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Ingela Wiklund, Milena Anatchkova, Hafiz Oko-Osi, Robyn von Maltzahn, Dina Chau, Fady I Malik, Donald L Patrick, John Spertus, John R Teerlink
BACKGROUND: Patient-reported outcome (PRO) measures can be used to support label claims if they adhere to US Food & Drug Administration guidance. The process of developing a new PRO measure is expensive and time-consuming. We report the results of qualitative studies to develop new PRO measures for use in clinical trials of omecamtiv mecarbil (a selective, small molecule activator of cardiac myosin) for patients with heart failure (HF), as well as the lessons learned from the development process...
2016: Health and Quality of Life Outcomes
Danyaal S Moin, Julia Sackheim, Carine E Hamo, Javed Butler
Despite the rising prevalence of HF, new evidence-based novel therapies for patients with worsening HF remain lacking, e.g., safe inotropic therapies. Traditional inotropes increase contractility by altering intracellular calcium flux, a pathway that may be responsible for the multitude of adverse effects associated with current options. Omecamtiv mecarbil, a direct myosin activator, increases contractility through a distinct pathway by increasing the proportion of myosin heads that are bound to actin in a high-affinity state...
October 2016: Current Cardiology Reports
Barry Greenberg
Despite advances in therapy, patients with heart failure (HF) continue to experience unacceptably high rates of hospitalization and death, as well as poor quality of life. As a consequence, there is an urgent need for new treatments that can improve the clinical course of the growing worldwide population of HF patients. Serelaxin and ularatide, both based on naturally occurring peptides, have potent vasodilatory as well as other effects on the heart and kidneys. For both agents, phase 3 studies that are designed to determine whether they improve outcomes in patients with acute HF have completed enrollment...
August 25, 2016: Circulation Journal: Official Journal of the Japanese Circulation Society
Péter Nánási, Krisztina Váczi, Zoltán Papp
Heart failure became a leading cause of mortality in the past few decades with a progressively increasing prevalence. Its current therapy is restricted largely to the suppression of the sympathetic activity and the renin-angiotensin system in combination with diuretics. This restrictive strategy is due to the potential long-term adverse effects of inotropic agents despite their effective influence on cardiac function when employed for short durations. Positive inotropes include inhibitors of the Na(+)/K(+) pump, β-receptor agonists, and phosphodiesterase inhibitors...
February 12, 2016: Canadian Journal of Physiology and Pharmacology
K M Broughton, J Li, E Sarmah, C M Warren, Y-H Lin, M P Henze, V Sanchez-Freire, R J Solaro, B Russell
We have investigated cardiac myocytes derived from human-induced pluripotent stem cells (iPSC-CMs) from two normal control and two family members expressing a mutant cardiac troponin T (cTnT-R173W) linked to dilated cardiomyopathy (DCM). cTnT is a regulatory protein of the sarcomeric thin filament. The loss of this basic charge, which is strategically located to control tension, has consequences leading to progressive DCM. iPSC-CMs serve as a valuable platform for understanding clinically relevant mutations in sarcomeric proteins; however, there are important questions to be addressed with regard to myocyte adaptation that we model here by plating iPSC-CMs on softer substrates (100 kPa) to create a more physiologic environment during recovery and maturation of iPSC-CMs after thawing from cryopreservation...
July 1, 2016: American Journal of Physiology. Heart and Circulatory Physiology
Hao A Tran, Felice Lin, Barry H Greenberg
INTRODUCTION: The prevalence of heart failure (HF) has increased globally in recent decades. Advances in our understanding of underlying pathophysiologic mechanisms have given rise to new therapies for treating the growing HF population. Nonetheless, morbidity and mortality associated with HF and its financial implications are daunting. Thus, novel therapies that can improve the natural history of HF patients are urgently needed. AREAS COVERED: This article reviews new investigational drugs being developed for the treatment of both acute decompensated heart failure (ADHF) and chronic heart failure with reduced ejection fraction (HFrEF)...
July 2016: Expert Opinion on Investigational Drugs
John R Teerlink, G Michael Felker, John J V McMurray, Piotr Ponikowski, Marco Metra, Gerasimos S Filippatos, Justin A Ezekowitz, Kenneth Dickstein, John G F Cleland, Jae B Kim, Lei Lei, Beat Knusel, Andrew A Wolff, Fady I Malik, Scott M Wasserman
BACKGROUND: Omecamtiv mecarbil (OM) is a selective cardiac myosin activator that increases myocardial function in healthy volunteers and in patients with chronic heart failure. OBJECTIVES: This study evaluated the pharmacokinetics, pharmacodynamics, tolerability, safety, and efficacy of OM in patients with acute heart failure (AHF). METHODS: Patients admitted for AHF with left ventricular ejection fraction ≤40%, dyspnea, and elevated plasma concentrations of natriuretic peptides were randomized to receive a double-blind, 48-h intravenous infusion of placebo or OM in 3 sequential, escalating-dose cohorts...
