Bovine cardiac myosin (IC50 = 490 nM); Human cardiac myosin (IC50 = 711 nM) [1].

Mavacamten selectively targets the beta-cardiac myosin heavy chain ATPase. It binds allosterically and reversibly to the catalytic domain of cardiac myosin, modulating the number of myosin heads that can enter the "on-actin" (power-generating) state and shifting the overall myosin population towards an energy-sparing, super-relaxed state.

In Vitro: Mavacamten (SAR-439152; MYK-461) acts as a modulator of cardiac myosin, affecting multiple stages of the myosin chemomechanical cycle. It reduces the ATPase activity of cardiac myosin, as demonstrated in in vitro assays with purified cardiac myosin. Additionally, it decreases the force generated by skinned cardiac muscle fibers and slows down the kinetics of cross-bridge cycling. In experiments with isolated cardiac myocytes, the compound reduces contractility, as measured by parameters such as sarcomere shortening velocity and amplitude [1]
Mavacamten is shown to have selectivity of >4-fold for cardiac myosin, with IC50 values of 490 nM in the bovine system, 711 nM in the human system, and 2140 nM in the rabbit system[1].

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Mavacamten potently inhibits the actin-stimulated ATPase activity of cardiac myosin in a concentration-dependent manner. It demonstrates selectivity for cardiac myosin with an IC50 of 490 nM for bovine cardiac myosin and 711 nM for human cardiac myosin. The compound inhibits the phosphate release step, which is the rate-limiting step of the cross-bridge cycle.

In Vivo: In feline models of hypertrophic cardiomyopathy (HCM) with left ventricular outflow tract (LVOT) obstruction, acute administration of Mavacamten (SAR-439152; MYK-461) relieved LVOT obstruction, as evidenced by a significant reduction in the peak gradient across the LVOT. This effect was accompanied by a decrease in left ventricular systolic pressure and an improvement in cardiac hemodynamics [2]
In a mouse model of HCM (Myh6-R403Q transgenic mice), chronic administration of Mavacamten (SAR-439152; MYK-461) suppressed the development of cardiac hypertrophy, as indicated by reduced heart weight-to-body weight ratio and decreased ventricular wall thickness. It also improved diastolic function, as measured by echocardiographic parameters such as E/A ratio, and reduced myocardial fibrosis, as assessed by histological analysis. Furthermore, the compound normalized gene expression patterns associated with hypertrophy, including reduced expression of genes such as Nppa and Myh7 [3]

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Mavacamten treatment lowers FS from 52±3% to 38±7%. Mavacamten treatment lowers FS from 81±7% to 60±13%, which is a 25% relative reduction. There is a linear relationship between FS and Mavacamten plasma concentrations across all assays; for every 100 ng/mL rise in Mavacamten concentration, FS is lowered by 4.9%[2]. By lowering the cardiac myosin heavy chain's adenosine triphosphatase activity, mavacamten decreases contractility. In mice with heterozygous human mutations in the myosin heavy chain, chronic Mavacamten treatment inhibits the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression[3].

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In vivo, Mavacamten reduces cardiac contractility without altering calcium transients. In mouse models of hypertrophic cardiomyopathy (HCM), chronic treatment attenuates the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis. In rats subjected to ischemia-reperfusion injury, administration of 2.0 mg/kg significantly reduces infarct size from 60% to 38%.

Steady-state characterization [1]
ATPase measurements were conducted using a coupled enzyme system utilizing pyruvate kinase and lactate dehydrogenase. Unless otherwise stated, the buffer system used in all experiments was 12 mm Pipes, 2 mm MgCl2, 1 mm DTT at pH 6.8 (PM12 buffer). All steady-state experiments were carried out at 20 °C using a SpectraMax 384Plus plate reader, and rates were recorded using the SoftMax Pro software package. For all steady-state experiments, data were collected in triplicate and averaged, with n = 3. The value for n refers to the number of individual experiments performed. All data analysis of the steady-state systems were conducted using GraphPad Prism.

