AZD-1305: A Comprehensive Monograph on a Multi-Ion Channel Blocker for Atrial Fibrillation

Executive Summary

AZD-1305 was an investigational small molecule antiarrhythmic agent developed by AstraZeneca for the management and pharmacological conversion of atrial fibrillation (AF). Its development was predicated on a sophisticated therapeutic hypothesis aimed at overcoming the principal limitation of existing Class III antiarrhythmic drugs: the risk of life-threatening ventricular proarrhythmia. The drug was rationally designed as a multi-ion channel blocker, combining potent inhibition of the rapid component of the delayed-rectifier potassium current ($I_{Kr}$) with targeted blockade of the late inward sodium current ($I_{NaLate}$) and the L-type calcium current ($I_{CaL}$). This combination was intended to preserve the atrial antiarrhythmic efficacy derived from prolonging the action potential duration while simultaneously suppressing the cellular mechanisms, such as early afterdepolarizations (EADs), that trigger Torsade de Pointes (TdP).

Preclinical studies robustly supported this hypothesis. In various animal models, AZD-1305 demonstrated a desirable atrial-predominant electrophysiological profile, prolonging the effective refractory period more in atrial than in ventricular tissue. Critically, in direct comparisons with selective $I_{Kr}$ blockers like dofetilide, AZD-1305 produced a similar degree of QT interval prolongation but with a markedly lower incidence of TdP and less repolarization instability. These compelling preclinical findings provided a strong rationale for advancing the compound into human trials.