SELECT-ACS: Hints of Myocardial Sparing With Inclacumab in NSTEMI

Shelley Wood

March 10, 2013

SAN FRANCISCO, California — A small, phase 2 study, with a biomarker test for its primary end point, offers some encouraging hints that the P-selectin antagonist inclacumab may be able to reduce myocardial damage in patients undergoing PCI for non-ST-elevation MI [1].

Presenting the SELECT-ACS results here during a late-breaking clinical-trial session at the American College of Cardiology 2013 Scientific Sessions--the study was simultaneously published online in the Journal of the American College of Cardiology--Dr Jean-Claude Tardif (Montreal Heart Institute, QC) stressed that the findings are early, but intriguing.

"We think that this consistent signal favoring inclacumab should lead us to perform additional studies in phase 3," he told a mid-day press conference.

P-selectin is a cell-adhesion molecule expressed on endothelial cells and platelets and is known to play a role in leukocyte and platelet "rolling." Animal studies have suggested that inhibition of this molecule may limit macrophage accumulation and neointimal formation after injury by decreasing neutrophil and platelet adhesion.

SELECT-ACS randomized 544 NSTEMI patients headed to coronary angiography to a placebo infusion or to either a 5-mg/kg or 20-mg/kg infusion of inclacumab. Of these, 340 patients went on for PCI and had peak troponin I (the primary end point for the 16- and 24-hour time points) and CK-MB measured at intervals postprocedure. Additional safety visits were conducted with all patients (including those who did not undergo PCI) at 30 and 120 days.

After 24 hours, peak troponin I was reduced in the 20-mg/kg dose, but not in the 5-mg/kg dose, compared with placebo, although the p value was only marginally significant (p=0.05). At 16 hours, a trend in the same direction did not reach statistical significance. CK-MB followed a similar pattern, but the placebo-adjusted change also missed statistical significance.

Serious adverse events were few, although numerically higher in the treatment groups, but with no statistical significance. No deaths occurred in the placebo group, whereas four and two were seen in the 5-mg/kg and 20-mg/kg groups, respectively. Rates of nonfatal MI were also more common in the treatment groups, but event rates were small.

Importantly, there was no increased bleeding and no increased infection, two key concerns when recombinant monoclonal antibodies are studied clinically.

In his concluding remarks, Tardif acknowledged that while troponin I and CK-MB are "reliable markers" of myocardial damage, the clinical significance of post-PCI elevations "remains open to debate." A larger study with hard outcomes is the key next step.

"Further clinical investigation will be required to determine the clinical value--benefit or harm--of inclacumab in patients presenting with myocardial infarction, whether or not they undergo PCI."

Commenting on the study, Dr Neil Kleiman (Methodist Hospital Research Institute, Houston, TX) pointed out that scientists have talked for decades about the link between inflammation and coronary disease. "For me, it's always very exciting to see things coming to the clinical realm, and that's exactly what we've got here. This is a challenging group of patients to take care of and a challenging group in which to show benefits," because they are already on effective medications.

He continued: ''This is still a pilot study with fewer than 600 patients--getting something definitive will take a much larger study. This, however, is the kind of study we should be doing: rationally based and scientific developed. This looks very promising, and I hope we get to see this in larger trials."

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