Targeted Medical Therapies for Hypertrophic Cardiomyopathy

Fumagalli, Carlo; Gregorio, Maria Grazia De; Zampieri, Mattia; Fedele, Elisa; Tomberli, Alessia; Chiriatti, Chiara; Marchi, Alberto; Olivotto, Iacopo

doi:10.1007/s11886-020-1258-x

Cited by 14 publications

(24 citation statements)

References 68 publications

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“…In addition, the expected normalization of myofilament Ca 2+ sensitivity in the presence of MAVA could reduce arrhythmia susceptibility in this potentially life-threatening disease. Together with the documented rescue of HCM in animal models following MAVA treatment (Green et al, 2016;Stern et al, 2016;Mamidi et al, 2018;Toepfer et al, 2019) and the growing body of positive results in MAVA clinical studies (Heitner et al, 2019;Fumagalli et al, 2020;Olivotto et al, 2020), the present results increase the perspectives of future research of novel myofilament targeting drugs for cardiac as well as skeletal myopathies.…”

Section: Discussionsupporting

confidence: 54%

“…Recently, it has been shown that MAVA decreases the Ca 2+ sensitivity in both human and mouse ventricle (Awinda et al, 2020;Awinda et al, 2021) and rescues the increase in Ca 2+ sensitivity caused by thin-filament HCM mutations in mouse models (Sparrow et al, 2019). These observations, indicating a window of opportunities in which restoration of physiological sarcomere performance may prevent cardiac remodeling, are the basis for the present use of MAVA in preclinical/clinical trials for HCM treatment, as confirmed by the very promising results of a phase 2 open-label trials (Heitner et al, 2019) and a recently completed multicenter placebocontrolled randomized phase 3 trial (EXPLORER-HCM; Olivotto et al, 2020).…”

Section: Introductionmentioning

confidence: 79%

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Mavacamten has a differential impact on force generation in myofibrils from rabbit psoas and human cardiac muscle

Scellini

Piroddi

Dente

et al. 2021

Journal of General Physiology

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Mavacamten (MYK-461) is a small-molecule allosteric inhibitor of sarcomeric myosins being used in preclinical/clinical trials for hypertrophic cardiomyopathy treatment. A better understanding of its impact on force generation in intact or skinned striated muscle preparations, especially for human cardiac muscle, has been hindered by diffusional barriers. These limitations have been overcome by mechanical experiments using myofibrils subject to perturbations of the contractile environment by sudden solution changes. Here, we characterize the action of mavacamten in human ventricular myofibrils compared with fast skeletal myofibrils from rabbit psoas. Mavacamten had a fast, fully reversible, and dose-dependent negative effect on maximal Ca2+-activated isometric force at 15°C, which can be explained by a sudden decrease in the number of heads functionally available for interaction with actin. It also decreased the kinetics of force development in fast skeletal myofibrils, while it had no effect in human ventricular myofibrils. For both myofibril types, the effects of mavacamten were independent from phosphate in the low-concentration range. Mavacamten did not alter force relaxation of fast skeletal myofibrils, but it significantly accelerated the relaxation of human ventricular myofibrils. Lastly, mavacamten had no effect on resting tension but inhibited the ADP-stimulated force in the absence of Ca2+. Altogether, these effects outline a motor isoform–specific dependence of the inhibitory effect of mavacamten on force generation, which is mediated by a reduction in the availability of strongly actin-binding heads. Mavacamten may thus alter the interplay between thick and thin filament regulation mechanisms of contraction in association with the widely documented drug effect of stabilizing myosin motor heads into autoinhibited states.

