Delcasertib

Delcasertib is a selective inhibitor of delta-protein kinase C (delta-PKC), which reduced infarct size during ischaemia/reperfusion in animal models and diminished myocardial necrosis and improved reperfusion in a pilot study during primary percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI).

A multicentre, double-blind trial was performed in patients presenting within 6 h and undergoing primary PCI for anterior (the primary analysis cohort, n = 1010 patients) or inferior (an exploratory cohort, capped at 166 patients) STEMI. Patients with anterior STEMI were randomized to placebo or one of three doses of delcasertib (50, 150, or 450 mg/h) by intravenous infusion initiated before PCI and continued for ∼2.5 h. There were no differences between treatment groups in the primary efficacy endpoint of infarct size measured by creatine kinase MB fraction area under the curve (AUC) (median 5156, 5043, 4419, and 5253 ng h/mL in the placebo, delcasertib 50, 150, and 450 mg/mL groups, respectively) in the anterior STEMI cohort. No treatment-related differences were seen in secondary endpoints of infarct size, electrocardiographic ST-segment recovery AUC or time to stable ST recovery, or left ventricular ejection fraction at 3 months. No differences in rates of adjudicated clinical endpoints (death, heart failure, or serious ventricular arrhythmias) were observed.

Selective inhibition of delta-PKC with intravenous infusion of delcasertib during PCI for acute STEMI in a population of patients treated according to contemporary standard of care did not reduce biomarkers of myocardial injury.

This editorial refers to ‘Inhibition of delta-protein kinase C by delcasertib as an adjunct to primary percutaneous coronary intervention for acute anterior ST-segment elevation myocardial infarction: results of the PROTECTION AMI Randomized Controlled Trial’[†][1], by A.M. Lincoff et al. , on page 2516 Reperfusion therapy reduces infarct size and improves left ventricular function in ST-segement elevation myocardial infarction (STEMI). Despite restoration of epicardial perfusion and commensurate reductions in morbidity and mortality, residual hazard persists. Restoration of coronary blood flow after prolonged ischaemia may exhibit a ‘double edge’ characterized as reperfusion injury with resulting cell death that can account for up to half of the final infarct size.1 The pathophysiology of reperfusion injury is probably multifactorial and includes distal embolization/platelet plugging of the microvasculature, release of toxic inflammatory mediators, production of oxygen free radicals, and accumulation of intracellular calcium. Whereas various cytoprotective agents have shown promise in animal models, to date translation of this benefit has been disappointing at best.2 Hence, combating reperfusion injury remains one of the final therapeutic frontiers in STEMI management. Because protein kinase C (PKC) isoenzymes modulate myocardial protection, their potential for therapeutic intervention has been of interest.3,4 However, counter-regulatory cardioprotective activity has been reported with specific PKC isoenzymes. This ‘ying–yang’ counterpoint is represented by activation of ePKC which provides cardioprotection whereas activation of δPKC induces myocardial cell damage following ischaemia.5 Application of this pathway to myocardial protection led to the development of the selective δPKC antagonist, delcasertib, which reduced infarct size and improved microvascular function following reperfusion in animal models.6,7 Given the experimental promise of delcasertib, a phase II dose-escalation study of 154 patients … [1]: #fn-2