-
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 -
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 -
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 -
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 -
European Journal of Heart Failure Feb 2023In the EXPLORER-HCM trial, mavacamten improved exercise capacity and symptoms in patients with obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten effects on the... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
In the EXPLORER-HCM trial, mavacamten improved exercise capacity and symptoms in patients with obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten effects on the primary endpoint, a composite of peak oxygen consumption (VO ) and New York Heart Association (NYHA) class, were greater in patients not receiving background beta-blockers than in those receiving beta-blockers. We sought to determine if the effect of background treatment was consistent across other clinically meaningful parameters.
METHODS AND RESULTS
Subgroup analyses by beta-blocker use were performed in patients with oHCM from the EXPLORER-HCM and mavacamten long-term extension (MAVA-LTE) studies. In EXPLORER-HCM, 189 patients (75.3%) were receiving beta-blockers, and 62 (24.7%) were receiving non-dihydropyridine calcium channel blockers or no background HCM medication; 170 patients (90.4%) receiving beta-blockers had chronotropic incompetence. Improvements in peak VO at week 30 with mavacamten versus placebo were lower with beta-blockers (mean difference [95% confidence interval (CI)]: 1.04 [0.12, 1.95] ml/kg/min) than without beta-blockers (mean difference [95% CI]: 2.69 [1.29, 4.09] ml/kg/min); improvements in non-heart rate-dependent parameters (V /VCO slope) appeared unaffected by beta-blockers. Improvements in functional capacity parameters at week 30 with mavacamten versus placebo were independent of beta-blockade for post-exercise left ventricular outflow tract gradient (mean difference [95% CI]: -37.9 [-48.0, -27.9] mmHg with beta-blockers; -33.5 [-53.6, -13.3] mmHg without beta-blockers), proportion of patients with reduction of ≥1 NYHA class, Kansas City Cardiomyopathy Questionnaire clinical summary scores and N-terminal pro-B-type natriuretic peptide. Mavacamten benefits were reproduced and maintained in MAVA-LTE regardless of beta-blockade.
CONCLUSION
Mavacamten improved measures of functional capacity, left ventricular outflow tract obstruction, symptom burden and biomarkers in patients with HCM regardless of beta-blocker use. Beta-blocker use was often associated with chronotropic incompetence, affecting peak VO and other heart rate-dependent measures, but had minimal impact on heart rate-independent measures.
Topics: Humans; Adrenergic beta-Antagonists; Benzylamines; Cardiomyopathy, Hypertrophic; Heart; Heart Failure
PubMed: 36404399
DOI: 10.1002/ejhf.2737 -
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 -
Neurotherapeutics : the Journal of the... Jan 2007Safinamide (SAF) ((S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino)propanamide) was initially synthetized by Farmitalia Carlo Erba (Italy). Following initial anticonvulsant... (Review)
Review
Safinamide (SAF) ((S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino)propanamide) was initially synthetized by Farmitalia Carlo Erba (Italy). Following initial anticonvulsant screening, safinamide was selected for its potency, broad spectrum of action, and good safety margin. Pharmacodynamic properties probably relevant to its antiepileptic activity are use- and frequency-dependent block of voltage sensitive Na+ channels, block of Ca++ channels, and glutamate release inhibition. Possibly contributing mechanism are also selective and reversible monoamide oxidase B inhibition and dopamine and noradrenaline uptake inhibition. The high selectivity for the sigma-1 receptor site does not entail psychotomimetic or behavioral changes. In several experimental in vitro and in vivo conditions, SAF exerts neurorescuing and neuroprotectant effects. Safinamide is water soluble and suitable for 1 times a day oral administration in humans. In a pilot phase II study in 38 refractory epilepsy patients affected by multiple types of seizures, 41% of subjects obtained > or =50% seizure reduction during a 12-week escalating dose up to 300 mg 1 times day compared with perspective baseline. Safinamide is being developed in phase III for treatment of Parkinson's disease, whereas the development in epilepsy relates to the industrial strategy of the company.
Topics: Alanine; Animals; Anticonvulsants; Benzylamines; Brain; Clinical Trials as Topic; Epilepsy; Humans; Parkinson Disease
PubMed: 17199024
DOI: 10.1016/j.nurt.2006.11.011 -
Circulation. Heart Failure Jun 2020Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by unexplained left ventricular (LV) hypertrophy associated with dynamic LV outflow tract obstruction....
BACKGROUND
Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by unexplained left ventricular (LV) hypertrophy associated with dynamic LV outflow tract obstruction. Current medical therapies are nonspecific and have limited efficacy in relieving symptoms. Mavacamten is a first-in-class targeted inhibitor of cardiac myosin, which has been shown to reduce LV outflow tract obstruction, improve exercise capacity, and relieve symptoms of oHCM in the PIONEER-HCM phase 2 study.
METHODS
EXPLORER-HCM is a multicenter, phase 3, randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of mavacamten in treating symptomatic oHCM. Eligible adults with oHCM and New York Heart Association Functional Class II or III are randomized 1:1 to receive once-daily, oral mavacamten, or matching placebo for 30 weeks. The primary composite functional end point is clinical response at week 30 compared to baseline defined as either (1) an increase in peak oxygen consumption ≥1.5 mL/kg/min and reduction of at least one New York Heart Association class; or (2) an improvement of ≥3.0 mL/kg/min in peak oxygen consumption with no worsening of New York Heart Association class. Secondary end points include change in postexercise LV outflow tract gradient, New York Heart Association class, peak oxygen consumption, and patient-reported outcomes assessed by the Kansas City Cardiomyopathy Questionnaire and a novel HCM-specific instrument. Exploratory end points aim to characterize the effect of mavacamten on multiple aspects of oHCM pathophysiology.
CONCLUSIONS
EXPLORER-HCM is a phase 3 trial in oHCM testing a first-in-class, targeted strategy of myosin inhibition to improve symptom burden and exercise capacity through reducing LV outflow tract obstruction. Results of this trial will provide evidence to support the first disease-specific treatment for HCM. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03470545.
Topics: Benzylamines; Cardiomyopathy, Hypertrophic; Cardiovascular Agents; Clinical Trials, Phase III as Topic; Double-Blind Method; Exercise Tolerance; Humans; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Recovery of Function; Treatment Outcome; Uracil; Ventricular Function, Left
PubMed: 32498620
DOI: 10.1161/CIRCHEARTFAILURE.120.006853 -
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 -
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