Mavacamten Favorably Impacts Cardiac Structure in Obstructive Hypertrophic Cardiomyopathy: EXPLORER-HCM CMR Substudy Analysis
Running Title: Saberi et al.; EXPLORER-HCM CMR Substudy Analysis
Sara Saberi, MD1; Nuno Cardim, MD2; Mohamad Yamani, MD3; Jeanette Schulz-Menger, MD4; Wanying Li, PhD5; Victoria Florea, MD5; Amy J. Sehnert, MD5;
Raymond Y. Kwong, MD, MPH6; Michael Jerosch-Herold, PhD6; Ahmad Masri, MD7; Anjali Owens, MD8; Neal K. Lakdawala, MD9; Christopher M. Kramer, MD10;
Mark Sherrid, MD11; Tim Seidler, MD12; Andrew Wang, MD13;
Farbod Sedaghat-Hamedani, MD14; Benjamin Meder, MD14; Ofer Havakuk, MD15; Daniel Jacoby, MD16 CA; 6Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 7Center for Hypertrophic Cardiomyopathy, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR; 8Center for Inherited Cardiac Disease, Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; 9Department of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 10Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville, VA; 11Hypertrophic Cardiomyopathy Program, NYU Langone Health, New York City, NY; 12Department of Cardiology and Pulmonology, University Medical Center Göttingen, Göttingen, Germany; 13Duke Cardiology, Duke Health Center at Southpoint, Durham, NC; 14Department of Internal Medicine III, Institute for Cardiomyopathies, University of Heidelberg, Heidelberg, Germany; 15Department of Cardiology, Tel Aviv Medical Center, affiliated to Sackler School of
Medicine, Tel Aviv University, Tel Aviv, Israel; 16Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT
Address for Correspondence:
Sara Saberi, MD, MS
1500 E. Medical Center Dr. CVC, Ste 2364, SPC 5853 Ann Arbor, MI 48109-5853 Tel: 734-232-6236
Email [email protected]
This work was presented as an abstract at the American Heart Association Scientific Sessions, November 13 to November 17, 2020.
This article is published in its accepted form, it has not been copyedited and has not appeared in an issue of the journal. Preparation for inclusion in an issue of Circulation involves copyediting, typesetting, proofreading, and author review, which may lead to differences between this accepted version of the manuscript and the final, published version.
No medical therapy for obstructive hypertrophic cardiomyopathy (oHCM) modifies disease expression or outcomes.1, 2 Mavacamten, a cardiac myosin inhibitor that reduces actin- myosin cross-bridge formation, improved exercise capacity, left ventricular outflow tract gradients, symptoms, and health status in patients with symptomatic oHCM in the phase 3 EXPLORER-HCM trial.3, 4 The cardiac magnetic resonance (CMR) imaging substudy examined the effect of mavacamten versus placebo on cardiac structure and function.
The EXPLORER-HCM trial has been described previously.3, 4 Each site’s institutional review board/independent ethics committee approved the study protocol. All participants provided written informed consent. In this substudy, the primary endpoint was the change in LV mass index (LVMI) from baseline to week 30; exploratory endpoints included change in cellular Healthcare) and included in this order: a) steady-state, free-precession breath-hold cine of a LV short-axis stack, b) native T1 mapping with Modified Look-Locker Inversion Recovery in 3 equally spaced short-axis cuts (base, mid, apical) covering 16 of the 17 American Heart Association segments, c) intravenous gadolinium contrast injection at 0.15 mmol/kg, d) long-axis cine (2, 3, 4-chamber), e) repeat T1 mapping in matching locations at 3, 10, and 25 minutes post- contrast, f) LGE short-axis stack matching cine locations started at 15 minutes post-contrast.
