SAN FRANCISCO – Inclacumab, an inhibitor of the P-selectin pathway, may be a novel treatment for reducing myocardial damage after percutaneous coronary intervention for non–ST-elevation myocardial infarction, based on results from a phase-II study.
The trial, SELECT-ACS, is best viewed as a proof-of-concept study utilizing a reduction in biomarkers of myocardial damage as the endpoint, Dr. Jean-Claude Tardif said at the annual meeting of the American College of Cardiology.
Dr. Jean-Claude Tardif
Periprocedural myocardial damage, albeit often mild in nature, is common in PCI patients and is due in part to platelet activation and inflammation. The clinical relevance of post-PCI changes in biomarkers of myocardial damage is uncertain. What is clear from SELECT-ACS is that inclacumab is biologically active in NSTEMI patients. Future phase III studies with hard clinical endpoints conducted in patients with or without PCI will be critical to determining the drug’s relevance, he said.
In addition, the results of the ongoing SELECT-CABG study, in which the effects of inclacumab are being studied in patients undergoing surgical revascularization, will be presented later this year, according to Dr. Tardif, professor of medicine and director of research at the Montreal Heart Institute.
Inclacumab is a human recombinant monoclonal antibody that is a highly specific P-selectin antagonist. P-selectin is a cell adhesion molecule known to play a critical role in communication between activated platelets, WBCs, and the arterial wall. In animal studies, P-selectin inhibition reduces platelet stickiness, macrophage accumulation, and neointimal formation after injury.
"The P-selectin pathway is really at the crossroads of thrombosis and inflammation," Dr. Tardif explained. "It’s probably important to see this drug, inclacumab, not only as an antithrombotic but as an anti-inflammatory agent."
In SELECT-ACS, 544 patients with NSTEMI scheduled for coronary angiography and possible PCI were randomized to receive a single 1-hour-long infusion of inclacumab at 5 or 20 mg/kg or a placebo infusion up to 24 hours before their procedure. Most patients received the infusion just a few hours before angiography.
The primary study endpoint in SELECT-ACS was change in troponin I level from baseline at 16 and 24 hours post-PCI, compared with placebo. Thus, the analysis was restricted to the 322 study participants who underwent PCI. The medically managed SELECT-ACS participants treated with inclacumab will be the subject of a future report.
In the inclacumab 20 mg/kg group, the drop in troponin I was 22% greater than seen in placebo-treated controls at 16 hours and 24% greater at 24 hours. Peak troponin I level was reduced by 24% relative to placebo, and the area under the curve over a 24-hour span was reduced by 34%.
In addition, the decrease in creatine kinase MB (CK-MB) fraction was 16% greater with inclacumab 20 mg/kg than with placebo at 16 hours, and it also showed a 17% greater decrease at 24 hours. The incidence of a CK-MB rise greater than three times the upper limit of normal within the first 24 hours following PCI was 8.9% with inclacumab 20 mg/kg, compared with 18% with placebo. Moreover, soluble P-selectin levels were 22% lower in the inclacumab 20 mg/kg group than in controls.
Inclacumab at 5 mg/kg had no effect.
The pattern and intensity of adverse events were similar in the inclacumab and placebo groups. Given the dual antithrombotic and anti-inflammatory effects of P-selectin inhibition, it’s encouraging to note that the inclacumab-treated patients had no increase in bleeding or infections, Dr. Tardif said.
The study was funded by F. Hoffmann-La Roche. Dr. Tardif reported having no relevant financial interests.
Simultaneous with Dr. Tardif’s presentation of the SELECT-ACS findings in San Francisco, the study was published online (J. Am. Coll. Cardiol. 2013 [doi:10.1016/j.jaac.2013.03.003]).