Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction: GALACTIC‐HF baseline characteristics and comparison with contemporary clinical trials

Abstract

Aims The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and results Adults with established HFrEF, New York Heart Association (NYHA) functional class ≥II, ejection fraction ≤35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N‐terminal pro‐B‐type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC‐HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure <100 mmHg (n = 1127), estimated glomerular filtration rate <30 mL/min/1.73 m2 (n = 528), and treated with sacubitril/valsartan at baseline (n = 1594). Conclusions GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation.

Timely and individualized heart failure management: need for implementation into the new guidelines

“…The Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF) [ 23 ] was a phase II trial that showed a decrease in NT-pro-BNP levels, heart rate and in ventricular dimensions [ 23 ]. More recently, the Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure (GALACTIC-HF) trial studied 8256 patients in a randomized fashion to omecamtiv mecarbil or placebo [ 24 ]. There was a nominal (8%) reduction in the composite endpoint of CV death and HF hospitalization, and this effect was formally significant ( p = 0.03).…”

The Genetic Pathways Underlying Immunotherapy in Dilated Cardiomyopathy

“…CK-1827452 also known as Omecamtiv mecarbil (INN) accelerates the transition of actin-myosin complex from weakly to strongly bound and increases the number of myosin heads engaged with the thin filament. These effects are independent of calcium transients because CK-1827452-treated cardiomyocytes with isoproterenol augment contraction, whereas β-adrenergic inhibition does not diminish contractility (77) ATOMIC (78). Additional studies indicated that CK-1827452 traps some myosin heads in a weak actin affinity state with slow force development and at high concentrations prolonged cellular relaxation in hiPSC-CMs (79).…”

“…A randomized, parallel-group, double-blind, phase II conducted over 87 sites in 13 countries (The Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure COSMIC-HF trial) showed that CK-1827452 administered to patients with chronic stable symptomatic heart failure increased stroke volume and modestly reduced left ventricular end-diastolic diameter, heart rate, and serum levels of N-terminal brain natriuretic factor, increased systolic ejection time, and it may have improved dyspnea in the high-dose group, though it did not meet the primary endpoint of dyspnea improvement. Many other trails have been conducted and are still under investigation to study this drug (Table 2) (77,78,80).…”

Biological nanomotors, driving forces of life

“…Milestone studies have uncovered the possibility of new treatments for such diseases by demonstrating that small molecules acting as allosteric effectors can modulate the force produced by myosin motors. Three drug candidates acting either as specific inhibitors or activators of cardiac myosin are under phase 3 clinical trials for treatment of distinct heart insufficiencies [60][61][62]. The pockets in which several of these specific allosteric effectors bind have been identified in the myosin molecule (Figure 5).…”

“…Des études marquantes ont permis de découvrir la possibilité de nouveaux traitements pour ces maladies en démontrant que de petites molécules agissant comme effecteurs allostériques peuvent moduler la force produite par les moteurs myosine. Trois candidats médicaments agissant soit comme inhibiteurs spécifiques soit comme activateurs de la myosine cardiaque sont en cours d'essais cliniques de phase 3 pour le traitement d'insuffisances cardiaques distinctes [60][61][62]. Les poches dans lesquelles plusieurs de ces effecteurs allostériques spécifiques se lient ont été identifiées dans la molécule de myosine (Figure 5).…”