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Transient kinetic characterization[1]
Transient kinetic experiments were performed using a stopped-flow apparatus (Hi-Tech Scientific, SF-61 DX2) to determine the effects of mavacamten on myosin association and dissociation from actin filaments, phosphate (Pi) release, and 2′-(or-3′)-O-(N-methylanthraniloyl)-ADP (mant-ADP/ATP) release by myosin. For each data point, transient traces were collected in triplicate and averaged for each experiment, with n = 3. All transient experiments were performed with either varying amounts of mavacamten or single concentrations of mavacamten at varying substrate concentrations to determine a concentration-dependent change in each kinetic parameter, and control experiments were carried out with 2% DMSO final. For mant-ATP or mant-ADP experiments, fluorescence emission was measured through a 400-nm cutoff filter with excitation at 365 nm. The increase in fluorescence upon myosin binding mant-ATP or decrease in fluorescence after release of mant-ADP was monitored as previously described.[1]
The rates of Pi release were measured using the bacterial phosphate-binding protein (PBP) modified with 7-diethyl-amino-3-[[[2-(maleimidyl)ethyl]amino]carbonyl] coumarin (MDCC) dye prepared according to Brune et al. The stopped flow instrument was set up in double mix mode. In this configuration nucleotide free myosin-S1 was mixed with ATP at a 1:1 molar ratio and aged for 2 s to allow for complete hydrolysis. The myosin-nucleotide complex was then rapidly mixed with actin plus MDCC-PBP, and the fluorescence increase due to phosphate binding was measured through a 455-nm cutoff filter with excitation at 425 nm. This system was used to measure the effect of mavacamten by varying the concentration of compound in all syringes and comparing the data to a DMSO control. Before data collection, contaminating phosphate was removed from the system by soaking with a “Pi-mop,” which consisted of purine nucleoside phosphorylase and 7-methylguanosine at concentrations of 1 units/ml and 0.5 mm, respectively. This Pi-mop was also present in all solutions at concentrations of 0.1 units/ml purine nucleoside phosphorylase and 0.25 mm 7-methylguanosine to remove any residual phosphate.[1]
Myosin-S1 association to pyrene-actin filaments was monitored by the quenching of pyrene fluorescence that occurs upon S1 binding to pyrene-actin. The kinetics of ATP-induced acto-S1 dissociation was measured by monitoring the increase in pyrene fluorescence upon mixing pyrene-acto-S1 with increasing concentrations of ATP. Pyrene fluorescence was measured using a 400-nm cutoff filter with excitation at 360 nm. This interaction was also used to monitor the transition from the weakly to strongly bound state of myosin to actin. Briefly, bovine cardiac myosin-S1 and ATP were mixed under single turnover conditions and allowed to age for 2 s to hydrolyze the ATP to ADP-Pi. This mixture was then mixed with pyrene actin in a 1:1 ratio with myosin and 1 mm ADP to shift the equilibrium to the strongly bound state. The quenching of pyrene actin was monitored with varying concentrations of mavacamten, and the reaction amplitudes were analyzed.[1]

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Enzyme Assay: To assess the effect of Mavacamten (SAR-439152; MYK-461) on cardiac myosin ATPase activity, purified cardiac myosin was incubated with different concentrations of the compound in the presence of ATP. The rate of ATP hydrolysis was measured by monitoring the production of inorganic phosphate over time using a colorimetric assay. The results were used to determine the impact of the compound on myosin's enzymatic activity [1]
For analyzing the effect on cross-bridge kinetics, skinned cardiac muscle fibers were prepared and mounted in a force transducer. The fibers were activated in a solution containing calcium, and the effect of Mavacamten (SAR-439152; MYK-461) on parameters such as force development, relaxation rate, and cross-bridge cycling kinetics was measured by recording force changes over time [1]

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The inhibitory activity of Mavacamten on cardiac myosin ATPase is typically measured using a NADH-coupled enzymatic assay. Purified bovine or human cardiac myosin is incubated with actin in an ATP regeneration system containing NADH, pyruvate kinase, and lactate dehydrogenase. The reaction is initiated by the addition of ATP, and the decrease in absorbance at 340 nm (reflecting NADH oxidation) is monitored continuously to determine the ATP hydrolysis rate in the presence of varying concentrations of Mavacamten.

