title: Dose escalation trial of the efficacy, safety, and pharmacokinetics of a novel fibrinolytic agent, BB-10153, in patients with ST elevation MI: results of the TIMI 31 trial.
abstract: BACKGROUND
  Currently available fibrinolytic agents are limited by their ability to restore normal blood flow in only half of patients, the risk of reocclusion, and the risk of intracranial hemorrhage. The genetically engineered agent BB-10153 is activated by thrombin, not plasminogen activator enzymes, which limits its activity to the site of thrombus which may in turn reduce the risk of systemic bleeding. BB-10153 also has a relatively long half-life of 3-4 hours, which may also limit the potential for early reocclusion [1, 2].
  
  
  METHODS
  The study was a phase II, open-label, multi-center, dose escalation, single-dose administration study to determine the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of BB-10153 in ST segment elevation MI (STEMI). STEMI patients (n = 50) received a single dose of BB-10153 at one of six dose levels (1.0, 2.0, 3.0, 5.0, 7.5 and 10 mg/kg). The primary endpoint was TIMI flow grade (TFG) 3 at 60 minutes following the intravenous bolus of BB-10153.
  
  
  RESULTS
  Mean area under the curve for drug concentration ranged from 48.0 microg.h/mL in the 1 mg/kg dose group to 788.6 microg.h/mL in the 10 mg/kg dose group. Likewise, mean Cmax generally increased with dose over the entire dose range, from 4.9 microg/mL in the 1 mg/kg dose group to 139.6 microg/mL in the 10 mg/kg dose group. The mean apparent terminal half-life (t1/2) was 4.4 hours (range 2.2 to 7.6 hours). Few patients in the 1-3 mg/kg dosage groups achieved TFG 3 on the one-hour post-dose angiogram (4/20, 20%), and no patients achieved complete ST segment resolution. The 5, 7.5 and 10 mg/kg doses were associated with similar rates of TIMI grade 3 flow of approximately three per seven patients. Pooling TFG 3 data from the 5, 7.5 and 10 mg/kg groups yielded a TIMI grade 3 flow rate of 34% (n = 10/29; range 29-43%). No patients experienced 30-day death, recurrent acute MI, cardiogenic shock, stroke or anaphylaxis during the study. One patient experienced recurrent angina and developed recurrent myocardial ischemia requiring urgent revascularization. Three patients sustained TIMI major bleeding events (one in 1 mg/kg group, two in 7.5 mg/kg group), six patients sustained TIMI minor bleeds (one in the 2, 3, 7.5 and 10 mg/kg groups, two in the 5 mg/kg group), twp patients sustained TIMI minimal bleeds (one in each of the 2 and 10 mg/kg groups) and no patients sustained intracranial hemorrhage (ICH).
  
  
  CONCLUSIONS
  In a dose escalation study of a single intravenous bolus, the novel fibrinolytic agent, BB-10153 was associated with a rise in the mean area under the curve and Cmax for drug concentration over the dose range 1 to 10 mg/kg. Higher doses were associated with a range of TIMI grade 3 flow of 29-43%, and no patients experienced 30-day death, recurrent acute MI, cardiogenic shock, stroke or anaphylaxis during the study. In a dose escalation study of a single intravenous bolus, the novel fibrinolytic agent, BB-10153 was associated with a rise in the mean area under the curve and Cmax for drug concentration over the dose range 1 to 10 mg/kg. Higher doses were associated with a range of TIMI grade 3 flow of 29-43%, and no patients experienced 30-day death, recurrent acute MI, cardiogenic shock, stroke or anaphylaxis during the study.
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham & Women's Hospital and the Department of Medicine, Harvard Medical School, 350 Longwood Avenue, First Floor, Boston, MA, 02115, USA. mgibson@timi.org
authors.forename: C Michael
authors.initials: CM
authors.lastname: Gibson
authors.forename: Cafer
authors.initials: C
authors.lastname: Zorkun
authors.forename: Peter
authors.initials: P
authors.lastname: Molhoek
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Zmudka
authors.forename: Mark
authors.initials: M
authors.lastname: Greenberg
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Mueller
authors.forename: Jan
authors.initials: J
authors.lastname: Wesdorp
authors.forename: Hans
authors.initials: H
authors.lastname: Louwerenburg
authors.forename: Alan
authors.initials: A
authors.lastname: Niederman
authors.forename: Jaap
authors.initials: J
authors.lastname: Westenburg
authors.forename: Mahesh
authors.initials: M
authors.lastname: Bikkina
authors.forename: John
authors.initials: J
authors.lastname: Batty
authors.forename: Jobst
authors.initials: J
authors.lastname: de Winter
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.forename: Carolyn H
authors.initials: CH
authors.lastname: McCabe
mesh_terms: D019540:Area Under Curve; D017023:Coronary Angiography; D004305:Dose-Response Relationship, Drug; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism; D015425:Myocardial Reperfusion / Q000379:methods*; D010958:Plasminogen / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012039:Regional Blood Flow; D015912:Thrombolytic Therapy / Q000379:methods; D016896:Treatment Outcome
chemical_list: C501338:BB-10153; D005343:Fibrinolytic Agents; D010958:Plasminogen