March 29, 2016: Journal of the American College of Cardiology
Rameshraja Palaparthy, Christopher Banfield, Paco Alvarez, Lucy Yan, Brian Smith, Jessica Johnson, Maria Laura Monsalvo, Fady Malik
OBJECTIVE: Omecamtiv mecarbil is a novel small molecule that directly activates cardiac myosin and increases cardiac contractility without increasing cardiac myocyte intracellular calcium. This study evaluated the relative bioavailability, food effect, and safety of several modified-release (MR) formulations of omecamtiv mecarbil. METHODS: This was a phase 1, randomized, open-label, 4-way crossover, incomplete block-design study evaluating 5 MR formulations of omecamtiv mecarbil vs...
March 2016: International Journal of Clinical Pharmacology and Therapeutics
Scott W Roberts, Jeroen M Bezemer, Michael T Kennedy, Tiffany L Correll, Raju Subramanian, Shawn D Walker
This mini-review describes the Chemistry, Manufacturing and Control activities associated with the manufacture of [(14)C]-labeled drug substance and subsequent drug compounding activities to generate clinical trial material utilized in human absorption, distribution, metabolism, and excretion clinical studies. Due to the unstable nature and increased decomposition rates observed with [(14)C]-labeled compounds, the manufacture, testing, release, formulation, and regulatory filings are uniquely challenging. A case study of the cardiac myosin activator AMG 423 (omecamtiv mercarbil), utilized in a dual oral/intravenous infusion clinical study is presented...
2016: Current Pharmaceutical Design
Sohaib Tariq, Wilbert S Aronow
The most common use of inotropes is among hospitalized patients with acute decompensated heart failure, with reduced left ventricular ejection fraction and with signs of end-organ dysfunction in the setting of a low cardiac output. Inotropes can be used in patients with severe systolic heart failure awaiting heart transplant to maintain hemodynamic stability or as a bridge to decision. In cases where patients are unable to be weaned off inotropes, these agents can be used until a definite or escalated supportive therapy is planned, which can include coronary revascularization or mechanical circulatory support (intra-aortic balloon pump, extracorporeal membrane oxygenation, impella, left ventricular assist device, etc...
2015: International Journal of Molecular Sciences
Licette Cy Liu, Bernard Dorhout, Peter van der Meer, John R Teerlink, Adriaan A Voors
INTRODUCTION: Current available inotropic agents increase cardiac contractility, but are associated with myocardial ischemia, arrhythmias, and mortality. A novel selective cardiac myosin activator, omecamtiv mecarbil (CK-1827452/ AMG-423) is a small molecule that activates the sarcomere proteins directly, resulting in prolonged systolic ejection time and increased cardiac contractility. AREAS COVERED: This paper discusses the chemistry, pharmacokinetics, clinical efficacy and safety of omecamtiv mecarbil...
January 2016: Expert Opinion on Investigational Drugs
Alfredo de Micheli Serra, Gustavo Pastelín Hernández
Since the end of the XVIII century, digitalis glycosides were employed in heart failure. They were considered initially as diuretics and later as cardiotonic agents or as positive inotropics. At the present time there are varied groups of positive inotropic agents, which have a beneficial action on the failing human myocardium. For example, the beta adrenergics, the phosphodiesterase III inhibitors such as milrinone, or the sensibilizers of myocardial proteins to Ca++ such as levosimendan and omecamtiv mecarbil...
September 2015: Gaceta Médica de México
Donald A Winkelmann, Eva Forgacs, Matthew T Miller, Ann M Stock
Omecamtiv Mecarbil (OM) is a small molecule allosteric effector of cardiac myosin that is in clinical trials for treatment of systolic heart failure. A detailed kinetic analysis of cardiac myosin has shown that the drug accelerates phosphate release by shifting the equilibrium of the hydrolysis step towards products, leading to a faster transition from weak to strong actin-bound states. The structure of the human β-cardiac motor domain (cMD) with OM bound reveals a single OM-binding site nestled in a narrow cleft separating two domains of the human cMD where it interacts with the key residues that couple lever arm movement to the nucleotide state...
2015: Nature Communications
L Nagy, Á Kovács, B Bódi, E T Pásztor, G Á Fülöp, A Tóth, I Édes, Z Papp
BACKGROUND AND PURPOSE: Omecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration-dependent mechanical effects of OM in permeabilized cardiomyocyte-sized preparations and single skeletal muscle fibres of Wistar-Kyoto rats under isometric conditions. EXPERIMENTAL APPROACHES: Ca(2+) -dependent active force production (Factive ), its Ca(2+) sensitivity (pCa50 ), the kinetic characteristics of Ca(2+) -regulated activation and relaxation, and Ca(2+) -independent passive force (Fpassive ) were monitored in Triton X-100-skinned preparations with and without OM (3nM-10 μM)...
