Investigational antiarrhythmic agents: promising drugs in early clinical development

ABSTRACT

Introduction: Although there have been important technological advances for the treatment of cardiac arrhythmias (e.g., catheter ablation technology), antiarrhythmic drugs (AADs) remain the cornerstone therapy for the majority of patients with arrhythmias. Most of the currently available AADs were coincidental findings and did not result from a systematic development process based on known arrhythmogenic mechanisms and specific targets. During the last 20 years, our understanding of cardiac electrophysiology and fundamental arrhythmia mechanisms has increased significantly, resulting in the identification of new potential targets for mechanism-based antiarrhythmic therapy.

Areas covered: Here, we review the state-of-the-art in arrhythmogenic mechanisms and AAD therapy. Thereafter, we focus on a number of antiarrhythmic targets that have received significant attention recently: atrial-specific K⁺-channels, the late Na⁺-current, the cardiac ryanodine-receptor channel type-2, and the small-conductance Ca²⁺-activated K⁺-channel. We highlight for each of these targets available antiarrhythmic agents and the evidence for their antiarrhythmic effect in animal models and early clinical development.

Expert opinion: Targeting AADs to specific subgroups of well-phenotyped patients is likely necessary to detect improved outcomes that may be obscured in the population at large. In addition, specific combinations of selective AADs may have synergistic effects and may enable a mechanism-based tailored antiarrhythmic therapy.

KEYWORDS:

• Antiarrhythmic drugs
• atrial fibrillation
• calcium handling
• ion channels
• sudden cardiac death

Article highlights

• Antiarrhythmic drugs, commonly grouped in Vaughn Williams Class I-IV according to their primary electrophysiological target, remain the most common treatment for patients with heart rhythm disorders.

• All antiarrhythmic drugs have multiple electrophysiological targets and diverse pro- and antiarrhythmic effects and there is a clear unmet clinical need for safer and more effective antiarrhythmic drugs.

• Recent research has identified a number of targets with promising properties (e.g., selective chamber occurrence, upregulation under disease conditions), including atrial-specific K⁺-currents (I_Kur, TASK-1), I_NaL, RyR2 and SK channels.

• Several compounds modulating these targets have been developed and have shown promising antiarrhythmic effects in preclinical studies. However, so far none of these compounds have been successful in clinical trials, although inhibition of TASK-1 and SK channels has not been tested yet.

• Future studies will need to improve our understanding of the fundamental arrhythmia mechanisms in individual patients to identify the optimal target group for the next generation of antiarrhythmic agents.

Declaration of interest

Dr. Dobrev is on the Scientific Advisory Board of OMEICOS and received speaker’s fees from Boston Scientific, Daiichi Sankyo and Servier. His laboratory has also executed a research contract for Omeicos. Since first submission of this manuscript, S. Ghezelbash has taken on a position at Novartis, but there are no conflicts of interest related to this manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.