Novel antiarrhythmic drug safe but not clinically effective in patients with paroxysmal AF
A randomized, double-blind, placebo-controlled trial assessing the efficacy of S66913 in patients with paroxysmal atrial fibrillation
Introduction and methods
Current antiarrhythmic drugs (AADs) for the treatment of atrial fibrillation (AF) are associated with moderate efficacy and adverse effects. It is hypothesized that inhibition of I-kur (ultra-rapid activating delayed rectifier K+ current), a major repolarizing current present in the atria  but absent in the ventricles, results in antiarrhythmic effects by prolonging the atrial action potential, without cardiac adverse effects such as ventricular pro-arrhythmic effects .
S66913 (also known as XEN-D0103) is a selective and potent I-kur-inhibitor, developed for therapy in paroxysmal AF, which showed earlier promising antiarrhythmic activity in an experimental study using atrial tissue of patients with AF and sinus rhythm (SR). This makes I-kur-inhibitors attractive drugs for atrial-specific therapy in AF .
The randomized Double-blind, International study AssessinG efficacy of S66913 in paRoxysmal Atrial Fibrillation – I-kur-inhibitor (DIAGRAF – I-KUR) trial investigated the antiarrhythmic effects and safety of the I-kur-inhibitor S66913 versus placebo in patients with symptomatic paroxysmal AF, by using an insertable continuous monitoring (ICM). Adults (n=58) had an ICM implanted and only those with AF-burden of 1-70% and ≥3 AF-episodes in a 4-week baseline period, were randomized to either S66913 (5, 25 or 100 mg, n=16, 13 and 15, respectively)) or placebo (n=14) once daily for four weeks.
The primary outcome was the absolute change in AF-burden (percentage time spent in AF/atrial tachycardia (AT)), compared with baseline, measured by ICM.
- The study was terminated prematurely due to non-study related preclinical safety outcomes.
- The median AF-burden varied from 4.4% to 10.4% at baseline in the four treatment groups, and was not balanced among groups.
- No dose-related significant effects on AF-burden were observed after treatment with S66913 as compared with baseline. Patients with over 50% reduction of AF-burden were only seen in the treatment groups, without a dose-response effect, and sample size was small.
- Median change from baseline in AF/AT-duration during the treatment period was small in all groups. A slight median decrease in AF/AT-episodes was seen in all S66913 groups, while the number of episodes remained stable in the placebo group.
- Change in AF duration and number of AF episodes were similar between groups. Nor were significant changes seen in time to first AF, time to first AF of a certain duration, or time to first symptomatic AF. Treatment did not affect symptoms.
- No safety concerns were noted related to treatment with S66913. In 18.6% of S66913-treated patients, emergent adverse effects were observed, without a dose-effect, compared to 21.4% in the placebo group.
The DIAGRAF-I-KUR was the first trial investigating the effect of AADs by using ICM-devices. The I-kur-inhibitor S66913 was safe, but not clinically meaningful in paroxysmal AF patients. However, more research is needed because of premature termination of the study and consequently insufficient power as a result of the limited sample size.