Abstract 1319: Platelet/Endothelial Activity in Subjects Treated with AGI-1067: For the Assessment of Lipoprotein Profiles Study (ALPS) Biomarker Substudy
Background: Oxidation sensitive signals play an important role triggering platelet/endothelial activation (PEA). AGI-1067 is a novel, phenolic antioxidant, which inhibits the expression of a number of pro-inflammatory genes, and PEA biomarkers in vitro. Whether treatment with AGI-1067 alters PEA in vivo is not known. Accordingly, we serially assessed release of established PEA biomarkers in subjects treated with AGI-1067 versus placebo in the Assessment of Lipoprotein Profiles Study (ALPS).
Methods: Healthy subjects (18 – 65 yr) were randomized 1:1 to receive 300 mg AGI-1067 (n=112) or matching placebo (n=117) daily for 12 weeks. Anticoagulants, aspirin, NSAIDS, and COX inhibitors were not permitted in this study. Plasma samples were collected at baseline, and at week 12 after randomization. Platelet factor 4 (PF4), β-thromboglobulin (βTG), P-selectin, thromboxane (TxB2), and prostacyclin (6-keto-PGF1a) were measured by ELISA.
Results: Treatment with AGI-1067 was associated with a highly significant reduction of TxB2 release (p<0.0001) when compared with the placebo arm (Table⇓). There were no differences in PF4, βTG, P-selectin, and prostacyclin between and within groups.
Conclusion: AGI-1067 selectively reduces ex vivo platelet TxB2 production in the frame of the Phase 2 (ALPS) randomized trial. These data support earlier in vitro, and pilot ex vivo experiments suggesting that AGI-1067 inhibits platelets. Lack of prostacyclin down regulation may represent an attractive advantage of AGI-1067 over currently available antiplatelet regimens. This hypothesis is currently being tested in the platelet substudy for the Phase 3 outcome trial (ARISE).