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
Literature - Camm AJ, Dorian P, Hohnloser SH et al. - Eur Heart J - Cardiovasc Pharmacother 2018Introduction 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 [1] 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 [2].
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 [3].
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.
Main results
- 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.
Conclusion
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.
References
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