Abstract 6: CAT-2003 is a Novel Small Molecule That Inhibits Proprotein Convertase Subtilisin/Kexin Type 9 Production and Lowers Non--High-Density Lipoprotein Cholesterol

Abstract

Introduction: CAT-2003 is an orally active small molecule that inhibits SREBP maturation (nSREBP-1 and nSREBP-2) and activation of SREBP-target genes, including PCSK9. CAT-2003 mechanism of action was studied in HepG2 cells and in the transgenic ApoE*3 Leiden mouse model of hyperlipoproteinemia.

Methods and Results: In vitro, CAT-2003 was studied in HepG2 cells and dose dependently reduced mature SREBP-2 protein levels (50% at 25 μM, n=3), PCSK9 mRNA (IC50 16.2 +/- 1.1 μM, n=3), and PCSK9 protein secretion (IC50 = 17.8 +/- 1.1 μM, n=3). CAT-2003 treatment also reduced expression of other SREBP target genes as well as SREBP processing genes including those encoding for HMG-CoA reductase, SCD-1, ACC2, S1P and S2P proteins. The reduction in PCSK9 protein correlated dose dependently with an increase in both low and high molecular weight LDLR protein. Statins increase nSREBP-2 and increase the production of PCSK9. CAT-2003 reversed atorvastatin-induced increases in nSREBP-2 and PCSK9 production in HepG2 cells.

In vivo CAT-2003 was studied in ApoE*3 Leiden mice (16 weeks, n=8 per arm). CAT-2003 reduced plasma PCSK9 (61%, p=0.001), total cholesterol (41%, p<0.0001) and TGs (33%, p=0.0034) compared to control and lowered aorta atherosclerotic lesions (p<0.01). An FPLC analysis showed the cholesterol reduction occurred primarily in non-HDL fractions. Liver histology showed reduced lipids and an increase in LDLR protein (104% increase, p=0.001). In a second ApoE*3 study (4 weeks, n=8 per arm) CAT-2003 was compared alone or in combination with atorvastatin. CAT-2003 reduced PCSK9 plasma levels alone (65%, p=0.001) and in combination with atorvastatin (58%, p=0.001) and produced a more than additive lowering of non-HDL-C (58%, p=0.001) compared to control. Expression of SREBP target genes in the liver were reduced in CAT-2003 and in atorvastatin combination treated mice.

Conclusions: CAT-2003 inhibits the maturation of SREBP-1 and -2 and inhibits the production of PCSK9. CAT-2003 lowers PCSK9, LDL-C and VLDL-C in ApoE*3 Leiden mice alone or in combination with atorvastatin. CAT-2003 is a potential new therapeutic to lower non-HDL-C and is in Phase 2 clinical studies.