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[[Image:JPEG Vorapaxar.jpg|frame|right|Vorapaxar]] | |||
{{ | {{SI}} | ||
'''Editors-in-Chief:''' Sergio Leonardi, M.D., Duke Clinical Research Institute and [[C. Michael Gibson]], M.S., M.D. | |||
''''' | '''''Synonyms:''' '' TRA, thrombin receptor antagonist, SCH 530348 | ||
==Overview== | |||
Vorapaxar is structurally similar to the natural product himbacine, but completely lacks the muscarinic M2 antagonist activity characteristic of himbacine. | |||
This agent is an '''orally-active''', potent, reversible, and selective '''inhibitor''' of the '''PAR-1 receptor''' with a '''very long''' terminal '''half-life''', which ranges from 126 to 269 h. Although reversible, vorapaxar dissociates very slowly from the PAR-1 receptor, which is a critical requirement to compete effectively with the resident tethered ligand. | |||
Vorapaxar is a '''direct acting drug''' (thus not a pro-drug) and is '''inactivated''' mainly '''via the CYP3A4 enzymatic system'''. Vorapaxar has '''no significant renal metabolism'''. The drug is currently not commercially available. | |||
== | ==Phase II of Vorapaxar: the TRA-PCI and the Japanese study == | ||
The key phase II study with vorapaxar was the '''TRA-PCI''', a large phase II study that tested the safety, tolerability, and preliminary efficacy of this agent in '''1,030''' '''patients''' with '''stable''' coronary artery disease ('''CAD''') '''presumed to be managed with PCI'''. The study showed '''similar bleeding incidence''' as measured by the TIMI scale (major or minor) between placebo and the 3 doses tested of vorapaxar (0.5, 1, and 2.5 mg). Also, exploratory analysis on efficacy showed a numerical reduction in the rate of myocardial infarction, mainly related to PCI. | |||
A similarly designed study was conducted in Japan in patients with [[NSTEACS]] invasively managed. This additional phase II study in Japanese patients had similar results compared with TRA-PCI. Specifically, this study showed similar incidence of bleeding between placebo and vorapaxar and a reduction of MIs with vorapaxar. | |||
== | ==Phase III of Vorapaxar: TRA 2°P and TRA•CER== | ||
Vorapaxar is currently tested in a large phase III program including approximately 39,000 patients. The program include 2 distinct studies, named TRA 2°P and TRA•CER, which will test the effectiveness of this compound in patient with stable and unstable CAD respectively. | |||
== | ==External Links== | ||
* {{cite journal | author = Becker RC, Moliterno DJ, Jennings LK, Pieper KS, Pei J, Niederman A, Ziada KM, Berman G, Strony J, Joseph D, Mahaffey KW, Van de Werf F, Veltri E, Harrington RA; TRA-PCI Investigators | title = Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. | journal = Lancet | volume = 373 | issue = 9667 | pages = 919-28 | year = 2009 | id = PMID 19286091}} | |||
== | * {{cite journal | author = Goto S, Yamaguchi T, Ikeda Y, Kato K, Yamaguchi H, Jensen P. | title = Safety and exploratory efficacy of the novel thrombin receptor (PAR-1) antagonist SCH530348 for non-ST-segment elevation acute coronary syndrome. | journal = J Atheroscler Thromb | volume = 17 | issue = 2 | pages = 156-64 | year = 2010 | id = PMID 20124733}} | ||
{{ | * {{cite journal | author = Morrow DA, Scirica BM, Fox KA, Berman G, Strony J, Veltri E, Bonaca MP, Fish P, McCabe CH, Braunwald E; TRA 2(o)P-TIMI 50 Investigators | title = Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: design and rationale for the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI 50 trial. | journal = Am Heart J | volume = 158 | issue = 3 | pages = 335-341 | year = 2009 | id = PMID 19699854}} | ||
* {{cite journal | author = TRA*CER Executive and Steering Committees. | title = The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA*CER) trial: study design and rationale. | journal = Am Heart J | volume = 158 | issue = 3 | pages = 327-334 | year = 2009 | id = PMID 19699853}} | |||
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Editors-in-Chief: Sergio Leonardi, M.D., Duke Clinical Research Institute and C. Michael Gibson, M.S., M.D.
Synonyms: TRA, thrombin receptor antagonist, SCH 530348
Overview
Vorapaxar is structurally similar to the natural product himbacine, but completely lacks the muscarinic M2 antagonist activity characteristic of himbacine. This agent is an orally-active, potent, reversible, and selective inhibitor of the PAR-1 receptor with a very long terminal half-life, which ranges from 126 to 269 h. Although reversible, vorapaxar dissociates very slowly from the PAR-1 receptor, which is a critical requirement to compete effectively with the resident tethered ligand.
Vorapaxar is a direct acting drug (thus not a pro-drug) and is inactivated mainly via the CYP3A4 enzymatic system. Vorapaxar has no significant renal metabolism. The drug is currently not commercially available.
Phase II of Vorapaxar: the TRA-PCI and the Japanese study
The key phase II study with vorapaxar was the TRA-PCI, a large phase II study that tested the safety, tolerability, and preliminary efficacy of this agent in 1,030 patients with stable coronary artery disease (CAD) presumed to be managed with PCI. The study showed similar bleeding incidence as measured by the TIMI scale (major or minor) between placebo and the 3 doses tested of vorapaxar (0.5, 1, and 2.5 mg). Also, exploratory analysis on efficacy showed a numerical reduction in the rate of myocardial infarction, mainly related to PCI. A similarly designed study was conducted in Japan in patients with NSTEACS invasively managed. This additional phase II study in Japanese patients had similar results compared with TRA-PCI. Specifically, this study showed similar incidence of bleeding between placebo and vorapaxar and a reduction of MIs with vorapaxar.
Phase III of Vorapaxar: TRA 2°P and TRA•CER
Vorapaxar is currently tested in a large phase III program including approximately 39,000 patients. The program include 2 distinct studies, named TRA 2°P and TRA•CER, which will test the effectiveness of this compound in patient with stable and unstable CAD respectively.
External Links
- Becker RC, Moliterno DJ, Jennings LK, Pieper KS, Pei J, Niederman A, Ziada KM, Berman G, Strony J, Joseph D, Mahaffey KW, Van de Werf F, Veltri E, Harrington RA; TRA-PCI Investigators (2009). "Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study". Lancet. 373 (9667): 919–28. PMID 19286091.
- Goto S, Yamaguchi T, Ikeda Y, Kato K, Yamaguchi H, Jensen P. (2010). "Safety and exploratory efficacy of the novel thrombin receptor (PAR-1) antagonist SCH530348 for non-ST-segment elevation acute coronary syndrome". J Atheroscler Thromb. 17 (2): 156–64. PMID 20124733.
- Morrow DA, Scirica BM, Fox KA, Berman G, Strony J, Veltri E, Bonaca MP, Fish P, McCabe CH, Braunwald E; TRA 2(o)P-TIMI 50 Investigators (2009). "Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: design and rationale for the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI 50 trial". Am Heart J. 158 (3): 335–341. PMID 19699854.
- TRA*CER Executive and Steering Committees. (2009). "The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA*CER) trial: study design and rationale". Am Heart J. 158 (3): 327–334. PMID 19699853.