Effects Of Omecamtiv Mecarbil Research Articles

Dynamics of the Pre-Powerstroke Myosin Lever Arm and the Effects of Omecamtiv Mecarbil.

The binding of small molecules to sarcomeric myosin can elicit powerful effects on the chemomechanical cycle, making them effective therapeutics in the clinic and research tools at the benchtop. However, these myotropes can have complex effects that act on different phases of the crossbridge cycle and which depend on structural, dynamic, and environmental variables. While small molecule binding sites have been identified crystallographically and their effects on contraction studied extensively, small molecule-induced dynamic changes that link structure-function are less studied. Here, we use molecular dynamics simulations to explore how omecamtiv mecarbil (OM), a cardiac myosin-specific myotrope, alters the coordinated dynamics of the lever arm and the motor domain in the pre-powerstroke state. We show that the lever arm adopts a range of orientations and find that different lever arm orientations are accompanied by changes in the hydrogen bonding patterns near the converter. We find that the binding of OM to myosin reduces the conformational heterogeneity of the lever arm orientation and also adjusts the average lever arm orientation. Finally, we map out the distinct conformations and ligand-protein interactions adopted by OM. These results uncover some structural factors that govern the motor domain-tail orientations and the mechanisms by which OM primes the pre-powerstroke myosin heads.

Effects of Omecamtiv Mecarbil on the Tension–Length Loop and Work in Right Ventricular Trabeculae from Rats with Pulmonary Heart Failure

Effects of Omecamtiv Mecarbil on the Tension–Length Loop and Work in Right Ventricular Trabeculae from Rats with Pulmonary Heart Failure

Effects of omecamtiv mecarbil and mavacamten 461 in isolated human atrium

Effects of omecamtiv mecarbil and mavacamten 461 in isolated human atrium

Effects of omecamtiv mecarbil and mavacamten in isolated human atrium

Heart failure is a syndrome that can result from impaired heart muscle contractions like in dilative cardiomyopathy but also from hypertrophic obstructive cardiomyopathy (HOCOM). A pharmacological therapy might lie in Ca2+-sensitizing or Ca2+-desensitizing drugs, respectively. Such drugs are thought to be omecamtiv mecarbil (OME) and mavacamten (MYK-461), respectively. Their function in contracting human muscle is not fully understood and was the focus of the present study. OME from 1 nM to 10 µM cumulatively applied failed to raise force of contraction in human right atrial preparations strips (HAP) or mouse left atrial preparations (LA). However, OME prolonged time to peak tension and time of relaxation in HAP and LA but did not alter the beating rate in right atrial preparations from mice (RA). In contrast, MYK-461 (10 nM to 10 µM) reduced concentration- and time-dependently force of contraction in HAP and LA. MYK-461 (10 µM) did not affect the beating rate in RA. In summary, the present data failed to detect an increase in force of contraction for OME, in human and mouse atrium. In contrast, a Ca2+ desensitizer studied for comparison was able to reduce force of contraction in HAP and LA. We conclude that putative beneficial effects of OME in dilated cardiomyopathy cannot be explained by positive inotropic effects in the HAP, whereas beneficial functional effects of MYK-461 in HOCOM can be explained by negative inotropic effects in HAP.

Effects of omecamtiv mecarbil on the contractile properties of skinned porcine left atrial and ventricular muscles.

Omecamtiv mecarbil (OM) is a novel inotropic agent for heart failure with systolic dysfunction. OM prolongs the actomyosin attachment duration, which enhances thin filament cooperative activation and accordingly promotes the binding of neighboring myosin to actin. In the present study, we investigated the effects of OM on the steady-state contractile properties in skinned porcine left ventricular (PLV) and atrial (PLA) muscles. OM increased Ca2+ sensitivity in a concentration-dependent manner in PLV, by left shifting the mid-point (pCa50) of the force-pCa curve (ΔpCa50) by ∼0.16 and ∼0.33 pCa units at 0.5 and 1.0 μM, respectively. The Ca2+-sensitizing effect was likewise observed in PLA, but less pronounced with ΔpCa50 values of ∼0.08 and ∼0.22 pCa units at 0.5 and 1.0 μM, respectively. The Ca2+-sensitizing effect of OM (1.0 μM) was attenuated under enhanced thin filament cooperative activation in both PLV and PLA; this attenuation occurred directly via treatment with fast skeletal troponin (ΔpCa50: ∼0.16 and ∼0.10 pCa units in PLV and PLA, respectively) and indirectly by increasing the number of strongly bound cross-bridges in the presence of 3 mM MgADP (ΔpCa50: ∼0.21 and ∼0.08 pCa units in PLV and PLA, respectively). It is likely that this attenuation of the Ca2+-sensitizing effect of OM is due to a decrease in the number of “recruitable” cross-bridges that can potentially produce active force. When cross-bridge detachment was accelerated in the presence of 20 mM inorganic phosphate, the Ca2+-sensitizing effect of OM (1.0 μM) was markedly decreased in both types of preparations (ΔpCa50: ∼0.09 and ∼0.03 pCa units in PLV and PLA, respectively). The present findings suggest that the positive inotropy of OM is more markedly exerted in the ventricle than in the atrium, which results from the strongly bound cross-bridge-dependent allosteric activation of thin filaments.

