Vorapaxar



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.