Abstract 12579: CVI-LM001, a First-in-class Novel Oral PCSK9 Modulator, Lowers Plasma Ldl-c and Reduces Circulating PCSK9 in Preclinical Animal Models and in Hyperlipidemic Human Subjects

Hypercholesterolemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD) and lowering low-density lipoprotein cholesterol (LDL-C) levels via upregulation of hepatic LDL receptor (LDLR) produces CVD benefits. More recently, monoclonal antibodies targeting PCSK9, a LDLR degradation protein, has emerged as a new therapeutic approach for lowering LDL-C levels, offering great efficacy and positive benefits in ASCVD patients. However, PCSK9 inhibitors require subcutaneous injections and the cost of therapy is high. CVI Pharmaceuticals has discovered a series of novel PCSK9 small molecule modulators that can reduce PCSK9 gene expression and increase LDLR abundance by PCSK9 dependent and independent mechanisms in hepatocytes. Among them, the lead compound CVI-LM001 is advanced to Phase 2 stage to treat hypercholesterolemic patients. Here we report that in hyperlipidemic hamsters, treatment with CVI-LM001 (40, 80 and 160 mg/kg, QD) for 4 weeks dose-dependently increased liver LDLR protein levels up to 3.5-fold and decreased circulating PCSK9 levels to 10% of control at the highest dose, this was accompanied by significant reductions in serum LDL-C. In a double-blind, randomized Phase 1a study conducted in healthy volunteers with normal lipid levels, compared to baseline, we observed a 36.4% (p<0.001) reduction in serum PCSK9 levels after 10 days of oral treatment with CVI-LM001 (300 mg, QD). Moreover, in a Proof of Mechanism Phase 1b study conducted in subjects with elevated LDL-C, compared with placebo cohort, treatment with CVI-LM001 (300 mg, QD) for 28 days significantly reduced serum LDL-C (-26.3% p<0.01), TC (-20.1%, p<0.01), Apo B (-17.4%, p=0.01) and PCSK9 (-39.2%, p<0.05). CVI-LM001 had a benign safety profile and was well tolerated in 105 treated healthy volunteers and 33 treated hyperlipidemic subjects. In addition, CVI-LM001 exhibited excellent pharmacokinetics properties with peak concentrations occurred approximately 1-1.5h post-dose. Mean half-lives ranged from 32 to 45h after single dosing and 62 to 68h following multiple dosing. These studies, for the first time, demonstrate that CVI-LM001, a novel PCSK9 modulator, has the potential to be a new oral cholesterol-lowering drug and warrant further development.