Cell Assay: Isolated cardiac myocytes were used to evaluate the effect of Mavacamten (SAR-439152; MYK-461) on contractility. Myocytes were loaded with a calcium indicator, and sarcomere length changes were monitored using video microscopy during electrical stimulation. Different concentrations of the compound were applied, and parameters such as sarcomere shortening amplitude, maximum shortening velocity, and relaxation time were quantified to assess changes in contractility [1]

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Cardiac myofibrils were prepared as previously described. Bovine cardiac tissue was harvested, placed immediately on wet ice, and shipped overnight, and the left ventricle and septum were dissected, frozen in liquid nitrogen, and stored at −80 °C. Human tissue was procured from BioReclamations IVT, and myofibrils were prepared on the day of receipt. Cardiac and skeletal myosin S1 was prepared using a chymotryptic digestion of full-length myosin prepared from bovine cardiac left ventricle and rabbit psoas muscle, respectively. Bovine cardiac HMM was prepared according to Margossian and Lowey. Human cardiac myosin subfragment-1 was expressed in differentiated murine C2C12 myotubes using an adenovirus infection method. The recombinant product utilized a 6×-histidine tag on the essential light chain for initial purification on Ni2+-resin with further purification by anion exchange and size exclusion chromatography. All myofibril and myosin-S1 preparations were brought to 10% sucrose, snap-frozen in liquid nitrogen, and stored at −80 °C. Actin was prepared from a bovine cardiac acetone powder (Pel Freez Biologicals) according to the method of Spudich and Watt. Pyrene actin was prepared according to the method of Criddle et al.[1]

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Primary adult rat ventricular cardiomyocytes (ARVC) are isolated and seeded in laminin-coated plates. After overnight incubation, cells are pre-treated with Mavacamten (e.g., 0.1-5 µM) or vehicle for 30 minutes. Hypercontracture is then induced by adding 5 µM carbonyl cyanide m-chlorophenylhydrazone (CCCP) to deplete ATP. Time-lapse microscopy is used to record the percentage of cells undergoing irreversible cell shortening over a 30-minute period.

Cats[2] Five cats are selected for study. At the completion of imaging, a tenminute intravenous infusion of Mavacamten (MYK-461 (n=5)) at 0.3 mg/kg/hr IV is started. Focused echocardiography is performed after five minutes. After ten minutes, the Mavacamten infusion rate is lowered to 0.12 mg/kg/hr IV, a blood sample is drawn and an echocardiogram performed. If ventricular function remains hypercontractile or within normal limits by visual inspection, another blood sample is obtained and the Mavacamten infusion rate is increased to 0.36 mg/kg/hr IV for ten minutes. Focused echocardiography is performed after five minutes. After ten minutes, the Mavacamten infusion rate is lowered to 0.15 mg/kg/hr IV, a blood sample is drawn and an echocardiogram performed. Following imaging, the isoproterenol infusion is discontinued. When heart rate returns to baseline levels, a complete echocardiogram is performed on Mavacamten alone. Study drug is then discontinued, and animals are awakened, extubated and moved to recovery. Three of five cats are available to return for a control arm of this experiment after a 6-week washout period[2].

