Inhibition of fractalkine signalling in patients with acute myocardial infarction - First results from the FRACTAL trial

Background We have previously demonstrated a strong association between expression of the fractalkine receptor CX3CR1 on lymphocytes and microvascular obstruction (MVO) in patients undergoing primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction. Our pre-clinical studies also found an improvement in infarct size, inflammation and intramyocardial haemorrhage (IMH) when rats were pre-treated with the fractalkine inhibitor KAND567. Purpose FRACTAL (FRACTalkine inhibition in Acute myocardial infarction) study was a phase IIa, pilot, randomized, 2-arm parallel group, placebo-controlled, double blinded, multi-centre trial. Its primary aim was to assess the safety and tolerability of intravenous and oral administration of the fractalkine inhibitor KAND567 as well as reducing signs of reperfusion injury in STEMI patients undergoing PPCI. Methods Patients with a new diagnosis of anterior STEMI, who had index chest pain within 5 hours and angiographic occlusion of the LAD, were randomised on a 1:1 basis to receive either KAND567 or placebo over a period of 72 hours. All patients then underwent a baseline MRI scan at 3 days with a follow-up scan at 3 months, paralleled by longitudinal deep immuno­phenotyping over 9 time points. Results A total of 71 patients were enrolled into the study with 64 (90.1%) being male patients. The mean age of patients was 59.2 years. 37 patients received KAND567, whilst 34 received placebo over 72-hour period. Throughout the 3-month follow-up period, 23 (62%) patients from the KAND567 arm as compared to 24 (71%) patients in the placebo arm had reported adverse events. There was no statistical difference in serious adverse events (SAEs) between both arms with 9 documented in the placebo arm and 12 in the KAND567 arm. Safety bloods also demonstrated no significant differences between the two groups across all time points. There was a higher incidence of left ventricular (LV) thrombus in the placebo arm as compared to the KAND567 arm (17.6% vs. 2.7%; p=0.049). Additionally, the study also demonstrated a lower occurrence of IMH in the KAND567 arm compared to the placebo arm (35.5% vs. 55.2%; p=0.19). Deep immunephenotyping suggested clear target engagement in the KAND567 arm in natural killer cells as well as in cytotoxic T-lymphocytes. Conclusion This first in-man study demonstrates that inhibition of the fractalkine pathway in STEMI patients appears safe and well-tolerated, while demonstrating a promising potential in preventing LV thrombus and IMH. The results suggest a new mechanism and class of drug to target reperfusion injury, clearly warranting a larger phase III study.LV thrombus and IMH