Between-group differences of those changes were evaluated using Wilcoxon–Mann–Whitney tests, and 95% confidence intervals (CIs) were based on normal approximation. All statistical tests were conducted as 2-sided tests with a significance level of 0.05; P values were not adjusted for multiplicity. Missing data were sparse and not imputed. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Thirty-five patients were randomized (mavacamten [n=17], placebo [n=18]). Mean age was 60.3 years and 42.9% were female. Demographics/baseline characteristics were balanced between groups. Patients receiving mavacamten experienced a greater reduction in mean (SD) LVMI, the primary endpoint, from baseline to week 30 versus patients in the placebo group (–
17.4 [12.1] g/m2 and –1.6 [7.4] g/m2, respectively); mean between-group difference: −15.8 g/m2 (95% CI, −22.6 to −9.0; P<0.0001) (Figure). LV mass decreased in the mavacamten group compared with placebo group (between-group difference: −30.0 g [95% CI, −43.3 to −16.7; P<0.0001]). The mean (SD) absolute intracellular myocardial mass index (((1-global ECVF)xLV and remained normal through week 30 despite a mild reduction observed with mavacamten (Figure). LVEF reduction with mavacamten in the CMR substudy was similar to that assessed by echocardiogram in the EXPLORER-HCM population (−6.6% [6.39%] and –3.9% [7.7%]). There was no LVEF <50% by CMR. Of the 9 patients in EXPLORER-HCM (7 mavacamten, 2 placebo) with a transient decrease in LVEF <50% (median 48%) by echocardiogram,4 two were in the CMR substudy (1 mavacamten, 1 placebo) and both were asymptomatic at time of the measure. Myocardial contractile fraction (MCF=(LVSV/LV myocardial volume)x100, LV myocardial volume=LV mass/1.05 g/mL), another parameter of LV systolic function, was similar in both groups at baseline (mavacamten: 61.0% [17.9%], placebo: 60.1% [17.3%]), and
remained unchanged at week 30 (mean between-group difference: 2.4% [95% CI, −4.5 to 9.3;P=0.7043]).
A greater reduction in maximum LAVI was observed with mavacamten versus placebo (mean between-group difference: −10.3 mL/m2 [95% CI, −16.0 to −4.6; P=0.0004]) (Figure). There was little fibrosis at baseline with no notable within- or between-group changes in LGE (Figure) and ECVF (mean change [SD] global ECVF: 0.02 [0.07] in the mavacamten group and
0.00 [0.03] in the placebo group). There was a 50% greater reduction in hs-cTnI and 80% greater reduction in NT-proBNP with mavacamten versus placebo (P<0.01). Change in LVMI was positively correlated with change in hs-cTnI (n=31; Rho=0.75 [95% CI, 0.53 to 0.87]).
The CMR substudy is the first to show favorable impact of a pharmacologic agent on
were observed concurrent with reductions in levels of plasma biomarkers of myocardial stress and injury. These findings suggest that even short-term mavacamten treatment had a favorable effect on cardiac structure in patients with oHCM.
The authors would like to thank the patients, the study site coordinators, and the EXPLORER- HCM study team members. Medical writing support was provided by Dr Nicolas Bertheleme of Oxford PharmaGenesis, Oxford, UK, with funding from MyoKardia.
Source of Funding
The EXPLORER_HCM trial was funded by MyoKardia.
Clinical Trial Registration
URL: https://clinicaltrials.gov. Unique identifier: NCT03470545.
Personal fees may include, but are not limited to, consulting fees, lecture fees, research funding, honoraria for steering committee activities, speaker fees or travel support. Dr Saberi received personal fees from MyoKardia. Dr Cardim received personal fees from MyoKardia. Dr. Kwong personal fees from Bayer, Cytokinetics, and MyoKardia. Dr Wang received personal fees from Cytokinetics, Medscape, and MyoKardia. Dr Sedaghat-Hamedani received personal fees from MyoKardia. Drs Li, Florea and Sehnert are employees of MyoKardia. The other authors have no conflicts of interest.
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Figure. Effects of mavacamten on parameters of cardiac structure, function, and fibrosis assessed by CMR.
aData are mean (95% CI) between-group difference at week 30.
Treatment with mavacamten reduced LVMI (A), max LV wall thickness (B), LAVI max (C) and LVEF (E) in the oHCM patient versus no changes in the patient from the placebo group. No changes is fibrosis assessed by LGE were observed (D). Panels F and G show cardiac magnetic resonance 4-chamber long-axis images in end diastole (ED) and end systole (ES) showing left ventricular basal septal hypertrophy and papillary muscle (white arrows) and Mavacamten enlarged left atrium (LA) at baseline. ED, end diastole; ES, end systole; IVS, interventricular septum; LA, left atrium; LAVI, left atrial volume index; LV, left ventricle; LVEF, left ventricular ejection