July 3, 2015: British Journal of Pharmacology
Ranganath Mamidi, Kenneth S Gresham, Amy Li, Cristobal G dos Remedios, Julian E Stelzer
Decreased expression of cardiac myosin binding protein-C (cMyBP-C) in the myocardium is thought to be a contributing factor to hypertrophic cardiomyopathy in humans, and the initial molecular defect is likely abnormal cross-bridge (XB) function which leads to impaired force generation, decreased contractile performance, and hypertrophy in vivo. The myosin activator omecamtiv mecarbil (OM) is a pharmacological drug that specifically targets the myosin XB and recent evidence suggests that OM induces a significant decrease in the in vivo motility velocity and an increase in the XB duty cycle...
August 2015: Journal of Molecular and Cellular Cardiology
Megan S Utter, David M Ryba, Betty H Li, Beata M Wolska, R John Solaro
Apart from transplant, there are no satisfactory therapies for the severe depression in contractility in familial dilated cardiomyopathy (DCM). Current heart failure treatments that act by increasing contractility involve signaling cascades that alter calcium homeostasis and induce arrhythmias. Omecamtiv mecarbil is a promising new inotropic agent developed for heart failure that may circumvent such limitations. Omecamtiv is a direct cardiac myosin activator that promotes and prolongs the strong myosin-actin binding conformation to increase the duration of systolic elastance...
October 2015: Journal of Cardiovascular Pharmacology
Jens Petter Bakkehaug, Anders Benjamin Kildal, Erik Torgersen Engstad, Neoma Boardman, Torvind Næsheim, Leif Rønning, Ellen Aasum, Terje Steinar Larsen, Truls Myrmel, Ole-Jakob How
BACKGROUND: Omecamtiv mecarbil (OM) is a novel inotropic agent that prolongs systolic ejection time and increases ejection fraction through myosin ATPase activation. We hypothesized that a potentially favorable energetic effect of unloading the left ventricle, and thus reduction of wall stress, could be counteracted by the prolonged contraction time and ATP-consumption. METHODS AND RESULTS: Postischemic left ventricular dysfunction was created by repetitive left coronary occlusions in 7 pigs (7 healthy pigs also included)...
July 2015: Circulation. Heart Failure
Thuy Vu, Peiming Ma, Jim J Xiao, Yow-Ming C Wang, Fady I Malik, Andrew T Chow
Data from 3 clinical trials of omecamtiv mecarbil in healthy volunteers and patients with stable heart failure (HF) were analyzed using a nonlinear mixed-effects model to investigate omecamtiv mecarbil's pharmacokinetics and relationship between plasma concentration and systolic ejection time (SET) and Doppler-derived left ventricular outflow tract stroke volume (LVOTSV). Omecamtiv mecarbil pharmacokinetics were described by a linear 2-compartment model with a zero-order input rate for intravenous administration and first-order absorption for oral administration...
November 2015: Journal of Clinical Pharmacology
Tural Aksel, Elizabeth Choe Yu, Shirley Sutton, Kathleen M Ruppel, James A Spudich
Cardiomyopathies due to mutations in human β-cardiac myosin are a significant cause of heart failure, sudden death, and arrhythmia. To understand the underlying molecular basis of changes in the contractile system's force production due to such mutations and search for potential drugs that restore force generation, an in vitro assay is necessary to evaluate cardiac myosin's ensemble force using purified proteins. Here, we characterize the ensemble force of human α- and β-cardiac myosin isoforms and those of β-cardiac myosins carrying left ventricular non-compaction (M531R) and dilated cardiomyopathy (S532P) mutations using a utrophin-based loaded in vitro motility assay and new filament-tracking software...
May 12, 2015: Cell Reports
Larissa Butler, Caroline Cros, Karen L Oldman, Alex R Harmer, Amy Pointon, Christopher E Pollard, Najah Abi-Gerges
We sought to investigate whether drug-induced changes in contractility were affected by pacing rates that represent the range of heart rates encountered in vivo. Using the cell geometry measurement system (IonOptix), we paced dog cardiomyocytes at different cycle lengths (CLs) of 2000, 1000, 500, and 333.3 ms, before and after exposure to 13 inotropic drugs. Time course data using vehicle control (0.1% dimethyl sulfoxide (DMSO)) demonstrated stability of the system at all CLs tested. Seven positive inotropes (eg isoproterenol) exerted rate-dependent increases in sarcomere shortening (Sarc...
June 2015: Toxicological Sciences: An Official Journal of the Society of Toxicology
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