Intracoronary KAI-9803 as an Adjunct to Primary Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction

Abstract

Background-KAI-9803, a ␦-protein kinase C inhibitor, has been shown to ameliorate injury associated with ischemia and reperfusion in animal models of acute myocardial infarction (MI). Methods and Results-Direct Inhibition of ␦-Protein Kinase C Enzyme to Limit Total Infarct Size in Acute Myocardial Infarction (DELTA MI) was a "first-in-human," dose-escalation study that evaluated the safety, tolerability, and activity of KAI-9803 for patients with acute anterior ST-segment elevation MI undergoing primary percutaneous coronary intervention. Patients who presented within 6 hours of symptom onset and had an occluded left anterior descending infarct artery on angiography were randomized in a 2:1 fashion to receive 1 of 4 doses of KAI-9803 (cohort 1, 0.05 mg; cohort 2, 0.5 mg; cohort 3, 1.25 mg; cohort 4, 5.0 mg) versus blinded concurrent placebo delivered in 2 divided doses via intracoronary injection before and after reestablishment of antegrade epicardial flow with percutaneous coronary intervention. Safety and biomarker end points were assessed. Overall, 154 patients were randomized and treated with study drug (37 in cohort 1, 38 in cohort 2, 38 in cohort 3, 41 in cohort 4). The incidence of serious adverse events was similar between patients treated with KAI-9803 versus placebo. Other safety end points, including changes in QT intervals and standard laboratory values after study drug administration, were similar between treatment groups. Although the study was not powered to demonstrate efficacy with the biomarker end points assessed, signs of drug activity with KAI-9803 were suggested by trends for consistent, nonsignificant reductions in creatine kinase-MB area under the curve and ST-recovery area under the curve values across all dosing cohorts with KAI-9803 compared with concurrent placebo, and similar trends were demonstrated for improvements in 99m technetium sestamibi infarct size values with active study drug in cohorts 1, 2, and 3. Conclusions-KAI-9803 had an acceptable safety and tolerability profile when delivered via intracoronary injection during primary percutaneous coronary intervention for ST-segment elevation MI. Signs of potential drug activity were demonstrated with biomarker end points in this small exploratory study, indicating that further testing of KAI-9803 as an adjunctive therapy for ST-segment elevation MI is warranted. (Circulation. 2008;117:886-896.)

Mechanisms of Altered Ca 2+ Handling in Heart Failure

“…Deletion of the PKCα gene 222285 or inhibition with drugs 286287135 have shown dramatic protective effects against the development of heart failure of various etiologies including ischemia, pressure overload or dilated cardiomyopathy induced by deleting LIM protein in animal models. However, clinical trials with PKC inhibitors or RACK inhibitor peptides were largely disappointing for improving heart failure 288 or reducing myocardial injury in MI patients 289290 .…”

Role for protein kinase C delta in the functional activity of human UGT1A6: implications for drug–drug interactions between PKC inhibitors and UGT1A6

“…HLM) otherwise inhibition of UGT enzymes via PKC or other kinase inhibition may be missed. Secondly, compounds with PKC δ inhibitory activity such as KAI-9803, which is being evaluated for the treatment of reperfusion injury following acute myocardial infarction, may potentially impair the metabolism of drugs requiring UGT1A6-mediated glucuronidation (Bates et al 2008). Finally, PKC modulation of UGT activity may be just one part of a complex kinase mediated regulation of drug-metabolizing enzymes possibly explaining variations observed in not only UGT but also cytochrome P450 mediated metabolism between individuals.…”

“…Furthermore, the role of specific PKC isoforms in UGT phosphorylation would be of importance as several isoform-specific PKC inhibitors are currently in clinical development. For example, ruboxistaurin (a PKC β inhibitor) is being developed for the treatment of diabetic neuropathy and macular oedema, while KAI-9803 (PKC δ inhibitor) is being tested for the treatment of acute myocardial infarction reperfusion injury (Bates et al 2008; Brooks et al 2008). …”

Cell-permeable protein therapy for complex I dysfunction

“…Targeting of recombinant cell-permeable proteins to mitochondria has been accomplished by several groups [74,70-72]. A 28 aa cell-penetrating peptide from azurin, a bacterial protein, is in Phase II clinical trial as an antiangiogenic cancer drug [81], and a cell-permeable peptide inhibiting protein kinase C delta was tested in a clinical trial for patients with acute myocardial infarction [82]. Morpholinos are in clinical trial for treatment of Duchenne muscular dystrophy and may be more effectively delivered if conjugated to cell-penetrating peptides (CPPs).…”