Gap junction modulation is a promising and completely novel mechanism of action for the treatment of cardiovascular disorders. Gap junctions are a class of protein channels that are responsible for conducting electrical impulses between cells in the heart to maintain normal rhythm. Rotigaptide (ZP-123, GAP-486), a stable antiarrhythmic peptide analogue that has been shown to increase gap junction intercellular conductance in cardiomyocytes, is currently under clinical investigation by Wyeth for the treatment of arrhythmias. This novel compound was the subject of presentations at two recent conferences.

The mechanism of action of rotigaptide and preclinical study results were presented at the International Gap Junction Conference in Whistler, British Columbia in August. Rotigaptide increased gap junction-mediated intercellular communication in cultures of cells expressing connexin43, without inducing any significant changes in the overall phosphorylation status of connexin43 (Martin, P.E.M. et al. Int Gap Junction Conf (Aug 13-18, Whistler) 2005, Abst 93). Studies in isolated perfused rat hearts established that global no-flow ischemia for 30 minutes induced dephosphorylation of three serine sites (Ser297, Ser306 and Ser368) in the carboxy-terminal domain of connexin43 and resulted in the development of asystole. Treatment with rotigaptide suppressed dephosphorylation and significantly increased time to asystole (Axelsen, L.N. et al., Abst). Incubation of isolated rat left atria with rotigaptide dose-dependently prevented atrial conduction velocity (CV) slowing and completely reverted established atrial CV slowing induced by metabolic stress, but had no significant effects on atrial CV during physiological conditions (Haugan, K. et al., Abst). The in vivo effects of rotigaptide were evaluated in dogs with ventricular arrhythmias associated with ischemia/reperfusion injury. All the animals first received a single intravenous bolus of vehicle or rotigaptide 10 minutes before reperfusion, followed by an i.v. infusion of vehicle or active drug. Compared to vehicle, the two highest rotigaptide doses employed were associated with significant reductions in the total incidence of ventricular tachycardia during the first 60 minutes of reperfusion and in the total number of premature ventricular complexes. Infarct size also decreased dose-dependently with roptigaptide, and the difference compared to vehicle was statistically significant with the highest dose tested. The compound had no significant effects on regional myocardial blood flow, blood pressure or heart rate (Hennan, J.K. et al. Int Gap Junction Conf (Aug 13-18, Whistler) 2005, Abst 52).

Chronic volume overload (CVO) has been reported to slow atrial conduction and increase susceptibility to the induction of atrial tachyarrhythmia in the heart. The in vivo effects of rotigaptide were further studied in rabbits with CVO induced by arterio-venous shunt formation. Compared to sham-operated rabbits, the expression of atrial gap junction proteins connexin40 and connexin43 in the heart of rabbits with CVO decreased by 32% and 72%, respectively. Treatment with rotigaptide significantly increased atrial conduction velocity, but had no effects on the incidence of atrial tachyarrhythmias. These results suggest that closure of gap junction channels contributes to slowing of atrial conduction in this model, but is not responsible for the increased susceptibility to arrhythmia (Haugan, K. et al. Eur Soc Cardiol Cong (Sept 3-7, Stockholm) 2005, Abst P3064).

Rotigaptide has reached phase II clinical trials at Wyeth. Earlier this year, Zealand Pharma and Wyeth expanded their existing research collaboration in the field of gap junction modulation. This is the third research agreement between the two companies following the initial licensing agreement in 2003 concerning rotigaptide. The focus of the expanded three-year agreement is research and development of new gap junction modulators targeting cardiovascular disorders.