eleclazine (GS-6615) / Gilead - LARVOL DELTA

Effects of Eleclazine (GS6615) on the proarrhythmic electrophysiological changes induced by myocardial stretch. (PubMed, Front Physiol) - "Under eleclazine perfusion, the VF activation patterns were less complex, and the arrhythmia stopped in 6 out of 11 experiments (55%; p < 0.05 vs. baseline). Eleclazine (GS6615) reduced the proarrhythmic electrophysiological changes induced by myocardial stretch and slowed and simplified activation patterns during VF in the experimental model used."

Journal • Cardiovascular

Eleclazine Suppresses Ventricular Fibrillation in Failing Rabbit Hearts with Ischemia- Reperfusion Injury Undergoing Therapeutic Hypothermia. (PubMed, Pharmacology) - "Eleclazine does not prevent VF at normothermia, but reduces VF inducibility and severity by extrastimulus pacing at TH in isolated failing hearts with regional IR injury."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Reperfusion Injury

Enhanced Late INa Induces Intracellular Ion Disturbances and Automatic Activity in the Guinea Pig Pulmonary Vein Cardiomyocytes. (PubMed, Int J Mol Sci) - "These phenomena were inhibited by eleclazine, a blocker of the late INa; SEA0400, an inhibitor of the Na+/Ca2+ exchanger (NCX); H89, a protein kinase A (PKA) inhibitor; and KN-93, a Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor. These results suggest that enhancement of late INa in the pulmonary vein cardiomyocytes causes disturbance of the intracellular ion environment through activation of the NCX and Ca2+-dependent enzymes. Such mechanisms are probably involved in the ectopic electrical activity of the pulmonary vein myocardium."

Journal

Late sodium current in synergism with Ca/calmodulin-dependent protein kinase II contributes to β-adrenergic activation-induced atrial fibrillation. (PubMed, Philos Trans R Soc Lond B Biol Sci) - "Ranolazine, eleclazine and KN-93 abolished ISO-induced AF, attenuated the phosphorylation of Na1.5 and CaMKII, and reversed the increase of late I (p < 0.05) in a synergistic mode. Overall, late I in association with the activation of CaMKII potentiates β-adrenergic stimulation-induced AF and the inhibition of both late I and CaMKII exerted synergistic anti-arrhythmic effects to suppress atrial arrhythmic activities associated with catecholaminergic activation. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'."

Journal • Atrial Fibrillation • Cardiovascular • Heart Failure

QT interval and ventricular action potential prolongation in the Mecp2 murine model of Rett syndrome. (PubMed, Physiol Rep) - "Application of the investigational I inhibitor GS-6615 (eleclazine; 10 μM) reduced both APD and AP triangulation in Mecp2 and WT myocytes. These results constitute the first direct demonstration of delayed repolarization in Mecp2 myocytes and provide further evidence that GS-6615 may have potential as an intervention against QT prolongation in RTT."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Movement Disorders • Psychiatry

Delayed Ventricular Repolarization and Sodium Channel Current Modification in a Mouse Model of Rett Syndrome. (PubMed, Int J Mol Sci) - "Effects of two I inhibitors, ranolazine and GS-6615 (eleclazine), were investigated. The observed changes in I and I can account for the corresponding ECG changes in this RTT model. GS-6615 merits further investigation as a potential treatment for QT prolongation in RTT."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Movement Disorders • Psychiatry

GS-967 and Eleclazine BlockSodium Channels in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes. (PubMed, Mol Pharmacol) - "We compared the effects of GS-967 and eleclazine with the antiarrhythmic drug lidocaine, the prototype I inhibitor ranolazine, and the slow inactivation enhancing drug lacosamide. Sodium channel inhibition by GS-967 and eleclazine has unique features including accelerating the onset of slow inactivation and impairing recovery from inactivation. These effects combined with rapid binding and moderate unbinding kinetics explain potent use-dependent block, which we propose contributes to their observed antiarrhythmic efficacy."

Journal

An increase in CO levels by upregulating late sodium current is proarrhythmic in the heart. (PubMed, Heart Rhythm) - "Increased CO levels enhance I and are proarrhythmic factors in the heart with reduced repolarization reserve, possibly through mechanisms related to the phosphorylations of CaMKIIδ and Na1.5."

Journal • Cardiovascular • Metabolic Disorders • Ventricular Tachycardia

[VIRTUAL] The selective late sodium current inhibitor eleclazine reduces atrial fibrillation dominant frequency and facilitates the suppression of arrhythmia in HL-1 cells (ESC 2020) - "In fact, under the action of eleclazine 5µM, fibrillatory activity was suppressed in 4 of the 10 monolayers, phenomenon that did not occur in any case of control situation. Conclusions Selective late INa inhibition with eleclazine reduced dominant frequency of atrial fibrillation and facilitates the termination of arrhythmia in cultured atrial myocyte monolayer."

Atrial Fibrillation • Cardiovascular

Inhibition of voltage-gated Na currents by eleclazine in rat atrial and ventricular myocytes. (PubMed, Heart Rhythm O2) - "Differences exist between rat atrial and ventricular myocytes in the biophysical properties of I. The more negative voltage dependence of I activation/inactivation in atrial myocytes underlies differences between the 2 cell types in the voltage dependence of instantaneous inhibition by eleclazine. Eleclazine warrants further investigation as an atrial-selective antiarrhythmic drug."

Journal • Preclinical • Atrial Fibrillation • Cardiovascular • Ventricular Tachycardia

Late sodium current in atrial cardiomyocytes contributes to the induced and spontaneous atrial fibrillation in rabbit hearts. (PubMed, J Cardiovasc Pharmacol) - "Eleclazine and ranolazine reduced AF window and AF burden in association with the inhibition of both endogenous and enhanced atrial late INa with half maximal inhibitory concentrations (IC50) of 1.14 and 9.78, and 0.94 and 8.31 μM, respectively...In conclusion, enhanced late INa in atrial myocytes increases the susceptibility for AF. Inhibition of either endogenous or enhanced late INa, with increased atrial potency of drugs is feasible for the treatment of AF."

Journal • Atrial Fibrillation • Cardiovascular

LIBERTY-HCM: Effect of Eleclazine (GS-6615) on Exercise Capacity in Subjects With Symptomatic Hypertrophic Cardiomyopathy (clinicaltrials.gov) - P2/3; N=172; Active, not recruiting; Sponsor: Gilead Sciences; Recruiting ➔ Active, not recruiting; Trial primary completion date: Jun 2017 ➔ Jan 2017

Enrollment closed • Trial primary completion date • Biosimilar