Delving into the Latest Updates on Troplasminogen alfa with Synapse

Overview

Basic Info

Drug Type

Enzyme

Synonyms

Tapgen

+ [4]

Target

PLG

Mechanism

PLG stimulants(Plasminogen stimulants)

Therapeutic Areas

Nervous System DiseasesCardiovascular Diseases

Active Indication-

Inactive Indication

Acute Ischemic StrokeStrokeThrombosis

Originator Organization

Ligand UK Ltd.

Active Organization-

Inactive Organization

Vernalis (R&D) Ltd.

BTG International Ltd.

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Gene Sequence

Sequence Code 546437760

Source: *****

BACKGROUNDCurrently 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].METHODSThe 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.RESULTSMean 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).CONCLUSIONIn 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.

01 Sep 2005·Current opinion in investigational drugs (London, England : 2000)

V-10153 (Vernalis).

Article

Author: Kamali, Farhad

Vernalis is developing V-10153, a recombinant plasminogen activator stimulator, for the potential treatment of thrombotic disorders and cardiovascular disease. By March 2004, a phase II trial in acute myocardial infarction had been completed, and by July 2005, Vernalis intended to initiate a phase II trial in stroke later that same year.

01 Jun 2005·Journal of Thrombosis and HaemostasisQ2 · MEDICINE

Pharmacokinetics and pharmacodynamics of BB‐10153 , a thrombin‐activatable plasminogen, in healthy volunteers

Q2 · MEDICINE

Article

Author: P.L. Meroni ; M. Cugno ; L. Gregorini ; J. Nussberger ; F. Donatelli ; P. Agostoni ; G.B. Anguissola ; D. Mari ; M. Bussotti

BACKGROUNDBB-10153 is an engineered variant of human plasminogen that is activated to plasmin by thrombin. Thrombus-selective induction of reperfusion and prevention of reocclusion have been demonstrated following bolus administration in animal models of thrombosis.OBJECTIVE AND METHODSThe objective of the study was to examine the pharmacokinetics and pharmacodynamics of BB-10153 administered as an intravenous bolus to healthy male human volunteers. Cohorts of four were dosed with BB-10153 (n = 3) or placebo (n = 1). In total, placebo was received by eight volunteers and 0.08, 0.2, 0.6, 1.2, 1.8, 2.4, 3.6 and 4.8 mg kg(-1) BB-10153 by three volunteers each.RESULTSThere was a linear relationship between AUC/Cmax and dose. The half-life of BB-10153 was approximately 3-4 h and all the BB-10153 in the circulation retained the ability to be activated by thrombin. There was a dose-related increase in plasma fibrin D-dimers. Ex vivo plasma clot lysis was observed at doses of 3.6 and 4.8 mg kg(-1), whereas lysis of clots formed from euglobulin-fractionated plasma was first evident at 0.6 mg kg(-1) and activity increased with dose. This activity decreased with time in line with the half-life. BB-10153 had no effect on plasma alpha2-antiplasmin or fibrinogen levels, coagulation assays or bleeding time. An increase in plasminogen was observed as BB-10153 was detected by the enzyme-linked immunosorbent assay (ELISA) for human plasminogen.CONCLUSIONSBB-10153 was well tolerated and had a 3-4-h plasma half-life. Fibrinolytic activity was demonstrated by dose-related ex vivo clot lysis and in vivo production of fibrin D-dimers. These effects were not accompanied by consumption of alpha2-antiplasmin or fibrinogen.

100 Deals associated with Troplasminogen alfa

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Stroke	Phase 2	DK	Vernalis (R&D) Ltd.	28 Mar 2008
Stroke	Phase 2	HU	Vernalis (R&D) Ltd.	28 Mar 2008
Stroke	Phase 2	CZ	Vernalis (R&D) Ltd.	28 Mar 2008
Acute Ischemic Stroke	Phase 2	CA	Vernalis (R&D) Ltd.	01 Aug 2005
Acute Ischemic Stroke	Phase 2	US	Vernalis (R&D) Ltd.	01 Aug 2005
Thrombosis	Phase 2	GB	BTG International Ltd.	01 Jan 2005