Key result
AP30663 prolongs QTcF interval by ~50 ms vs. placebo at the 8 mg/kg dose.
Why the study?
AP30663 is a novel compound targeting the K Ca 2 channel in development for conversion of AF, and this extension phase 1 study aimed to evaluate higher single doses than tested in the first-in-human trial.
Does AP30663 cause QTcF prolongation or other safety issues in healthy male volunteers?
RCT (n=16)
double blind, placebo-controlled
randomized in a 6:2 ratio
No
Does AP30663 cause QTcF prolongation or other safety issues in healthy male volunteers?
AP30663 causes significant QTcF prolongation at higher doses, likely due to off-target IKr channel inhibition, limiting its dose escalation.
AP30663 at 8 mg/kg causes clinically relevant QTcF prolongation; cautions against dose escalation and challenges further development for atrial fibrillation.
Aims AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca 2+ activated K + (K Ca 2) channel. The aim of this extension phase 1 study was to test AP30663 at higher single doses compared to the first‐in‐human trial. Methods Sixteen healthy male volunteers were randomized into 2 cohorts: 6‐ and 8‐mg/kg intravenous single‐dose administration of AP30663 vs . placebo. Safety, pharmacokinetic and pharmacodynamic data were collected. Results AP30663 was associated with mild and transient infusion site reactions with no clustering of other adverse events but with an estimated maximum mean QTcF interval prolongation of 45.2 ms (95% confidence interval 31.5–58.9) in the 6 mg/kg dose level and 50.4 ms (95% confidence interval 36.7–64.0) with 8 mg/kg. Pharmacokinetics was dose proportional with terminal half‐life of around 3 h. Conclusion AP30663 in doses up to 8 mg/kg was associated with mild and transient infusion site reactions and an increase of the QTcF interval. Supporting Information support that the QTc effect may be explained by an off‐target inhibition of the I Kr channel.
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Yfanti et al. (2023) conducted an RCT in healthy male volunteers (n=16). AP30663 vs. Placebo (5% glucose) was evaluated on Maximum mean QTcF interval prolongation (MD 50.4 ms, 95% CI 36.7-64.0, p=<0.0001). AP30663 at 8 mg/kg was associated with an estimated maximum mean QTcF interval prolongation of 50.4 ms compared to placebo.
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