Myocardial salvage in acute myocardial infarction - Challenges in clinical translation

Abstract

In 2001, the Mochly-Rosen laboratory published the first evidence that inhibition of delta protein kinase C (δPKC) at the onset of reperfusion reduced tissue injury in preclinical models of acute myocardial infarction (AMI). In various models of cardiac ischemia and reperfusion (I/R)including cultured neonatal cardiac myocytes [1], ex vivo whole rat heart [2], and in vivo porcine heart [3], we demonstrated that delivering a rationally designed peptide allosteric inhibitor of δPKC (δV1-1) at reperfusion reduced infarct size by about 70% [3]. δV1-1 treatment reduced necrosis and apoptosis, accelerated ATP regeneration, preserved mitochondrial structure, and preserved organization of contractile elements [3–6]. We also found that treatment with δV1-1 protected the vascular endothelium, leading to improved microvasculature flow and rapid recovery of coronary flow reserve [5]. All the benefits of δV1-1 treatment delivered at ~500 ng/kg at reperfusion were sustained through 12 days after treatment, including a ~70% smaller infarct size than control, normal ejection fraction, and normal coronary flow reserve [5]. Finally, independent studies that contributed to the characterization of δPKC in reperfusion injury in the heart were carried out in the laboratories of Drs. Gerald Dorn and Roberto Bolli [1], and Elizabeth Murphy [5], and were also corroborated independently using other systems, e.g. when using human atrial trabeculae strips in a transient ischemia model[7]. This preclinical evidence together with δV1-1’s excellent safety profile led KAI pharmaceuticals to test whether similar benefits could be achieved in AMI patients. The DELTA MI trial was a first-in-human, double-blinded, placebo controlled phase 1/2a trial to assess the safety of intracoronary δV1-1 (KAI-9803) in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). (For patient characteristics and detailed trial design, see ref [8].) Drug administration was based on the porcine STEMI model, in which the peptide was delivered through the lumen of a balloon catheter to the area down-stream of the occlusion, just prior to balloon deflation. Based on discussions with the FDA and bridging animal studies, a second dose was given through the guide catheter after balloon deflation, to allow drug delivery to myocardium supplied by arterial side branches that might have been blocked by the inflated balloon. The trial included five arms: a concurrent placebo arm of 51 patients and 4 drug-treated arms of 0.05, 0.5, 1.25, and 5 mg, with 25–26 patients each. The lowest dose was calculated to be efficacious based on the porcine model. DELTA MI demonstrated that δV1-1 was safe at all dose levels tested. Although the trial was not designed to achieve statistical significance, a trend towards benefit was seen in biomarkers that correlate with AMI clinical outcomes when the combined treatment groups were compared to placebo. These biomarkers included resolution of ST segment elevation, as measured by ST segment area under the curve (AUC), and infarct size, as measured by creatine kinase AUC (Figure 1; summarized from data in [8]). Late ischemic events (as measured by ST segment re-elevation in the 24 hrs after treatment) also declined by 63% (unpublished data). Figure 1 DELTA MI Biomarker Results These encouraging data on the safety and potential efficacy of δPKC inhibition led to a phase 2b trial testing intravenous δV1-1 in STEMI patients undergoing primary angioplasty (sponsored by KAI Pharmaceuticals with Bristol-Myers Squibb). The rationale for switching from intracoronary to intravenous administration was three-fold: 1) to allow earlier and more timely drug delivery to the increasing percentage of patients (up to 40%) who were achieving partial reperfusion prior to PCI as evidenced by TIMI 2/3 flow on initial angiography; 2) given δV1-1’s exceptionally short serum half-life (<2 minutes), continuous intravenous infusion allowed longer exposure of ischemic myocardium to the drug with the potential to increase efficacy, and 3) ease of use for the treating cardiologists. The trial sponsors had performed further preclinical [9]and human phase 1 studies to predict efficacious dose range and duration of therapy, establish safety, and characterize pharmacokinetics of intravenous infusion of δV1-1. The PROTECTION AMI trial enrolled 908 patients across four groups (~227 patients/group). Subjects received a 2.5 hour infusion of placebo or one of three doses (125, 375 or 1125 mg)of δV1-1 (called delcasertib in the trial). Preliminary results of PROTECTION AMI were presented at the American College of Cardiology meeting in March, 2011. The data showed that the inhibitor was safe at all doses tested, but failed to show a statistically significant benefit in the primary endpoint of CK-MB area under the curve with δV1-1 administration. Subgroup analysis revealed a trend towards reduced infarct size (~14%) in the two highest doses in patients with anterior MI and TIMI 0/1 flow on initial angiography, which represented 60–65% of the patients in each treatment arm [10]. Although the full analysis of PROTECTION MI has yet to be completed and published, several issues may inform the design of future myocardial salvage studies.