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Animal Protocol: For the feline HCM model, cats with naturally occurring HCM and LVOT obstruction were used. Mavacamten (SAR-439152; MYK-461) was administered intravenously as a single bolus at a specified dose. Hemodynamic parameters, including LVOT gradient, left ventricular pressure, and aortic pressure, were measured using invasive catheterization before and after drug administration [2]
In the mouse HCM model (Myh6-R403Q transgenic mice), Mavacamten (SAR-439152; MYK-461) was administered orally via food at a specified dose starting from a young age (4 weeks) and continued for a prolonged period (up to 24 weeks). Mice were monitored regularly, and echocardiographic assessments were performed at different time points to evaluate cardiac structure and function. At the end of the treatment period, mice were euthanized, and hearts were collected for histological and molecular analyses [3]

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Healthy male Sprague-Dawley rats are anesthetized and subjected to coronary artery ligation for 30 minutes to induce ischemia, followed by 2 hours of reperfusion. Mavacamten (2.0 mg/kg) or vehicle is administered via intraperitoneal injection 10-30 minutes prior to reperfusion. At the end of the protocol, the area at risk is determined by Evans Blue staining, and infarct size is measured by tetrazolium chloride (TTC) staining.

Absorption, Distribution and Excretion
The estimated oral bioavailability of mavacamten is at least 85%, with a Tmax of 1 hour. In patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, the exposure (AUC) of mavacamten is increased by up to 220%. The effect in severe (Child-Pugh C) hepatic impairment is unclear. Following a single 25 mg dose of radiolabeled mavacamten, 7% of the dose is recovered in feces (1% unchanged) and 85% in urine (3% unchanged). The volume of distribution of mavacamten in humans is predicted to be 9.5 L/kg by simple allometric scaling of the free blood steady-state volume of distribution in four animal groups (mice, rats, dogs, and cynomolgus monkeys).
Mavacastin has a long terminal half-life, resulting in low clearance; plasma clearance estimated using human hepatocytes is less than 4.9 mL/min/kg. Assuming a single-compartment model and using simple allometric scaling of free plasma clearance in mice, rats, dogs, and cynomolgus monkeys, the estimated human plasma clearance of malavacastin is 0.51 mL/min/kg.
Absorption
The oral bioavailability of malavacastin is estimated to be at least 85%, with a time to peak concentration (Tmax) of 1 hour. Malavacastin exposure (AUC) is increased by up to 220% in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. The effect in patients with severe (Child-Pugh C) hepatic impairment is unclear.
Elimination Pathway
After a single 25 mg dose of radiolabeled malavacasine, 7% of the dose is recovered in feces (1% unchanged) and 85% is recovered in urine (3% unchanged).
Volume of Distribution
The volume of distribution of malavacasine in humans is predicted to be 9.5 L/kg using simple allometric scaling of the free blood steady-state volume of distribution in mice, rats, dogs, and cynomolgus monkeys.
Clearance
Mavacasine has a long terminal half-life, resulting in a low clearance rate. The plasma clearance estimated using human hepatocytes is less than 4.9 mL/min/kg. Assuming a single-compartment model and using simple allometric scaling of free blood clearance in mice, rats, dogs, and cynomolgus monkeys, the plasma clearance of malavacasine in humans is estimated to be 0.51 mL/min/kg.

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Metabolism/Metabolites
Mavacamten has a wide range of metabolic pathways, primarily through CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%).

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Biological Half-Life
The terminal half-life (t1/2) of mavacamten varies depending on the CYP2C19 metabolic state. In normal CYP2C19 metabolizers (NM), the terminal half-life of mavacamten is 6–9 days; while in weak CYP2C19 metabolizers (PM), the terminal half-life can be extended to 23 days.

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Mavacamten exhibits high permeability and low efflux, with excellent oral bioavailability and a long terminal elimination half-life across species. It is primarily metabolized in the liver by CYP2C19 (74%), with minor contributions from CYP3A4 (18%) and CYP2C9 (8%). The pharmacokinetics are linear and well-described by a two-compartment model. CYP2C19 phenotype is the most significant covariate affecting exposure.

Toxicity Overview
Overdose Symptoms and Signs
Mavacartan overdose is associated with systolic dysfunction, which may manifest as decreased functional capacity and worsening heart failure. Although no carcinogenic or mutagenic effects have been found in malavacartan, animal studies have shown that subjects taking 10 mg/kg daily may experience QT interval prolongation and cardiac ossification.

