Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial


Iacopo Olivotto, Azienda Ospedaliera Careggi
Artur Oreziak, Instytut Kardiologii im. Prymasa Tysiaclecia Stefana Kardynała Wyszynskiego
Roberto Barriales-Villa, Instituto de Investigación Biomédica de A Coruña
Theodore P. Abraham, David Geffen School of Medicine at UCLA
Ahmad Masri, OHSU School of Medicine
Pablo Garcia-Pavia, Centro de Investigación Biomédica en Red
Pablo Garcia-Pavia, Centro de Investigación Biomédica en Red
Sara Saberi, University of Michigan, Ann Arbor
Neal K. Lakdawala, Brigham and Women's Hospital
Matthew T. Wheeler, Stanford University School of Medicine
Anjali Owens, University of Pennsylvania Perelman School of Medicine
Milos Kubanek, Institutu Klinické a Experimentální Medicíny
Wojciech Wojakowski, Slaski Uniwersytet Medyczny w Katowicach
Morten K. Jensen, Aarhus Universitetshospital
Juan Gimeno-Blanes, Hospital Virgen de la Arrixaca
Juan Gimeno-Blanes, Hospital Virgen de la Arrixaca
Kia Afshar, Intermountain Medical Center
Jonathan Myers, VA Palo Alto Health Care System
Sheila M. Hegde, Brigham and Women's Hospital
Scott D. Solomon, Brigham and Women's Hospital
Amy J. Sehnert, MyoKardia
David Zhang, MyoKardia
Wanying Li, MyoKardia
Mondira Bhattacharya, MyoKardia
Jay M. Edelberg, MyoKardia
Cynthia Burstein Waldman, HCMBeat
Steven J. Lester, Mayo Clinic Scottsdale-Phoenix, Arizona
Andrew Wang, Duke University School of Medicine
Carolyn Y. Ho, Brigham and Women's Hospital
Daniel Jacoby, Yale University
Jozef Bartunek
Antoine Bondue
Emeline Van Craenenbroeck

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The Lancet


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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