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Drugs Jul 2022Mavacamten (Camzyos™) is an oral small-molecule cardiac myosin inhibitor developed by MyoKardia, Inc., a wholly owned subsidiary of Bristol Myers Squibb, for the... (Review)
Review
Mavacamten (Camzyos™) is an oral small-molecule cardiac myosin inhibitor developed by MyoKardia, Inc., a wholly owned subsidiary of Bristol Myers Squibb, for the treatment of hypertrophic cardiomyopathy (HCM) and diseases of diastolic dysfunction. In April 2022, mavacamten was approved for use in the USA in the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive HCM to improve functional capacity and symptoms. This article summarizes the milestones in the development of mavacamten leading to this first approval for the treatment of adults with symptomatic NYHA class II-III obstructive HCM.
Topics: Adult; Benzylamines; Cardiac Myosins; Cardiomyopathy, Hypertrophic; Humans; Uracil
PubMed: 35802255
DOI: 10.1007/s40265-022-01739-7 -
Journal of the American College of... Jun 2020Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By... (Randomized Controlled Trial)
Randomized Controlled Trial
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).
Topics: Adult; Aged; Benzylamines; Biomarkers; Cardiomyopathy, Hypertrophic; Double-Blind Method; Echocardiography; Female; Humans; Male; Middle Aged; Uracil
PubMed: 32466879
DOI: 10.1016/j.jacc.2020.03.064 -
Science (New York, N.Y.) Feb 2016Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an...
Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an abnormal thickening of the heart, but the earliest signs of disease are hyperdynamic contraction and impaired relaxation. Whereas some in vitro studies of power generation by mutant and wild-type sarcomere proteins are consistent with mutant sarcomeres exhibiting enhanced contractile power, others are not. We identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. Here we demonstrate that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human mutations in the myosin heavy chain. These data indicate that hyperdynamic contraction is essential for HCM pathobiology and that inhibitors of sarcomere contraction may be a valuable therapeutic approach for HCM.
Topics: Adenosine Triphosphatases; Animals; Benzylamines; Cardiac Myosins; Cardiomyopathy, Hypertrophic, Familial; Cells, Cultured; Disease Models, Animal; Fibrosis; Heart Ventricles; Heterozygote; Humans; Male; Mice; Mice, Inbred Strains; Mutation; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Myosin Heavy Chains; Rats; Sarcomeres; Uracil
PubMed: 26912705
DOI: 10.1126/science.aad3456 -
Drug Design, Development and Therapy 2023Hypertrophic cardiomyopathy (HCM) is a condition with abnormal hypertrophy of the left ventricle in the absence of common causes. The most common form involves the basal... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a condition with abnormal hypertrophy of the left ventricle in the absence of common causes. The most common form involves the basal septum and can lead to obstruction of the left ventricular outflow tract. Patients can experience exertional symptoms such as chest pain, dyspnea and syncope. Traditional treatment has included beta blockers and nondihydropyridine calcium channel blockers with second-line therapy being disopyramide. Recently, mavacamten, a cardiac myosin inhibitor, has demonstrated improvement in quantitative measures of obstruction and symptom relief to such a degree that patients were able to defer invasive management of the disease. This review focuses on the pharmacology of mavacamten, its clinical trial data and guidance on how to incorporate this drug into clinical practice. Furthermore, it discusses emerging therapies currently being investigated for HCM.
Topics: Humans; Cardiomyopathy, Hypertrophic; Heart; Benzylamines; Calcium Channel Blockers
PubMed: 37064432
DOI: 10.2147/DDDT.S368590 -
European Heart Journal Nov 2023Mavacamten is a first-in-class, targeted, cardiac-specific myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic... (Review)
Review
Mavacamten is a first-in-class, targeted, cardiac-specific myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic New York Heart Association Classes II and III obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten was developed to target the hyper-contractile phenotype, which plays a critical role in the pathophysiology of the disease. In Phase 2 and 3 clinical trials, mavacamten was well tolerated, reduced left ventricular outflow tract gradients, improved exercise capacity and symptoms, and was associated with improvements in other clinically relevant parameters, such as patient-reported outcomes and circulating biomarkers. In addition, treatment with mavacamten was associated with evidence of favourable cardiac remodelling in multi-modality imaging studies. Mavacamten substantially reduced guideline eligibility for septal reduction therapy candidates with oHCM and drug-refractory symptoms. In this article, the available efficacy and safety data from completed and ongoing clinical studies of mavacamten in patients with symptomatic oHCM are reviewed. Longer term extension studies may help address questions related to the positioning of mavacamten in current oHCM management algorithms, interactions with background therapy, as well as the potential for disease modification beyond symptomatic relief of left ventricular outflow tract obstruction.
Topics: Adult; Humans; Benzylamines; Cardiomyopathy, Hypertrophic; Heart; United States; Uracil
PubMed: 37804245
DOI: 10.1093/eurheartj/ehad637 -
Circulation Research Apr 2019Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in combination with CRISPR/Cas9 genome editing provide unparalleled opportunities to study cardiac...