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Overdose Management
There is currently no specific antidote for malavacartan. In case of overdose, malavacartan should be discontinued immediately, and efforts should be made to maintain hemodynamic stability while closely monitoring left ventricular function. Activated charcoal taken within 2 hours of administration can effectively reduce the absorption of malavacartan; however, taking it 6 hours after administration has no effect on the level of drug exposure. Contact a poison control center or medical toxicologist for the latest advice.

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Use During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information regarding the use of malavacartan during lactation. Because of its high plasma protein binding rate of 97% to 98%, the malavacartan content in breast milk may be very low. If a mother needs to take malavacartan, this is not a reason to stop breastfeeding. Until more data is available, malavacartan should be used with caution during lactation, especially when breastfeeding newborns or premature infants.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Adverse Reactions Malavacartan can reduce contractility, potentially leading to worsening heart failure or complete ventricular block. Left ventricular ejection fraction (LVEF) has been reported to decrease by up to 10%. In the Phase III EXPLORER trial, dizziness (27%) and syncope (6%) were the most common adverse reactions. Potential adverse reactions associated with mavacamten treatment include: Acute stress cardiomyopathy Ventricular tachycardia Angina pectoris Headache Dyspnea Chest pain Fatigue Palpitation Foot edema Atrial fibrillation Drug Interactions: Concomitant use with weak CYP2C19 inhibitors or intermediate-acting CYP3A4 inhibitors increases mavacamten exposure. For patients receiving stable therapy with these inhibitors, the starting dose of mavacamten should be 5 mg daily. For patients already taking mavacamten, the dose should be reduced (e.g., from 15 mg to 10 mg) when starting these inhibitors. Due to the lack of lower dose options, patients taking 2.5 mg mavacamten should avoid using weak CYP2C19 inhibitors and intermediate-acting CYP3A4 inhibitors.
Concomitant use of malavacattan with drugs that have adverse positive inotropic effects may worsen cardiac dysfunction. Due to the increased risk of left ventricular systolic dysfunction and heart failure, it should be avoided with disopyramide, ranolazine, verapamil, beta-blockers, or diltiazem. Close monitoring of left ventricular ejection fraction (LVEF) is crucial before initiating or adjusting the dose of negative inotropic drugs until a stable dose and clinical efficacy are achieved.
Plasma protein binding

The plasma protein binding rate of malavacattan is between 97% and 98%.

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In preclinical studies, Mavacamten demonstrates a predictable and reversible effect on cardiac function, with contractile inhibition correlating directly with plasma concentrations. Clinical data show a concentration-dependent increase in the QTc interval at high doses in healthy volunteers, though this is not considered clinically relevant at therapeutic exposures in HCM patients. The compound is not a significant inhibitor of CYP enzymes, suggesting a low risk for drug-drug interactions.

[1]. A small-molecule modulator of cardiac myosin acts on multiple stages of the myosin chemomechanical cycle. J Biol Chem. 2017 Oct 6;292(40):16571-16577.

[2]. A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Left Ventricular Outflow Tract Obstruction in Feline Hypertrophic Cardiomyopathy. PLoS One. 2016 Dec 14;11(12):e0168407.

[3]. A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science. 2016 Feb 5;351(6273):617-21.

Mavacamten is a myosin inhibitor indicated for the treatment of symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) in adult patients. It received preliminary approval from the U.S. FDA in 2022, becoming one of the first myosin inhibitors to be used in humans. Mavacamten also received approval from Health Canada in October 2022 and the European Medicines Agency (EMA) in July 2023 for the same indication. Mavacamten is a cardiac myosin inhibitor. Its mechanism of action is as a cardiac myosin inhibitor.

