Original Investigation
Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy

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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)

Key Words

cardiac troponin I (cTnI)
clinical study
hypertrophic cardiomyopathy
mavacamten
N-terminal pro-B-type natriuretic peptide (NT-proBNP)

Abbreviations and Acronyms

cTnI
cardiac troponin I
HCM
hypertrophic cardiomyopathy
LV
left ventricular
LVEF
left ventricular ejection fraction
nHCM
nonobstructive hypertrophic cardiomyopathy
NT-proBNP
N-terminal pro-B-type natriuretic peptide
NYHA
New York Heart Association
oHCM
obstructive hypertrophic cardiomyopathy
PK
pharmacokinetic
pVO2
peak oxygen consumption
SAE
serious adverse event
ITT
intention to treat

Cited by (0)

This study was supported by MyoKardia, Inc. MyoKardia, Inc. was involved in the study design and interpretation of the data, analysis, writing of the report, and in the decision to submit the manuscript for publication. Dr. Ho has been a consultant and a member of the EXPLORER study steering committee for MyoKardia, Inc.; and has served on an advisory board for Ambry Genetics. Drs. Mealiffe, Edelberg, Bhattacharya, Sehnert, and Ma hold stock in MyoKardia, Inc. Dr. Hegde has performed Core Imaging Lab services for MyoKardia, Inc. Dr. Bach has received an institutional grant from MyoKardia, Inc. Dr. Jacoby has received grants from and consulting fees/honorarium for serving on an Advisory Board for MyoKardia, Inc.; and has been a member of the Steering Committee for EXPLORER. Dr. Lakdawala has received consulting fees/honorarium from MyoKardia, Inc. Dr. Marian has received travel expense reimbursements from MyoKardia, Inc. Dr. Owens has received consulting fees/honorarium from MyoKardia, Inc. Dr. Rader has received consulting fees/honorarium and other support from MyoKardia, Inc. Dr. Saberi has received honorarium and travel expense reimbursement for serving on an Advisory Board for MyoKardia, Inc. Dr. Sherrid has received consulting fees/honorarium and other support from Celltrion, Inc. Dr. Solomon has received grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, Inc., National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has received consulting fees/honorarium from Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, MyoKardia, Inc., Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. Dr. Wang has received grants from, has been a primary investigator, and serves on the steering committee for the EXPLORER trial for MyoKardia, Inc.; and has served on an Advisory Board and received an educational grant for the HCM Care App. Dr. Wong has received support to attend an investigator’s meeting for MyoKardia, Inc. Dr. Heitner has received grants from MyoKardia, Inc. during the conduct of the study; and has received other support from MyoKardia, Inc. and Cytokinetics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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