title: Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction.
abstract: BACKGROUND
  KAI-9803, a delta-protein kinase C inhibitor, has been shown to ameliorate injury associated with ischemia and reperfusion in animal models of acute myocardial infarction (MI).
  
  
  RESULTS
  Direct Inhibition of delta-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.
authors.affiliation: Duke Clinical Research Institute, 2400 Pratt St, Room 7035, Durham, NC 27705. matthew.roe@duke.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Bates
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Marco
authors.initials: M
authors.lastname: Costa
authors.forename: C Michael
authors.initials: CM
authors.lastname: Gibson
authors.forename: Christopher
authors.initials: C
authors.lastname: Granger
authors.forename: Cindy
authors.initials: C
authors.lastname: Green
authors.forename: Kevin
authors.initials: K
authors.lastname: Grimes
authors.forename: Robert
authors.initials: R
authors.lastname: Harrington
authors.forename: Kurt
authors.initials: K
authors.lastname: Huber
authors.forename: Neal
authors.initials: N
authors.lastname: Kleiman
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
authors.forename: Matthew
authors.initials: M
authors.lastname: Roe
authors.forename: Zygmunt
authors.initials: Z
authors.lastname: Sadowski
authors.forename: Scott
authors.initials: S
authors.lastname: Solomon
authors.forename: Petr
authors.initials: P
authors.lastname: Widimsky
mesh_terms: D015906:Angioplasty, Balloon, Coronary; D015415:Biomarkers; D002317:Cardiovascular Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D003131:Combined Modality Therapy; D017023:Coronary Angiography; D003331:Coronary Vessels; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007269:Injections, Intra-Arterial; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D015425:Myocardial Reperfusion; D010455:Peptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D002317:Cardiovascular Agents; C527142:KAI 9803; D010455:Peptides; D047428:Protein Kinase Inhibitors; D051745:Protein Kinase C-delta