Vorapaxar
Vorapaxar (previously known as SCH 530348) is an himbacine derivative but completely lacks the muscarinic M2 antagonist activity characteristic of himbacine.
This agent is a 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.
The key phase II study with vorapaxar was the TRA-PCI, a large phase II study that tested the safety and preliminary efficacy of this agent in 1,030 patients with stable CAD presumed to be managed with PCI. In this study bleeding as measured by the TIMI scale (major or minor) was similar between placebo and the 3 doses tested of vorapaxar (0.5, 1, and 2.5 mg). Exploratory analysis on efficacy also showed a numerical reduction in the myocardial infarction component, mainly related to PCI. A similarly designed study was conducted in Japan in patients with NSTE-ACS invasively managed. This additional phase II study in Japanese patients had similar results compared with TRA-PCI. Specifically, this study showed a similar incidence of bleeding between placebo and vorapaxar and a reduction of MIs with vorapaxar.