5234KAND567, the first selective small molecule CX3CR1 antagonist in clinical development, mediates anti-inflammatory cardioprotective effects in rodent models of atherosclerosis and myocardial infarction

Abstract Background Fractalkine is a chemokine that mediates recruitment and extravasation of CX3CR1-expressing subsets of leukocytes and monocytes and has been implicated in the inflammation-driven pathology of cardiovascular disease. More specifically, fractalkine signaling has been proposed to contribute to increased infarct size and enhanced atherosclerotic plaque vulnerability in patients and experimental models. Blocking fractalkine/CX3CR1 signaling is suggested as a promising anti-inflammatory strategy for the treatment of both acute and chronic cardiovascular disease. KAND567 is a small molecule, selective, non-competitive, allosteric antagonist of the fractalkine receptor CX3CR1, that is under preparation for a clinical phase IIa study in AMI patients. Purpose To explore the therapeutic effects of the short and long term administration of KAND567 in experimental rodent models of acute myocardial infarction and atherosclerosis, respectively. Methods Myocardial infarction was induced in Wistar rats (N=6–8 per group) by ligation of the left anterior descending (LAD) coronary artery for 30 minutes followed by 2 h of reperfusion. The drug or vehicle infusion started either 5 min before or 30 min after start of reperfusion and continued during the remainder of the experiment. Hearts were collected and subjected to triphenyl tetrazolium chlorine (TTC) staining and the infarction area/area at risk of the left ventricle was determined by planimetry and compared against vehicle group. Atherosclerosis-prone LDL-receptor deficient mice on a high-cholesterol diet, (N=15–25 per group) were treated with KAND567 for 15–23 weeks. Atherosclerotic plaque development in the thoracic arch was determined by ultrasound imaging and histology. Immunohistochemistry was used to follow changes in the cellular composition in the atherosclerotic lesions. Results In the acute myocardial infarction study, the infusion of KAND567 before the start of reperfusion significantly reduced infarcted/risk area (by up to 50%) as compared to the vehicle group. However, the infusion had no effect on the infarct size when administration was initiated 30 min after start of reperfusion. In the atherogenesis study, oral treatment with KAND567 significantly reduced vascular macrophage infiltration by 50% and reduced intima media thickness. Furthermore, reduced plaque volume and a more stable plaque phenotype was noted following treatment with KAND567. KAND567 experimental results Conclusion Specific inhibition of fractalkine-driven inflammation by KAND567 provides cardioprotective, anti-atherosclerotic and plaque stabilizing effects via mechanisms related to immune cell infiltration, in rodent models. Further studies should be initiated to test if KAND567 is a potential candidate drug, targeting the excessive inflammatory injury associated with ischemia/reperfusion in myocardial infarction and providing plaque stabilization by reducing inflammatory risk for recurrent coronary events.