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Drug Indications
Approved by the U.S. Food and Drug Administration (FDA), Health Canada, and the European Medicines Agency (EMA), mavacamten is indicated for the treatment of symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) in adult patients to improve their function and symptoms.
Treatment of symptomatic obstructive hypertrophic cardiomyopathy.
Therapeutic Effects on Hypertrophic Cardiomyopathy

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Mechanism of Action
Myosin is an enzyme that generates mechanical output through ATP-mediated cyclic interactions with actin. When ATP binds to the myosin head, myosin ATPase activity hydrolyzes it into ADP and an organophosphate, storing the energy produced in the myosin head. When the organophosphate dissociates from myosin, it creates a strong binding state between myosin and actin, forming a myosin-actin complex, the so-called "cross-bridge." The dissociation of the organophosphate also leads to a conformational change in myosin, generating stress in the actin-myosin bridge. This stress is only released when actin and myosin filaments slide against each other, shortening the sarcomere and causing muscle contraction. After sliding, ADP is released, further propelling the myosin head. Although the amplitude of this ADP release-induced movement is small and unlikely to have a significant effect on sarcomere movement, researchers speculate that this movement may be crucial in limiting the sliding speed of actin. Finally, myosin binds to new ATP molecules, restarting the chemomechanical cycle. Mavacamten reduces sarcomere hypercontractility by acting as an allosteric reversible regulator of the myosin β-cardiac isoform, thereby decreasing its ATPase activity and consequently reducing actin-myosin cross-bridges. Specifically, mavacamten inhibits phosphate release (the rate-limiting step in the ATP cycle) without affecting the rate of ADP release from actin-bound myosin. Furthermore, mavacamten inhibits ADP binding between myosin and actin, as well as ADP release, thus preventing the myosin head from initiating ATP turnover. Recent studies have also found that when myosin is not in an active state interacting with actin, it exists in a balance between two energy-saving states: a disordered relaxation state, in which actin and myosin interact through filament-regulated proteins; and a hyperrelaxed state, in which significant interactions between myosin heads prolong the ATP turnover rate. The binding of mavacamten to myosin shifts this balance towards the hyperrelaxed state, effectively exerting both basal ATP inhibition and actin-activated ATP inhibition.

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Pharmacodynamics
Mavacartan is a myosin inhibitor used to prevent excessive muscle contraction. It binds to myosin and inhibits the interaction between myosin and actin at various stages of the thermomechanical cycle. Mechanistic studies have shown that magavacartan inhibits myosin in both active and relaxed states, thereby effectively alleviating the hallmark of hypertrophic cardiomyopathy—excessive sarcomere power. In the EXPLORER-HCM trial, patients showed a reduction in mean resting and evoked (Valsalva action) left ventricular outflow tract (LVOT) pressure gradients at week 4, which was maintained throughout the 30-week trial. At week 30, the mean (standard deviation) changes from baseline in the CAMZYOS group for resting and Valsalva action LVOT pressure gradients were -39 (29) mmHg and -49 (34) mmHg, respectively, compared to -6 (28) mmHg and -12 (31) mmHg in the placebo group. The decrease in LVOT gradient during the Valsalva action was accompanied by a decrease in left ventricular ejection fraction (LVEF), but usually within the normal range. Eight weeks after discontinuation of CAMZYOS, the mean LVEF and Valsalva left ventricular outflow tract (LVOT) gradient were similar to baseline. Echocardiographic measurements of cardiac structures showed that at week 30, the mean left ventricular mass index (LVMI) in the mavacamten group was -7.4 [17.8] g/m² from baseline, while the LVMI in the placebo group was increased (8.9 [15.3] g/m²). The mean left atrial volume index (LAVI) in the mavacamten group was also decreased from baseline (-7.5 [7.8] mL/m²), while there was no change in the placebo group (-0.1 [8.7] mL/m²). The clinical significance of these findings is unclear. A decrease in the level of the myocardial wall stress biomarker NT-proBNP was observed at week 4 and persisted until the end of treatment. At week 30, the reduction in NT-proBNP levels after mavacamten treatment was 80% greater than in the placebo group compared to baseline (geometric mean odds ratio 0.20 [95% CI: 0.17, 0.24]). The clinical significance of these findings is unclear. In healthy volunteers receiving multiple doses of mavacamten at once-daily doses up to 25 mg, a concentration-dependent prolongation of the QTc interval was observed. No similar acute QTc interval changes were observed at single-dose studies. The mechanism of QT interval prolongation is unclear. A meta-analysis of clinical studies in HCM patients showed that QTc interval prolongation was not clinically significant within the therapeutic exposure range. In HCM patients, the QT interval itself may be prolonged due to underlying disease, ventricular pacing, or medications commonly used in the HCM population with QT interval prolongation potential. The role of mavacamten in combination with QT prolonging drugs or in patients with QT prolongation due to potassium channel mutations is not yet clear.