RATIONALE
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in combination with CRISPR/Cas9 genome editing provide unparalleled opportunities to study cardiac biology and disease. However, sarcomeres, the fundamental units of myocyte contraction, are immature and nonlinear in hiPSC-CMs, which technically challenge accurate functional interrogation of contractile parameters in beating cells. Furthermore, existing analysis methods are relatively low-throughput, indirectly assess contractility, or only assess well-aligned sarcomeres found in mature cardiac tissues.
OBJECTIVE
We aimed to develop an analysis platform that directly, rapidly, and automatically tracks sarcomeres in beating cardiomyocytes. The platform should assess sarcomere content, contraction and relaxation parameters, and beat rate.
METHODS AND RESULTS
We developed SarcTrack, a MatLab software that monitors fluorescently tagged sarcomeres in hiPSC-CMs. The algorithm determines sarcomere content, sarcomere length, and returns rates of sarcomere contraction and relaxation. By rapid measurement of hundreds of sarcomeres in each hiPSC-CM, SarcTrack provides large data sets for robust statistical analyses of multiple contractile parameters. We validated SarcTrack by analyzing drug-treated hiPSC-CMs, confirming the contractility effects of compounds that directly activate (CK-1827452) or inhibit (MYK-461) myosin molecules or indirectly alter contractility (verapamil and propranolol). SarcTrack analysis of hiPSC-CMs carrying a heterozygous truncation variant in the myosin-binding protein C ( MYBPC3) gene, which causes hypertrophic cardiomyopathy, recapitulated seminal disease phenotypes including cardiac hypercontractility and diminished relaxation, abnormalities that normalized with MYK-461 treatment.
CONCLUSIONS
SarcTrack provides a direct and efficient method to quantitatively assess sarcomere function. By improving existing contractility analysis methods and overcoming technical challenges associated with functional evaluation of hiPSC-CMs, SarcTrack enhances translational prospects for sarcomere-regulating therapeutics and accelerates interrogation of human cardiac genetic variants.
Topics: Algorithms; Benzylamines; Cardiovascular Agents; Carrier Proteins; Clustered Regularly Interspaced Short Palindromic Repeats; Computer-Aided Design; Fluorescence; Humans; Induced Pluripotent Stem Cells; Microscopy, Atomic Force; Myocardial Contraction; Myocytes, Cardiac; Myosins; Propranolol; Sarcomeres; Software; Uracil; Urea; Verapamil; Video Recording
PubMed: 30700234
DOI: 10.1161/CIRCRESAHA.118.314505 -
Journal of the American College of... Dec 2021EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy) demonstrated that mavacamten, a cardiac... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy) demonstrated that mavacamten, a cardiac myosin inhibitor, improves symptoms, exercise capacity, and left ventricular outflow tract (LVOT) obstruction in patients with obstructive hypertrophic cardiomyopathy (oHCM).
OBJECTIVES
The purpose of this study was to evaluate mavacamten's effect on measures of cardiac structure and function and its association with changes in other clinical measures.
METHODS
Key echocardiographic parameters from serial echocardiograms over 30 weeks from 251 symptomatic oHCM patients (mavacamten [n = 123], placebo [n = 128]) were assessed in a core laboratory.
RESULTS
More patients on mavacamten (80.9%; n = 76 of 94) vs placebo (34.0%; n = 33 of 97) showed complete resolution of mitral valve systolic anterior motion after 30 weeks (difference, 46.8%; P < 0.0001). Mavacamten also improved measures of diastolic function vs placebo, including left atrial volume index (LAVI) (mean ± SD baseline: 40 ± 12 mL/m vs 41 ± 14 mL/m; mean change from baseline of -7.5 mL/m [95% CI: -9.0 to -6.1 mL/m] vs -0.09 mL/m [95% CI: -1.6 to 1.5 mL/m]; P < 0.0001) and lateral E/e' (baseline, 15 ± 6 vs 15 ± 8; change of -3.8 [95% CI: -4.7 to -2.8] vs 0.04 [95% CI: -0.9 to 1.0]; P < 0.0001). Among mavacamten-treated patients, improvement in resting, Valsalva, and post-exercise LVOT gradients, LAVI, and lateral E/e' was associated with reduction in N-terminal pro-B-type natriuretic peptide (P ≤ 0.03 for all). Reduction in LAVI was associated with improved peak exercise oxygen consumption (P = 0.04).
CONCLUSIONS
Mavacamten significantly improved measures of left ventricular diastolic function and systolic anterior motion. Improvement in LVOT obstruction, LAVI, and E/e' was associated with reduction in a biomarker of myocardial wall stress (N-terminal pro-B-type natriuretic peptide). These findings demonstrate improvement in important markers of the pathophysiology of oHCM with mavacamten. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545).
Topics: Aged; Benzylamines; Biomarkers; Cardiac Myosins; Cardiomyopathy, Hypertrophic; Double-Blind Method; Echocardiography; Exercise Tolerance; Female; Heart; Humans; Male; Middle Aged; Uracil
PubMed: 34915982
DOI: 10.1016/j.jacc.2021.09.1381 -
Cell Death & Disease Aug 2021Atrial fibrillation (AF) is an increasingly prevalent arrhythmia with significant health and socioeconomic impact. The underlying mechanism of AF is still not well...
