Abstract 1519: The Atrial Antiarrhythmic Drug XEN-D0101 Selectively Inhibits the Human Ultra-Rapid Delayed-Rectifier Potassium Current (IKur) Over Other Cardiac Ion Channels
Atrial fibrillation (AF) is the most common cardiac arrhythmia facing physicians, and the prevalence is predicted to rise dramatically further increasing the associated financial burden on healthcare providers. Sinus rhythm control is the preferred, and most effective, treatment for AF however; all currently available antiarrhythmic drugs are associated with significant negative side-effects. There is a clear unmet need for new antiarrhythmics with improved efficacy and safety. The ultra-rapid delayed-rectifier cardiac potassium ionic current (IKur), encoded by Kv1.5 in man, is a putative atrial-selective drug target for the treatment of AF. XEN-D0101 is a new antiarrhythmic currently in Phase I clinical development for AF, and has previously been shown to selectively prolong the atrial effective refractory period in the dog. The effect of XEN-D0101 on native atrial and cloned cardiac ion channels was studied. Whole-cell patch-clamp experiments were performed at room temperature using isolated human atrial myocytes and recombinant cell lines. Data are presented as mean and 95% confidence intervals (95% CI.). Data were fitted with a sigmoidal concentration-response function to yield a half-maximal inhibitory concentration (IC50) and Hill coefficient (nH). XEN-D0101 inhibited the native human atrial ultra-rapid delayed-rectifier (IKur) and transient-outward (Ito) potassium currents with IC50 values of 154 nM (95% CI. 128–184 nM, n=6 –9 cells/concentration) and 9 uM (95% CI. 7.0 –11.6 uM) n=6 –9 cells/concentration), respectively. This was concordant with inhibition data for the cloned molecular correlates hKv1.5 and hK4.3, expressed in CHO cells, IC50 values were 241 nM (95% CI. 152–383 nM, n=6 –12 cells/concentration), 4.2 uM (95% CI. 2.8 – 6.4 uM, n=5 cells/concentration), respectively. Cardiac safety screening against the cloned channels hERG and hNav1.5 revealed >50- and >100-fold selectivity respectively for IKur/Kv1.5. Selective prolongation of atrial refractoriness described in previous dog efficacy studies is consistent with the selective atrial ion channel blocking profile of XEN-D0101.