SK ion channel inhibitor shows ability to convert atrial fibrillation to sinus rhythm
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Key takeaways:
- A novel SK ion channel inhibitor more often converted atrial fibrillation to sinus rhythm compared with placebo.
- There were no cases of ventricular arrhythmias, in contrast with existing cardioversion agents.
In a proof-of-concept phase 2 trial, a novel SK ion channel inhibitor successfully converted atrial fibrillation to sinus rhythm compared with placebo.
The researchers evaluated the efficacy of two doses of the first-in-class SK ion channel inhibitor (AP30663, Acesion Pharma) — 3 mgkg–1 and 5mgkg–1 — compared with placebo in patients with a current AF episode lasting 7 days or less.
Image: Adobe Stock
“Current pharmacological options for cardioversion have limited efficacy and a substantial risk of serious adverse effects, particularly an increased risk of causing potentially life-threatening ventricular arrhythmia, also known as proarrhythmia,” Anders Gaarsdal Holst, MD, PhD, CEO of Acesion Pharma, and colleagues wrote in Nature Medicine. “Consequently, use of these drugs are restricted in patients with left ventricular hypertrophy, ischemic heart disease and heart failure, resulting in barriers for prescribing the drugs and making many patients with AF ineligible for treatment. ... “The KCa2 ion (or SK) channel is a calcium-activated potassium channel that conducts a repolarizing current in the heart. It has the strongest association with AF in genome-wide association studies among genes encoding for ion channels, with no association to the ECG QT interval. Inhibiting KCa2 results in prolongation of the atrial action potential duration in tissue from humans with AF; KCa2 inhibitors have demonstrated efficacy in a range of animal models of AF without ventricular effects. AP30663 is a new KCa2 inhibitor with demonstrated efficacy in animals; it was well tolerated in a phase 1 trial, although with a finding of transient QTc prolongation.”
The trial, which was discontinued early due to slow enrollment during the COVID-19 pandemic, included 59 patients with AF assigned to AP30663 3 mgkg–1 (mean age, 65 years; 80% men), AP30662 5mgkg–1 (mean age, 65 years; 62% men) or placebo (mean age, 64 years; 69% men), all delivered via IV infusion.
The primary endpoint of cardioversion from AF to sinus rhythm within 90minutes from the start of the infusion occurred in 42% of the AP30663 3 mgkg–1 group, 55% of the AP30663 5 mgkg–1 group and none of the placebo group, the researchers wrote.
In a Bayesian analysis, both doses had a more than 99.9% probability of superiority over placebo, beating the performance goal of 95%, according to the researchers.
Mean time to cardioversion was 47 minutes (standard deviation, 23) in the AP30663 3 mgkg–1 group and 41 minutes (standard deviation, 24) in the AP30663 5 mgkg–1 group.
There were no ventricular arrhythmias, and adverse event rates were similar in the AP30663 and placebo groups, the researchers wrote.
“We are pleased that Nature Medicine has recognized the importance of our AP30663 results for conversion of AF to sinus rhythm and accepted them for publication in their prestigious journal,” Holst said in a press release. “Based on this achievement of clinical proof-of-mechanism, and enabled by our recent successful series B financing, we have now also moved our oral SK inhibitor AP31969 into clinical development. Through this study, we will learn about the safety, as well as the pharmacokinetics of AP31969 and it is an important step towards addressing the large unmet need within atrial fibrillation.”
Reference:
- Acesion Pharma announces Nature Medicine publication of clinical results in atrial fibrillation. https://www.acesionpharma.com/post/acesion-pharma-announces-nature-medicine-publication-of-clinical-results-in-atrial-fibrillation. Published Dec. 13, 2023. Accessed Dec. 13, 2023.
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