Stephen B. Heitner, MD; Daniel Jacoby, MD; Steven J. Lester, MD; Anjali Owens, MD; Andrew Wang, MD; David Zhang, PhD, MBA; Joseph Lambing, PhD; June Lee, MD; Marc Semigran, MD; Amy J. Sehnert, MD
Acknowledgment: The authors thank the study participants and their families for giving their time despite the innate risks involved in early-phase research. They also thank the research staff, nurses, technologists, cardiac sonographers, and administrators who were inextricably intertwined in the production of this article.
Financial Support: By MyoKardia.
Disclosures: Dr. Heitner reports a grant from MyoKardia during the conduct of the study, other support from MyoKardia and Cytokinetics outside the submitted work, and service on the steering committee for the EXPLORER trial for MyoKardia. Dr. Jacoby reports grants and personal fees from MyoKardia during the conduct of the study, other support from MyoKardia outside the submitted work, and service on the steering committee for the EXPLORER trial for MyoKardia. Dr. Wang reports grants from MyoKardia, Abbott Vascular, and Gilead Sciences; personal fees from Cytokinetics outside the submitted work; and is on the steering committee for the EXPLORER trial for MyoKardia. Dr. Zhang reports employment with MyoKardia. Dr. Lambing reports employment with MyoKardia and a pending patent for treatment of hypertrophic cardiomyopathy with pyrimidinedione. Dr. Lee reports employment with MyoKardia. Dr. Semigran reports employment with MyoKardia. Dr. Sehnert reports employment with MyoKardia. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-3016.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor, Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Data Sharing Statement: The complete deidentified patient data set, the analytic and statistical code, and the informed consent form will be made available to researchers whose proposed use of the data has been approved by a publications committee for study of specific questions related to oHCM (e-mail, email@example.com).
Corresponding Author: Stephen B. Heitner, MD, Knight Cardiovascular Institute, Oregon Health & Science University, UHN62, 3181 SW Sam Jackson Park Road, Portland, OR 97239; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Heitner: Knight Cardiovascular Institute, Oregon Health & Science University, UHN62, 3181 SW Sam Jackson Park Road, Portland, OR 97239.
Dr. Jacoby: Section of Cardiovascular Medicine, Yale University School of Medicine, 15 York Street, New Haven, CT 06510.
Dr. Lester: Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259.
Dr. Owens: Perelman Center for Advanced Medicine, University of Pennsylvania, East Pavilion, 2nd Floor, 3400 Civic Center Boulevard, Philadelphia, PA 19104.
Dr. Wang: Duke University Medical Center, DUMC 3428, Durham, NC 27710.
Drs. Zhang, Lambing, Lee, Semigran, and Sehnert: MyoKardia, 333 Allerton Avenue, South San Francisco, CA 94080.
Author Contributions: Conception and design: S.B. Heitner, S.J. Lester, A. Owens, J. Lambing, J. Lee, M. Semigran.
Analysis and interpretation of the data: S.B. Heitner, D. Jacoby, S.J. Lester, A. Owens, A. Wang, D. Zhang, J. Lambing, J. Lee, M. Semigran, A.J. Sehnert.
Drafting of the article: S.B. Heitner, D. Jacoby, S.J. Lester, A. Wang, D. Zhang, J. Lambing, J. Lee, A.J. Sehnert.
Critical revision of the article for important intellectual content: S.B. Heitner, D. Jacoby, S.J. Lester, A. Owens, A. Wang, J. Lee, M. Semigran, A.J. Sehnert.
Final approval of the article: S.B. Heitner, D. Jacoby, S.J. Lester, A. Owens, A. Wang, D. Zhang, J. Lambing, J. Lee, M. Semigran, A.J. Sehnert.
Provision of study materials or patients: S.B. Heitner, D. Jacoby, S.J. Lester, A. Owens, A. Wang.
Statistical expertise: D. Zhang.
Obtaining of funding: S.B. Heitner, M. Semigran.
Administrative, technical, or logistic support: S.B. Heitner, J. Lambing, M. Semigran, A.J. Sehnert.
Collection and assembly of data: S.B. Heitner, S.J. Lester, A. Wang, J. Lee, M. Semigran.
Mavacamten, an orally administered, small-molecule modulator of cardiac myosin, targets underlying biomechanical abnormalities in obstructive hypertrophic cardiomyopathy (oHCM).
To characterize the effect of mavacamten on left ventricular outflow tract (LVOT) gradient.
Open-label, nonrandomized, phase 2 trial. (ClinicalTrials.gov: NCT02842242)
5 academic centers.
21 symptomatic patients with oHCM.
Patients in cohort A received mavacamten, 10 to 20 mg/d, without background medications. Those in cohort B received mavacamten, 2 to 5 mg/d, with β-blockers allowed.
The primary end point was change in postexercise LVOT gradient at 12 weeks. Secondary end points included changes in peak oxygen consumption (pVO2), resting and Valsalva LVOT gradients, left ventricular ejection fraction (LVEF), and numerical rating scale dyspnea score.
In cohort A, mavacamten reduced mean postexercise LVOT gradient from 103 mm Hg (SD, 50) at baseline to 19 mm Hg (SD, 13) at 12 weeks (mean change, −89.5 mm Hg [95% CI, −138.3 to −40.7 mm Hg]; P = 0.008). Resting LVEF was also reduced (mean change, −15% [CI, −23% to −6%]). Peak VO2 increased by a mean of 3.5 mL/kg/min (CI, 1.2 to 5.9 mL/kg/min). In cohort B, the mean postexercise LVOT gradient decreased from 86 mm Hg (SD, 43) to 64 mm Hg (SD, 26) (mean change, −25.0 mm Hg [CI, −47.1 to −3.0 mm Hg]; P = 0.020), and mean change in resting LVEF was −6% (CI, −10% to −1%). Peak VO2 increased by a mean of 1.7 mL/kg/min (SD, 2.3) (CI, 0.03 to 3.3 mL/kg/min). Dyspnea scores improved in both cohorts. Mavacamten was well tolerated, with mostly mild (80%), moderate (19%), and unrelated (79%) adverse events. The most common adverse events definitely or possibly related to mavacamten were decreased LVEF at higher plasma concentrations and atrial fibrillation.
Small size; open-label design.
Mavacamten can reduce LVOT obstruction and improve exercise capacity and symptoms in patients with oHCM.
Heitner SB, Jacoby D, Lester SJ, Owens A, Wang A, Zhang D, et al. Mavacamten Treatment for Obstructive Hypertrophic Cardiomyopathy: A Clinical Trial. Ann Intern Med. [Epub ahead of print 30 April 2019]:. doi: 10.7326/M18-3016
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Published: Ann Intern Med. 2019.
Cardiac Diagnosis and Imaging, Cardiology.
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