Human Electrophysiological and Pharmacological Properties of XEN-D0101

Abstract

The human electrophysiological and pharmacological properties of XEN-D0101 were evaluated to assess its usefulness for treating atrial fibrillation (AF). XEN-D0101 inhibited Kv1.5 with an IC50 of 241 nM and is selective over non-target cardiac ion channels (IC50 Kv4.3, 4.2 μM; hERG, 13 μM; activated Nav1.5, >100 μM; inactivated Nav1.5, 34 μM; Kir3.1/3.4, 17 μM; Kir2.1, >>100 μM). In atrial myocytes from patients in sinus rhythm (SR) and chronic AF, XEN-D0101 inhibited non-inactivating outward currents (Ilate) with IC50 of 410 and 280 nM, respectively, and peak outward currents (Ipeak) with IC50 of 806 and 240 nM, respectively. Whereas Ilate is mainly composed of IKur, Ipeak consists of IKur and Ito. Therefore, the effects on Ito alone were estimated from a double-pulse protocol where IKur was inactivated (3.5 µM IC50 in SR and 1 µM in AF). Thus, inhibition of Ipeak is because of IKur reduction and not Ito. XEN-D0101 significantly prolonged the atrial action potential duration at 20%, 50%, and 90% of repolarization (AF tissue only) and significantly elevated the atrial action potential plateau phase and increased contractility (SR and AF tissues) while having no effect on human ventricular action potentials. In healthy volunteers, XEN-D0101 did not significantly increase baseline- and placebo-adjusted QTc up to a maximum oral dose of 300 mg. XEN-D0101 is a Kv1.5/IKur inhibitor with an attractive atrial-selective profile.

Rate-Dependent Role of I Kur in Human Atrial Repolarization and Atrial Fibrillation Maintenance

“…Mathematical simulations support these findings and suggest that I Kur blockers with rapid binding or slow unbinding kinetics have the strongest antiarrhythmic effects (22,29 Consistent with this study, XEN-D0101, a selective I Kur blocker, prolonged the atrial effective refractory period (AERP) and decreased AF vulnerability in a dose-and rate-dependent manner in atrial tachycardia-induced remodeled canine atria (30,31). In human cardiomyocytes, XEN-D0101 prolonged AERP in AF-remodeled but not in non-remodeled tissue (32). However, experiments were conducted using a stimulation frequency of 1 Hz at which we predict no effect on APD and AERP based on this study; rapid stimulation rates at which I Kur -block induced prolongation of APD/atrial refractoriness would be expected were not reported.…”

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS

“…Trwają badania kliniczne dotyczące kilku leków hamują-cych ultraszybki prąd potasowy (I Kur ) oraz innych inhibitorów nietypowych kanałów jonowych [673][674][675]. Leki te nie są jeszcze dostępne w praktyce klinicznej.…”

Status of Antiarrhythmic Drug Development for Atrial Fibrillation

“…40,41 It has been assessed in a phase 1 study to establish the safety of modulating the Kv1.5 target in vivo and is currently being assessed in a proof-of-mechanism electrophysiology phase 1 study at multiple European sites. 42 XEN-D0103/S66913 is more potent and more selective than XEN-D0101 and has recently completed preclinical development. It causes a significant extension of the APD in atrial tissue, but has no effect on the APD in human ventricular tissue.…”