First Clinical Study with AP30663 ‐ a K_Ca2 Channel Inhibitor in Development for Conversion of Atrial Fibrillation

Abstract

Pharmacological cardioversion of atrial fibrillation (AF) is frequently inefficacious. AP30663, a small conductance Ca 2+ activated K + (K Ca 2) channel blocker, prolonged the atrial effective refractory period in preclinical studies and subsequently converted AF into normal sinus rhythm. This first-inhuman study evaluated the safety and tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects were explored. Forty-seven healthy male volunteers (23.7 ± 3.0 years) received AP30663 intravenously in ascending doses. Due to infusion site reactions, changes to the formulation and administration were implemented in the latter 24 volunteers. Extractions from a 24-hour continuous electrocardiogram were used to evaluate the PD effect of AP30663. Data were analyzed with a repeated measure analysis of covariance, noncompartmental analysis, and concentration-effect analysis. In total, 33 of 34 adverse events considered related to AP30663 exposure were related to the infusion site, mild in severity, and temporary in nature, although full recovery took up to 110 days. After formulation and administration changes, the local infusion site reaction remained, but the median duration was shorter despite higher dose levels. AP30663 displayed a less than dose proportional increase in peak plasma concentration (C max) and a terminal half-life of around 5 hours. In healthy volunteers, no effect of AP30663 was observed on electrocardiographic parameters, other than a concentration-dependent effect on the corrected QT Fridericia's formula interval (+18.8 ± 4.3 ms for the highest dose level compared with time matched placebo). In conclusion, administration of AP30663, a novel K Ca 2 channel inhibitor, was safe and well-tolerated systemically in humans, supporting further development in patients with AF undergoing cardioversion. Episodes of atrial fibrillation (AF) often convert spontaneously but can otherwise be converted to sinus rhythm by electrical or pharmacological treatment. Although electrical direct current cardioversion is generally considered highly effective, it is cumbersome because it requires anesthesia and is not available 24 hours a day in all hospitals. Pharmacological cardioversion is a tempting alternative, but current options are limited by lower efficacy compared with electrical treatment and by the fact that not all patients are eligible for treatment. 1 Several cardiac ion channels are targets for marketed antiarrhythmic drugs. Conventional class III antiarrhythmic

Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates)

“…From a review of the literature in November 2020, data on J-Tpeakc now exists for 51 different drugs/interventions, of which there is clinical data for 27 and nonclinical data for 35, with 11 overlapping (see Supplementary Materials Table S1). For clinical data, this includes new clinical drug studies, [62][63][64][65][66][67][68][69] comparison of different measurement algorithms, [70][71][72][73] improved heart rate assessment correction, 74 and multiple studies from independent groups re-analyzing the FDA clinical trial data. 70,71,75,76 For nonclinical studies, this includes drugs overlapping with clinical study drugs and many interesting drugs without clinical data.…”

Modulation of SK Channels: Insight Into Therapeutics of Atrial Fibrillation

“…It induced a transient concentration-dependent QT Fridericia's formula interval prolongation. These findings suggest that AP30663 could be an ideal compound for cardioversion of AF [87]. It is expected that this will open up a new therapeutic avenue targeting the modulation of SK channels in the management of AF.…”

Anti‐arrhythmic investigations in large animal models of atrial fibrillation

“…However, it is also worth mentioning that the atrial expression of SK channels is down‐regulated during chronic AF in the remodelled atrium, which could limit the use of such channel blockers in this particular patient group (Skibsbye et al, 2014). SK channel blockers currently under development for cardioversion of AF have shown good safety results in Phase I studie and SK channel blockers are for now considered to be safe for human use (Gal et al, 2020).…”