Effects of omecamtiv mecarbil in heart failure with reduced ejection fraction according to blood pressure: the GALACTIC-HF trial.

Patients with heart failure with reduced ejection fraction and low systolic blood pressure (SBP) have high mortality, hospitalizations, and poorly tolerate evidence-based medical treatment. Omecamtiv mecarbil may be particularly helpful in such patients. This study examined its efficacy and tolerability in patients with SBP ≤100 mmHg enrolled in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF). The GALACTIC-HF enrolled patients with baseline SBP ≥85 mmHg with a primary outcome of time to cardiovascular death or first heart failure event. In this analysis, patients were divided according to their baseline SBP (≤100 vs. >100 mmHg). Among the 8232 analysed patients, 1473 (17.9%) had baseline SBP ≤100 mmHg and 6759 (82.1%) had SBP >100 mmHg. The primary outcome occurred in 715 (48.5%) and 2415 (35.7%) patients with SBP ≤100 and >100 mmHg, respectively. Patients with lower SBP were at higher risk of adverse outcomes. Omecamtiv mecarbil, compared with placebo, appeared to be more effective in reducing the primary composite endpoint in patients with SBP ≤100 mmHg [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.70-0.94] compared with those with SBP >100 mmHg (HR, 0.95; 95% CI, 0.88-1.03; P-value for interaction = 0.051). In both groups, omecamtiv mecarbil did not change SBP values over time and did not increase the risk of adverse events, when compared with placebo. In GALACTIC-HF, risk reduction of heart failure outcomes with omecamtiv mecarbil compared with placebo was large and significant in patients with low SBP. Omecamtiv mecarbil did not affect SBP and was well tolerated independent of SBP values.

Effects of omecamtiv mecarbil on calcium-transients and contractility in a translational canine myocyte model

Omecamtiv mecarbil (OM) is a selective cardiac myosin activator (myotrope), currently in Phase 3 clinical investigation as a novel treatment for heart failure with reduced ejection fraction. OM increases cardiac contractility by enhancing interaction between myosin and actin in a calcium-independent fashion. This study aims to characterize the mechanism of action by evaluating its simultaneous effect on myocyte contractility and calcium-transients (CTs) in healthy canine ventricular myocytes. Left ventricular myocytes were isolated from canines and loaded with Fura-2 AM. With an IonOptix system, contractility parameters including amplitude and duration of sarcomere shortening, contraction and relaxation velocity, and resting sarcomere length were measured. CT parameters including amplitude at systole and diastole, velocity at systole and diastole, and duration at 50% from peak were simultaneously measured. OM was tested at 0.03, 0.1, 0.3, 1, and 3 µmol\L concentrations to simulate therapeutic human plasma exposure levels. OM and isoproterenol (ISO) demonstrated differential effects on CTs and myocyte contractility. OM increased contractility mainly by prolonging duration of contraction while ISO increased contractility mainly by augmenting the amplitude of contraction. ISO increased the amplitude and velocity of CT, shortened duration of CT concurrent with increasing myocyte contraction, while OM did not change the amplitude, velocity, and duration of CT up to 1 µmol\L. Decreases in relaxation velocity and increases in duration were present only at 3 µmol\L. In this translational myocyte model study, therapeutically relevant concentrations of OM increased contractility but did not alter intracellular CTs, a mechanism of action distinct from traditional calcitropes.

Effects of Omecamtiv Mecarbil on Symptoms and Health-Related Quality of Life in Patients With Chronic Heart Failure: Results From the COSMIC-HF Study.

Background:Chronic heart failure with reduced ejection fraction impairs health-related quality of life (HRQL). Omecamtiv mecarbil (OM)—a novel activator of cardiac myosin—improves left ventricular systolic function and remodeling and reduces natriuretic peptides. We sought to evaluate the effect of OM on symptoms and HRQL in patients with chronic heart failure with reduced ejection fraction and elevated natriuretic peptides enrolled in the COSMIC-HF trial (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure).Methods:Patients (n=448) were randomized 1:1:1 to placebo, 25 mg of OM BID, or to pharmacokinetically guided dose titration (OM-PK) for 20 weeks. The Kansas City Cardiomyopathy Questionnaire was administered to assess HRQL at baseline, 16 weeks, and 20 weeks. The primary scores of interest were the Total Symptom Score, Physical Limitation Scale, and Clinical Summary Score.Results:Mean change in score from baseline to 20 weeks for the Total Symptom Score was 5.0 (95% CI, 1.8–8.1) for placebo, 6.6 (95% CI, 3.4–9.8) for OM 25 mg (P=0.32 versus placebo), and 9.9 (95% CI, 6.7–13.0) for OM-PK (P=0.03 versus placebo); for the Physical Limitation Scale, it was 3.1 for placebo (95% CI, −0.3 to 6.6), 6.0 (95% CI, 3.1–8.9) for OM 25 mg (P=0.12), and 4.3 (95% CI, 0.7–7.9) for OM-PK (P=0.42); for the Clinical Summary Score, it was 4.1 (95% CI, 1.4–6.9) for placebo, 6.3 (95% CI, 3.6–9.0) for OM 25 mg (P=0.19), and 7.0 (95% CI, 4.1–10.0) for OM-PK (P=0.14). Differences between OM and placebo were greater in patients who were more symptomatic at baseline.Conclusions:HRQL as measured by the Total Symptom Score improved in patients with heart failure with reduced ejection fraction assigned to the OM-PK group relative to placebo. Ongoing trials are prospectively testing whether OM improves symptoms and HRQL in heart failure with reduced ejection fraction.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01786512.

