Abstract 237: CAT-2003 is a Novel Small Molecule That Activates Lipoprotein Lipase and Reduces Fasting and Postprandial Triglycerides

Abstract

Introduction: Triglycerides from chylomicron and VLDL particles are cleared in the periphery through Lipoprotein lipase (LPL). LPL is negatively regulated by Angiopoietin-like proteins 3 and 4 (Angptl3/4) and Apolipoprotein C3 (apoC3). CAT-2003 is an orally active small molecule that reduces fasting and postprandial triglycerides (TGs) in rat models of hypertriglyceridemia. We hypothesize that CAT-2003 activates LPL by reduction of Angptl3/4 and apoC3. Methods and Results: In vitro addition of CAT-2003 to THP-1 cells increased heparin releasable LPL activity rapidly (28% increase at 2 hr, p=0.01) and was sustained (52% increase at 20 hr, p=.0002). Angptl4 mRNA was decreased, while levels of LPL mRNA remained unchanged. In HepG2 cells CAT-2003 lowers apoC3 (94%, p<0.001) and Angptl3 (99%, p<0.001) mRNA. Secretion of newly made apoC3 protein was significantly inhibited (54%, p=0.004) within 1 hour of CAT-2003 treatment and was reduced by 84% (p<0.0001) after 4 hours. In vivo administration of a single oral dose of CAT-2003 (100 mg/kg) reduced plasma TGs excursion by 80% (p<0.014) at 2 hours and by 91% (p<0.031) at 4 hours following an oral oleate challenge in Sprague-Dawley (SD) rats (n=4 per arm). In a separate SD rat study CAT-2003 (30 mg/kg) was administered as a single oral dose and a time course (0.5 to 4 hrs, n=4 per time point) of PCSK9, apoC3 and Angtpl4 gene regulation in intestine and liver was studied. Expression of these genes was reduced as rapidly as 30 minutes and the reduction was sustained through 4 hours. In a 5-day study in Zucker fa/fa rats with TGs elevated above 900 mg/dL, qd oral dosing with CAT-2003 (10, 30, 100 and 300 mg/kg, n=8 per arm) resulted in dose-dependent reductions in fed and fasted plasma TGs with fasting reductions ranging from 41% (p<0.01) at 10 mg/kg to 67% (p<0.0001) at 300 mg/kg. Conclusion: CAT-2003 inhibits the negative regulators of LPL in vitro and in vivo. The time course of action is rapid and sustained in vitro with a translation to in vivo SD and fa/fa rats. CAT-2003 offers a potential new therapeutic for the treatment of severe hypertriglyceridemia and is being evaluated in Phase 2 clinical studies.