Carolyn Y Ho1, Matthew E Mealiffe2, Richard G Bach3, Mondira Bhattacharya2, Lubna Choudhury4, Jay M Edelberg2, Sheila M Hegde5, Daniel Jacoby6, Neal K Lakdawala5, Steven J Lester7, Yanfei Ma2, Ali J Marian8, Sherif F Nagueh9, Anjali Owens10, Florian Rader11, Sara Saberi12, Amy J Sehnert2, Mark V Sherrid13, Scott D Solomon6, Andrew Wang14, Omar Wever-Pinzon15, Timothy C Wong16, Stephen B Heitner17. 1. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address: cho@bwh.harvard.edu. 2. MyoKardia, Inc., Brisbane, California. 3. Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri. 4. Bluhm Cardiovascular Institute, Northwestern Memorial Hospital, Chicago, Illinois. 5. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts. 6. Department of Internal Medicine, Section of Cardiovascular Diseases, Yale University School of Medicine, New Haven, Connecticut. 7. Department of Cardiovascular Diseases, Mayo Clinic Arizona, Phoenix, Arizona. 8. Center for Cardiovascular Genetics, Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas. 9. Methodist DeBakey Heart and Vascular Center, Houston Methodist Hospital, Houston, Texas. 10. Heart and Vascular Center, Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 11. Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California. 12. Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan. 13. Hypertrophic Cardiomyopathy Program, New York University School of Medicine, New York, New York. 14. Duke Cardiology, Duke Health Center at Southpoint, Durham, North Carolina. 15. Division of Cardiovascular Medicine, University of Utah, Salt Lake City, Utah. 16. Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. 17. Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon.
Abstract
BACKGROUND:Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM. OBJECTIVES: MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM. METHODS: The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6. RESULTS:Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of -435 and -6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of -0.008 and 0.001 ng/ml, respectively (p = 0.009). CONCLUSIONS:Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764).
RCT Entities:
BACKGROUND:Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM. OBJECTIVES:MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM. METHODS: The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6. RESULTS: Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of -435 and -6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of -0.008 and 0.001 ng/ml, respectively (p = 0.009). CONCLUSIONS:Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764).
Authors: Peter O Awinda; Yemeserach Bishaw; Marissa Watanabe; Maya A Guglin; Kenneth S Campbell; Bertrand C W Tanner Journal: Br J Pharmacol Date: 2020-10-21 Impact factor: 8.739
Authors: Peter O Awinda; Marissa Watanabe; Yemeserach Bishaw; Anna M Huckabee; Keinan B Agonias; Katarzyna Kazmierczak; Danuta Szczesna-Cordary; Bertrand C W Tanner Journal: Am J Physiol Heart Circ Physiol Date: 2020-12-18 Impact factor: 4.733