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Mavacamten (SAR-439152; MYK-461) is a small molecule sarcomere contractility inhibitor that works by modulating cardiac myosin function. Its mechanism of action is to reduce the number of myosin heads available for cross-bridge formation, thereby reducing myocardial contractility. This characteristic makes it a potential drug for treating diseases characterized by excessive myocardial contractility, such as hypertrophic cardiomyopathy.

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Myosin is a class of enzymes that produce mechanical output through ATP-mediated cyclic interactions with actin. When ATP binds to a myosin head, myosin ATPase activity hydrolyzes it into ADP and an organophosphate, storing the energy produced in the myosin head. When the organophosphate dissociates from myosin, it creates a strong binding state between myosin and actin, forming a myosin-actin complex, the so-called "cross-bridge". The dissociation of organophosphates also leads to conformational changes in myosin, generating stress in the actin-myosin bridges. This stress is only released when actin and myosin filaments slide against each other, shortening the sarcomere and inducing muscle contraction. After sliding, ADP is released, further propelling the myosin head. Although the amplitude of this ADP release-induced movement is small and unlikely to significantly affect sarcomere motion, researchers speculate that this movement may be crucial in limiting the sliding speed of actin. Finally, myosin binds to new ATP molecules, restarting the chemomechanical cycle. Mavacamten reduces sarcomere hypercontractility by acting as an allosteric reversible regulator of the myosin β-cardiac isoform, thereby reducing its ATPase activity and consequently decreasing actin-myosin cross-bridges. Specifically, Mavacamten inhibits phosphate release (the rate-limiting step in the ATP cycle) without affecting the rate of ADP release from actin-bound myosin. Furthermore, Mahalakamen inhibits ADP binding to myosin and actin, as well as ADP release, thereby preventing the myosin head from initiating ATP turnover. Recent studies have also found that when myosin is not in an active state interacting with actin, it exists in a balance between two energy-saving states: a disordered relaxation state, in which actin and myosin interact through filament-regulated proteins; and a hyperrelaxed state, in which significant interactions between myosin heads prolong the ATP turnover rate. The binding of Mahalakamen to myosin can shift this balance towards the hyperrelaxed state, thus effectively exerting a dual effect of basal ATP inhibition and actin-activated ATP inhibition.

C15H19N3O2

273.336

273.147

C, 65.91; H, 7.01; N, 15.37; O, 11.71

1642288-47-8

Mavacamten-d6;2453251-18-6;Mavacamten-d1;2453251-02-8;Mavacamten-d5;2453251-00-6

117761397

White to off-white solid powder

1.2±0.1 g/cm3

1.591

2.65

2

3

4

20

411

1

O=C1NC(=CC(N1C(C)C)=O)N[C@@H](C)C1C=CC=CC=1

RLCLASQCAPXVLM-NSHDSACASA-N

InChI=1S/C15H19N3O2/c1-10(2)18-14(19)9-13(17-15(18)20)16-11(3)12-7-5-4-6-8-12/h4-11,16H,1-3H3,(H,17,20)/t11-/m0/s1

(S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione

MYK 461; SAR-439152; MYK-461; SAR 439152; SAR439152; Camzyos; MYK-461; SAR-439152; 6-[[(1S)-1-phenylethyl]amino]-3-propan-2-yl-1H-pyrimidine-2,4-dione; Mavacamten [INN]; Mavacamten [USAN]; MYK461; Mavacamten

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~83.33 mg/mL (~304.87 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.15 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (7.61 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)