Effects of omecamtiv mecarbil on calcium-transients and contractility in a translational canine myocyte model.

Omecamtiv mecarbil (OM) is a selective cardiac myosin activator (myotrope), currently in Phase 3 clinical investigation as a novel treatment for heart failure with reduced ejection fraction. OM increases cardiac contractility by enhancing interaction between myosin and actin in a calcium‐independent fashion. This study aims to characterize the mechanism of action by evaluating its simultaneous effect on myocyte contractility and calcium‐transients (CTs) in healthy canine ventricular myocytes. Left ventricular myocytes were isolated from canines and loaded with Fura‐2 AM. With an IonOptix system, contractility parameters including amplitude and duration of sarcomere shortening, contraction and relaxation velocity, and resting sarcomere length were measured. CT parameters including amplitude at systole and diastole, velocity at systole and diastole, and duration at 50% from peak were simultaneously measured. OM was tested at 0.03, 0.1, 0.3, 1, and 3 µmol\\L concentrations to simulate therapeutic human plasma exposure levels. OM and isoproterenol (ISO) demonstrated differential effects on CTs and myocyte contractility. OM increased contractility mainly by prolonging duration of contraction while ISO increased contractility mainly by augmenting the amplitude of contraction. ISO increased the amplitude and velocity of CT, shortened duration of CT concurrent with increasing myocyte contraction, while OM did not change the amplitude, velocity, and duration of CT up to 1 µmol\\L. Decreases in relaxation velocity and increases in duration were present only at 3 µmol\\L. In this translational myocyte model study, therapeutically relevant concentrations of OM increased contractility but did not alter intracellular CTs, a mechanism of action distinct from traditional calcitropes.

Effects of Omecamtiv Mecarbil on the Interaction of Atrial and Ventricular Myosin with Actin

Effects of Omecamtiv Mecarbil on the Interaction of Atrial and Ventricular Myosin with Actin

Omecamtiv mecarbil activates ryanodine receptors from canine cardiac but not skeletal muscle

Due to the limited results achieved in the clinical treatment of heart failure, a new inotropic strategy of myosin motor activation has been developed. The lead molecule of myosin activator agents is omecamtiv mecarbil, which binds directly to the heavy chain of the cardiac β-myosin and enhances cardiac contractility by lengthening the lifetime of the acto-myosin complex and increasing the number of the active force-generating cross-bridges. In the absence of relevant data, the effect of omecamtiv mecarbil on canine cardiac ryanodine receptors (RyR 2) has been investigated in the present study by measuring the electrical activity of single RyR 2 channels incorporated into planar lipid bilayer. When applying 100nM Ca2+ concentration on the cis side ([Ca2+]cis) omecamtiv mecarbil (1–10µM) significantly increased the open probability and opening frequency of RyR 2, while the mean closed time was reduced. Mean open time was increased moderately by 10µM omecamtiv mecarbil. When [Ca2+]cis was elevated to 322 and 735nM, the effect of omecamtiv mecarbil on open probability was evident only at higher (3–10µM) concentrations. All effects of omecamtiv mecarbil were fully reversible upon washout. Omecamtiv mecarbil (up to 10µM) had no effect on the open probability of RyR 1, isolated from either canine or rabbit skeletal muscles. It is concluded that the direct stimulatory action of omecamtiv mecarbil on RyR 2 has to be taken into account when discussing the mechanism of action or the potential side effects of the compound.

Omecamtiv mecarbil: a new cardiac myosin activator for the treatment of heart failure

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. Omecamtiv mecarbil represents a novel therapeutic approach to directly improve cardiac function and is therefore proposed as a potential new treatment of patients with systolic heart failure. The authors review results of previous studies investigating the effect of omecamtiv mecarbil in heart failure animal models, healthy volunteers, and patients with acute and chronic systolic heart failure.Expert opinion: Results of phase I and phase II studies demonstrate that omecamtiv mecarbil is safe and well tolerated both as an intravenous and oral formulation. In healthy volunteers and chronic systolic heart failure patients, administration of omecamtiv mecarbil resulted in a concentration-dependent increase of left ventricular ejection time, ejection fraction, fractional shortening, and stroke volume. The first results of a double-blind, randomized, placebo-controlled phase IIb dose-finding study with the oral formulation of omecamtiv mecarbil demonstrated beneficial effects on cardiac function and N-terminal pro-brain natriuretic peptide levels. This study will provide essential dosing information for the requisite phase III trials which will investigate whether the beneficial effects of omecamtiv mecarbil translate into improved clinical outcomes.