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 79%

Mavacamten has a differential impact on force generation in myofibrils from rabbit psoas and human cardiac muscle

Scellini

Piroddi

Dente

et al. 2021

Journal of General Physiology

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“…In 2016 a small-molecule allosteric inhibitor of myosin was discovered (initially coded MYK-461), currently named mavacamten [19]. In contrast to non-specific inotropic negative drugs, mavacamten is a specific compound targeting the primary molecular defect of the cardiomyocyte function [20][21][22].…”

Section: Unmet Clinical Needs In Ohcm With Lvotomentioning

confidence: 99%

Mavacamten — a new disease-specific option for pharmacological treatment of symptomatic patients with hypertrophic cardiomyopathy

Pysz

Rajtar-Salwa²,

Smołka

et al. 2021

Kardiol Pol

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Current pharmacotherapy for hypertrophic cardiomyopathy (HCM) is not disease-specific and has suboptimal efficacy, often necessitating interventional treatment. EXPLORER-HCM was a phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trial investigating the effects of mavacamten, a first-in-class selective cardiac myosin inhibitor, in patients with HCM, left ventricular outflow tract obstruction (LVOTO) and New York Heart Association (NYHA) class II or III symptoms. The primary endpoint was defined as either a ≥1.5 ml/kg/min increase in peak oxygen consumption (pVO 2 ) and ≥1 NYHA class reduction or a ≥3.0 ml/kg/min pVO 2 increase without NYHA class worsening. Secondary endpoints evaluated changes in post-exercise LVOT gradient, pVO 2 , NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). A total of 251 patients were randomized to receiving mavacamten or placebo. The primary endpoint and all secondary endpoints were met significantly more frequently in the mavacamten arm versus placebo. The safety profile of mavacamten was similar to that of placebo. In conclusion, disease-specific treatment with mavacamten in patients with obstructive HCM led to reduced LVOTO and improvement in both objective functional parameters and patient-related health status.

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“…More recently, OM was shown to activate the cardiac ryanodine receptor (RyR) calcium release channel, which may promote a proarrhythmic risk (10,11). Mava is in the third phase of clinical trials as a therapeutic for hypercontractility in HCM caused by myosin mutations (12). Recently, Mava was also proposed for treatment of HCM caused by mutations in the calcium regulatory thin filament protein troponin (13).…”

Section: Introductionmentioning

confidence: 99%

Actin-binding compounds that affect the kinetics of the interaction of cardiac myosin with actin

Roopnarine

Thomas

2020

Preprint

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We measured the effects of ten actin-binding compounds on the interaction of cardiac myosin subfragment 1 (S1) with pyrene labeled F-actin (PFA). These compounds, previously identified from a small-molecule high-throughput screen (HTS), perturb the microsecond structural dynamics of actin and the steady-state activity of actin-activated myosin ATPase. In the present study, we have further characterized their mechanisms of action by measuring their effects on PFA fluorescence, which is decreased specifically by the strong binding of myosin to actin, and is restored upon release of S1 by MgATP. We measured the effects of compounds under equilibrium and steady-state conditions, as affected by S1 and ATP, and also under transient conditions, in stopped-flow experiments following rapid addition of ATP to S1-bound PFA. We observe that these compounds affect the early steps of the myosin ATPase cycle to different extents (mild, moderate, and severe). The compounds decrease the equilibrium constant for the formation of the collision complex and the rate constant for subsequent isomerization to the ternary complex, indicating increased ATP affinity and trapping of ATP in the myosin active site. These compound effects on actin structure inhibit the kinetics of the actin-myosin interaction in ways that may be desirable for possible treatment of hypercontractile forms of hypertrophic cardiomyopathy (HCM). This work helps to elucidate the mechanisms of action of these compounds, several of which are currently used therapeutically, and it sets the stage for future HTS campaigns on a larger scale, to discover new drugs for treatment of heart failure.

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Targeted Medical Therapies for Hypertrophic Cardiomyopathy

Cited by 14 publications

References 68 publications

Mavacamten has a differential impact on force generation in myofibrils from rabbit psoas and human cardiac muscle

Mavacamten has a differential impact on force generation in myofibrils from rabbit psoas and human cardiac muscle

Mavacamten — a new disease-specific option for pharmacological treatment of symptomatic patients with hypertrophic cardiomyopathy

Actin-binding compounds that affect the kinetics of the interaction of cardiac myosin with actin

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