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 - Bartunek, Jozef
AU - Bondue, Antoine
AU - Van Craenenbroeck, Emeline
AU - Zemanek, David
AU - Jensen, Morten
AU - Mogensen, Jens
AU - Thune, Jens Jakob
AU - Charron, Philippe
AU - Hagege, Albert
AU - Lairez, Olivier
AU - Trochu, Jean Noël
AU - Axthelm, Christoph
AU - Duengen, Hans Dirk
AU - Frey, Norbert
AU - Mitrovic, Veselin
AU - Preusch, Michael
AU - Schulz-Menger, Jeanette
AU - Seidler, Tim
AU - Arad, Michael
AU - Halabi, Majdi
AU - Katz, Amos
AU - Monakier, Daniel
AU - Paz, Offir
AU - Viskin, Samuel
AU - Zwas, Donna
AU - Brunner-La Rocca, Hans Peter
AU - Michels, Michelle
AU - Dudek, Dariusz
AU - Oko-Sarnowska, Zofia
AU - Cardim, Nuno
AU - Pereira, Helder
AU - García Pavia, Pablo
AU - Gimeno Blanes, Juan
AU - Hidalgo Urbano, Rafael
AU - Rincón Diaz, Luis Miguel
AU - Elliott, Perry
AU - Yousef, Zaheer
AU - Abraham, Theodore
AU - Alvarez, Paulino
AU - Bach, Richard
AU - Becker, Richard
AU - Choudhury, Lubna
AU - Fermin, David
AU - Jefferies, John
AU - Kramer, Christopher
AU - Lakdawala, Neal
AU - Lester, Steven
AU - Marian, Ali
AU - Maurer, Mathew
AU - Nagueh, Sherif
AU - Owens, David
AU - Rader, Florian
AU - Sherrid, Mark
AU - Shirani, Jamshid
AU - Symanski, John
AU - Turer, Aslan
AU - Wever-Pinzon, Omar
AU - Wong, Timothy
AU - Yamani, Mohamad
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.
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 (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, 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; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB −1·8, −2·4 to −1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. Interpretation: 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. Funding: MyoKardia.
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 (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, 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; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB −1·8, −2·4 to −1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. Interpretation: 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. Funding: MyoKardia.
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U2 - 10.1016/S0140-6736(20)31792-X
DO - 10.1016/S0140-6736(20)31792-X
M3 - Article
C2 - 32871100
AN - SCOPUS:85090425933
VL - 396
SP - 759
EP - 769
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10253
ER -