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

C. Michael Gibson, Cafer Zorkun, Peter Molhoek, Krzysztof Zmudka, Mark A. Greenberg, Hiltrud Mueller, Jan Wesdorp, Hans Louwerenburg, Alan Niederman, Jaap Westenburg, Mahesh Bikkina, John Batty, Jobst de Winter, Sabina A. Murphy, Carolyn H. McCabe, Eugene Braunwald, Tara Yoder, Jennifer Adgey, Erica Stein, David M. Morrow & 1 others Russell Tracy

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 μg·h/mL in the 1 mg/kg dose group to 788.6 μg·h/ mL in the 10 mg/kg dose group. Likewise, mean Cmax generally increased with dose over the entire dose range, from 4.9 μg/mL in the 1 mg/kg dose group to 139.6 μg/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). Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)13-21
Number of pages9
JournalJournal of Thrombosis and Thrombolysis
Volume22
Issue number1
DOIs
StatePublished - Aug 2006

Fingerprint

Fibrinolytic Agents
Pharmacokinetics
Safety
Cardiogenic Shock
Intracranial Hemorrhages
Anaphylaxis
Area Under Curve
Half-Life
BB-10153
Stroke
Enzyme Activators
Hemorrhage
Plasminogen Activators
Thrombin
Pharmaceutical Preparations
Myocardial Ischemia
Angiography
Thrombosis

Keywords

  • Fibrinolytic
  • ST elevation myocardial infarction
  • TIMI Flow Grade
  • TIMI frame count

ASJC Scopus subject areas

  • Hematology
  • Cardiology and Cardiovascular Medicine

Cite this

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. / Gibson, C. Michael; Zorkun, Cafer; Molhoek, Peter; Zmudka, Krzysztof; Greenberg, Mark A.; Mueller, Hiltrud; Wesdorp, Jan; Louwerenburg, Hans; Niederman, Alan; Westenburg, Jaap; Bikkina, Mahesh; Batty, John; de Winter, Jobst; Murphy, Sabina A.; McCabe, Carolyn H.; Braunwald, Eugene; Yoder, Tara; Adgey, Jennifer; Stein, Erica; Morrow, David M.; Tracy, Russell.

In: Journal of Thrombosis and Thrombolysis, Vol. 22, No. 1, 08.2006, p. 13-21.

Research output: Contribution to journalArticle

Gibson, CM, Zorkun, C, Molhoek, P, Zmudka, K, Greenberg, MA, Mueller, H, Wesdorp, J, Louwerenburg, H, Niederman, A, Westenburg, J, Bikkina, M, Batty, J, de Winter, J, Murphy, SA, McCabe, CH, Braunwald, E, Yoder, T, Adgey, J, Stein, E, Morrow, DM & Tracy, R 2006, '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', Journal of Thrombosis and Thrombolysis, vol. 22, no. 1, pp. 13-21. https://doi.org/10.1007/s11239-006-8080-1
Gibson, C. Michael ; Zorkun, Cafer ; Molhoek, Peter ; Zmudka, Krzysztof ; Greenberg, Mark A. ; Mueller, Hiltrud ; Wesdorp, Jan ; Louwerenburg, Hans ; Niederman, Alan ; Westenburg, Jaap ; Bikkina, Mahesh ; Batty, John ; de Winter, Jobst ; Murphy, Sabina A. ; McCabe, Carolyn H. ; Braunwald, Eugene ; Yoder, Tara ; Adgey, Jennifer ; Stein, Erica ; Morrow, David M. ; Tracy, Russell. / 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. In: Journal of Thrombosis and Thrombolysis. 2006 ; Vol. 22, No. 1. pp. 13-21.
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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 μg·h/mL in the 1 mg/kg dose group to 788.6 μg·h/ mL in the 10 mg/kg dose group. Likewise, mean Cmax generally increased with dose over the entire dose range, from 4.9 μg/mL in the 1 mg/kg dose group to 139.6 μg/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). Conclusion: 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.",
keywords = "Fibrinolytic, ST elevation myocardial infarction, TIMI Flow Grade, TIMI frame count",
author = "Gibson, {C. Michael} and Cafer Zorkun and Peter Molhoek and Krzysztof Zmudka and Greenberg, {Mark A.} and Hiltrud Mueller and Jan Wesdorp and Hans Louwerenburg and Alan Niederman and Jaap Westenburg and Mahesh Bikkina and John Batty and {de Winter}, Jobst and Murphy, {Sabina A.} and McCabe, {Carolyn H.} and Eugene Braunwald and Tara Yoder and Jennifer Adgey and Erica Stein and Morrow, {David M.} and Russell Tracy",
year = "2006",
month = "8",
doi = "10.1007/s11239-006-8080-1",
language = "English (US)",
volume = "22",
pages = "13--21",
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TY - JOUR

T1 - Dose escalation trial of the efficacy, safety, and pharmacokinetics of a novel fibrinolytic agent, BB-10153, in patients with ST elevation MI

T2 - Results of the TIMI 31 trial

AU - Gibson, C. Michael

AU - Zorkun, Cafer

AU - Molhoek, Peter

AU - Zmudka, Krzysztof

AU - Greenberg, Mark A.

AU - Mueller, Hiltrud

AU - Wesdorp, Jan

AU - Louwerenburg, Hans

AU - Niederman, Alan

AU - Westenburg, Jaap

AU - Bikkina, Mahesh

AU - Batty, John

AU - de Winter, Jobst

AU - Murphy, Sabina A.

AU - McCabe, Carolyn H.

AU - Braunwald, Eugene

AU - Yoder, Tara

AU - Adgey, Jennifer

AU - Stein, Erica

AU - Morrow, David M.

AU - Tracy, Russell

PY - 2006/8

Y1 - 2006/8

N2 - 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 μg·h/mL in the 1 mg/kg dose group to 788.6 μg·h/ mL in the 10 mg/kg dose group. Likewise, mean Cmax generally increased with dose over the entire dose range, from 4.9 μg/mL in the 1 mg/kg dose group to 139.6 μg/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). Conclusion: 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.

AB - 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 μg·h/mL in the 1 mg/kg dose group to 788.6 μg·h/ mL in the 10 mg/kg dose group. Likewise, mean Cmax generally increased with dose over the entire dose range, from 4.9 μg/mL in the 1 mg/kg dose group to 139.6 μg/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). Conclusion: 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.

KW - Fibrinolytic

KW - ST elevation myocardial infarction

KW - TIMI Flow Grade

KW - TIMI frame count

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