A Novel Approach for the Treatment of Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia facing physicians, with recent epidemiological studies estimating that there are over 11 million AF sufferers in the seven major economies. The prevalence of AF is predicted to increase two- to three-fold in the next 50 years.¹

AF is clinically significant because it contributes to the incidence of stroke and overall cardiovascular morbidity and mortality. Patients with AF have a five-fold increased risk for stroke; indeed, in the United States approximately 15% to 25% of all strokes can be attributed to AF.²

The treatment of AF is controversial and can be problematic. While electrical cardioversion restores sinus rhythm in many patients with AF, up to 40% revert to AF within a year. Consequently, the maintenance of sinus rhythm often requires chronic treatment with anti-arrhythmic drugs. Although there is a consensus among cardiologists that sinus rhythm control with anti-arrhythmic drugs is the preferred and most effective treatment of AF, the current stable of drugs come with significant negative side effects. For example, existing anti-arrhythmic drugs may increase mortality by inducing ventricular arrhythmia, this being the result of drug interactions with targets that are expressed in the ventricle as well as the atrium. The safety of existing anti-arrhythmic drugs in AF patients is further complicated by the presence of other cardiovascular co-morbidities such as heart failure.

To address this unmet medical need, Xention Limited is developing novel anti-arrhythmic agents with a much improved efficacy and safety profile that are selective for an atrium-specific ion channel. Additionally, these drugs extend action potential duration in human atrial myocytes but not ventricular myocytes. It is expected that such agents will demonstrate clinical efficacy in AF patients and be safe and well-tolerated when administered chronically. There are two channels expressed only in the atria that play a significant role in atrial repolarisation and are thus promising targets for AF—Kv1.5 (IKur) and Kir3.1/3.4 (IKACh).

XEN-D0103 from Xention is a highly potent and selective blocker of the Kv1.5 channel. In particular, XEN-D0103 demonstrates a high degree of selectivity over other cardiac ion channels such as hERG, Nav1.5, and the L-type cardiac calcium channel. Such selectivity is important for the avoidance of QTc liability and ventricular effects.

In addition to demonstrating in vitro selectivity, XEN-D0103 has also demonstrated efficacy in a canine model representing persistent AF in the clinical setting. Administration of XEN-D0103 reduced AF duration, AF inducibility, and increased the atrial effective refractory period, without affecting QTc, heart rate, or blood pressure. XEN-D0103 has completed pre-clinical studies and is being evaluated in a first-in-man study in 2011.

References
1. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006; 114:119–125.
2. Steinberg JS. Atrial fibrillation: an emerging epidemic? Heart. 2004;90: 239–240.