Atopaxar
Overview
Atopaxar (previously known as E5555) is a potent and orally-active PAR-1 inhibitor that was developed by Eisai. Compared with vorapaxar, atopaxar is a synthetic agent with a shorter elimination half-life and a primary gastrointestinal metabolism. This small molecule inhibits the binding of thrombin either at or very close to the tethered ligand-binding site and available evidence indicates that atopaxar may have potential anti-inflammatory properties.
Phase II of Atopaxar: the LANCELOT studies
The phase II of atopaxar included 4 clinical trials conducted in patients with atherothrombosis, 2 studies in Japanese subjects and 2 in subjects of non-Japanese ethnicity.
The J-LANCELOT studies were conducted in Japanese patients with NSTEACS (n = 241) and high-risk CAD (n = 263) respectively. All patients were treated with aspirin. Patients were assigned to 1 of 4 groups: atopaxar 50, 100, or 200 mg or matching placebo for a 12- (ACS patients) or 24-weeks (CAD patients) duration. The primary end-point was the occurrence of bleeding classified against the CURE scale and the TIMI scale. The incidence of major bleeding with either scales was very low and similar between atopaxar and placebo while the occurrence of any TIMI bleeding was numerically higher with the highest atopaxar doses. The incidence of major adverse cardiovascular events (MACEs) was low overall and no cardiovascular death was reported. Overall, 13 MACEs were observed in the ACS study and 5 in the CAD study with a numerical reduction in atopaxar treated patients observed in both studies. The platelet substudy showed that, after stimulation with 15 µM of TRA peptide, platelet aggregation inhibition reached > 90% with 100 mg and 200 mg of atopaxar while the inhibition provided by the 50 mg dose was 50-60% in CAD patients and only 20-50% in ACS patients. A dose-dependent increase in liver function abnormalities was observed in both studies in atopaxar treated patients (especially in patients on dual antiplatelet therapy), and also, a prolongation of the QTc interval.
Recently, it was presented the LANCELOT ACS trial, where atopaxar was tested in 603 patients with NSTEACS of non-Japanese ethnicity as a 400-mg loading dose followed by a daily dose of 50 mg, 100 mg, or 200 mg for 12 weeks or matching placebo in addition to aspirin and, in > 75% of patients, dual antiplatelet therapy with aspirin and a thienopyridine. The study showed a similar incidence of bleeding between the 3 doses of atopaxar and placebo and a favorable trends for efficacy indicated by a reduction in Holter-detected ischemia. The study however, like the Japanese studies, showed a dose-dependent increase in liver-function enzymes and a prolongation of the QTc interval at the highest doses.
External Links
- Serebruany VL, Kogushi M, Dastros-Pitei D, Flather M, Bhatt DL. (2009). "The in-vitro effects of E5555, a protease-activated receptor (PAR)-1 antagonist, on platelet biomarkers in healthy volunteers and patients with coronary artery disease". Thromb Haemost. 102 (1): 111–119. PMID 19572075.
- Goto S, Ogawa H, Takeuchi M, Flather MD, Bhatt DL; on behalf of the J-LANCELOT (Japanese-Lesson from Antagonizing the Cellular Effect of Thrombin) Investigators. (2010). "Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease". Eur Heart J. PMID 20805115. [Epub ahead of print]