KAND567 administration in STEMI patients undergoing primary PCI significantly reduced left ventricular thrombus compared to placebo (2.7% vs 17.6%; p=0.049).
RCT (n=71)
Double-blind
1:1
Yes
Does KAND567 improve safety and reduce reperfusion injury in STEMI patients with LAD occlusion undergoing PPCI?
Inhibition of the fractalkine pathway with KAND567 in STEMI patients undergoing PPCI appears safe and significantly reduces the incidence of left ventricular thrombus.
Absolute Event Rate: 2.7% vs 17.6%
p-value: p=0.049
Abstract Background One of the clinical needs in patients with large myocardial infarction (MI) and timely primary percutaneous coronary intervention (PPCI) remains the prevention of reperfusion injury, in particular intramyocardial haemorrhage (IMH), which carries a 5-fold greater risk for adverse outcome than patients without IMH. We have previously demonstrated a strong association between expression of the fractalkine receptor CX3CR1 and microvascular obstruction in patients undergoing PPCI for ST-elevation MI (STEMI). Purpose The FRACTAL study (FRACTalkine inhibition in Acute myocardial infarction) was a multicenter, phase IIa, pilot, randomised, two-arm parallel group, double-blind, and placebo-controlled investigation in 71 patients. Its main goals were to evaluate KAND567's safety and tolerability when administered orally and iv, as well as to reduce the symptoms of reperfusion injury in STEMI patients receiving PPCI. Methods and Results We found that inhibition of CX3CR1 with an allosteric small molecule inhibitor (KAND567) prior to reperfusion, reduces IMH by 50% in a rat MI model. Patients with angiographic occlusion of the LAD were then randomised on a 1:1 basis to receive either KAND567 or placebo over a period of 72 hours. All patients underwent 2 MRI scans, at 3 days and at 3 months, paralleled by deep immunophenotyping and proteomic analysis. There was no statistical difference in adverse or serious adverse events between both study arms, and we confirmed KAND567 target engagement in CX3CR1 expressing cells. Surprisingly, we found a significant reduction in left ventricular thrombus (LVT) in the KAND567 arm compared to the placebo arm (2.7% vs 17.6%; p=0.049), as well as a trend towards a lower occurrence of IMH in the KAND567 arm compared to the placebo arm (37.9% vs. 57.1%; p=0.15). Infarct size after 3 months was 25% smaller in patients without IMH under KAND567 treatment compared to placebo. OLINK analysis of 5400 proteins showed that 5 out of the top 6 pathways downregulated by KAND567 were related to coagulation, clot formation or platelet activation. Single-cell RNA sequencing in 16 patients found that platelet factor 4 (PF4) and pro-platelet basic protein (PPBP) were upregulated 4.5-fold (p10E-23) and 4.2 fold (p10E-23) in patients with IMH. Accordingly, this was reversed in patients treated with KAND567. Conclusion This first in-man study demonstrates that inhibition of the fractalkine pathway in STEMI patients by KAND567 appears safe and well-tolerated, while demonstrating a promising potential in preventing LV thrombus and IMH. Our data show the potential of fractalkine signalling inhibition in acute MI, reducing reperfusion injury as well as thrombotic complications, that are both linked to a potential novel mechanism of immunothrombosis. The results suggest a new mechanism and class of drug to target reperfusion injury, clearly warranting a larger phase IIb/III study.
Spyridopoulos et al. (Sat,) conducted a rct in ST-elevation myocardial infarction (STEMI) (n=71). KAND567 vs. Placebo was evaluated on Left ventricular thrombus (LVT) (p=0.049). KAND567 administration in STEMI patients undergoing primary PCI significantly reduced left ventricular thrombus compared to placebo (2.7% vs 17.6%; p=0.049).