reserved.
AB - Background Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy.Methods In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1.5 mL/kg per min or greater increase in peak oxygen consumption (pVO 2) and at least one NYHA class reduction or a 3.0 mL/kg per min or greater pVO 2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO(2), NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545.Findings Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19.4%, 95% CI 8.7 to 30.1; p=0.0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43.2 to -28.1; pInterpretation Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. Copyright (C) 2020 Elsevier Ltd. All rights reserved.
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U2 - 10.1016/S0140-6736(20)31792-X
DO - 10.1016/S0140-6736(20)31792-X
M3 - Article
SN - 0140-6736
VL - 396
SP - 759
EP - 769
JO - Lancet
JF - Lancet
IS - 10253
ER -