Atrial fibrillation (AF) is an increasingly prevalent arrhythmia with significant health and socioeconomic impact. The underlying mechanism of AF is still not well understood. In this study, we sought to identify hub genes involved in AF, and explored their functions and underlying mechanisms based on bioinformatics analysis. Five microarray datasets in GEO were used to identify the differentially expressed genes (DEGs) by Robust Rank Aggregation (RRA), and hub genes were screened out using protein-protein interaction (PPI) network. AF model was established using a mixture of acetylcholine and calcium chloride (Ach-CaCl) by tail vein injection. We totally got 35 robust DEGs that mainly involve in extracellular matrix formation, leukocyte transendothelial migration, and chemokine signaling pathway. Among these DEGs, we identified three hub genes involved in AF, of which CXCL12/CXCR4 axis significantly upregulated in AF patients stands out as one of the most potent targets for AF prevention, and its effect on AF pathogenesis and underlying mechanisms were investigated in vivo subsequently with the specific CXCR4 antagonist AMD3100 (6 mg/kg). Our results demonstrated an elevated transcription and translation of CXCL12/CXCR4 axis in AF patients and mice, accompanied with the anabatic atrial inflammation and fibrosis, thereby providing the substrate for AF maintenance. Blocking its signaling via AMD3100 administration in AF model mice reduced AF inducibility and duration, partly ascribed to decreased atrial inflammation and structural remodeling. Mechanistically, these effects were achieved by reducing the recruitment of CD3+ T lymphocytes and F4/80+ macrophages, and suppressing the hyperactivation of ERK1/2 and AKT/mTOR signaling in atria of AF model mice. In conclusion, this study provides new evidence that antagonizing CXCR4 prevents the development of AF, and suggests that CXCL12/CXCR4 axis may be a potential therapeutic target for AF.
Topics: Animals; Atrial Fibrillation; Benzylamines; Case-Control Studies; Chemokine CXCL12; Computational Biology; Cyclams; Databases, Genetic; Disease Models, Animal; Electrocardiography; Fibrosis; Gene Expression Profiling; Gene Ontology; Gene Regulatory Networks; Heart Atria; Humans; Inflammation; Macrophages; Mice, Inbred C57BL; Phosphorylation; Receptors, CXCR4; Signal Transduction; T-Lymphocytes; Vascular Remodeling; Mice
PubMed: 34453039
DOI: 10.1038/s41419-021-04109-5 -
Urology Journal Nov 2021The purpose of this study was to compare the effectiveness of Dapoxetine, and Paroxetine as well as Dapoxetine/Tadalafil and Paroxetine/Tadalafil combinational... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The purpose of this study was to compare the effectiveness of Dapoxetine, and Paroxetine as well as Dapoxetine/Tadalafil and Paroxetine/Tadalafil combinational therapies, for the treatment of patients with premature ejaculation.
MATERIALS AND METHODS
In this clinical trial study, 120 patients with premature ejaculation were randomly divided into 4 groups: The first group was treated with Paroxetine (Pa), while the second group received Dapoxetine(Da). The third group received Paroxetine combined with Tadalafil(PT) whereas the fourth group's treatment involved the use of Dapoxetine and Tadalafil(DT) for one month. In the next 2 and 4 weeks, the cases were evaluated in terms of ejaculation duration, frequency of intercourse per week, and drug side effects.
RESULTS
The mean age of the Da, Pa, PT, DT groups was 32 ± 6.9, 32.4 ± 7.2, 31.6 ± 1.9, and 32.9 ± 7.7 years, respectively. There was a significant difference between the Da and DT groups (p = .029) in the ejaculation latency in the 4-week follow-up. In the two weeks follow-up, a significant difference was observed between DA and DT (p = 0.043), Pa and PT (p = 0.006), and Pa and DT groups (p = 0.004) in terms of ejaculation latency. Four weeks after the intervention, a significant difference was detected in the intercourse frequency of Da and PT groups (p =0.033), Pa and PT groups (p = 0.043), Pa and DT groups (p = 0.02), and Da and DT groups (p = 0.016).
CONCLUSION
Combination therapy (Tadalafil plus Paroxetine or Dapoxetine) was more effective in IELT (Intra ejaculation latency time) than mono-therapy especially in younger patients despite its slightly more side effects.
Topics: Benzylamines; Ejaculation; Humans; Male; Naphthalenes; Paroxetine; Premature Ejaculation; Selective Serotonin Reuptake Inhibitors; Tadalafil; Treatment Outcome
PubMed: 34773634
DOI: 10.22037/uj.v18i.6644 -
International Braz J Urol : Official... 2023
Topics: Male; Humans; Premature Ejaculation; Ejaculation; Benzylamines; Naphthalenes; Treatment Outcome
PubMed: 37267615
DOI: 10.1590/S1677-5538.IBJU.2023.9908