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

Abstract

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.

PCSK9 Targeting in the Management of Hypercholesterolaemia

“…Preliminary clinical data show that CVI-LM001 reduces the expression level of the PCSK9 gene by 90%, and exhibits good pharmacokinetics. 37 The addition of oral PCSK9 targeting agents to the lipid-lowering armamentarium may be particularly useful in patients who are not comfortable with injections, leading to improved treatment compliance, and eventually better cardiovascular prognosis.…”

Recent Update on the Development of PCSK9 Inhibitors for Hypercholesterolemia Treatment

“…CVI-LM001 ( 1) is a fluorobenzenesulfonate derivative of corydaline and operates by suppressing the expression of the PCSK9 gene (Figure 6). 88 A 300 mg dose of CVI-LM001 (1) for 28 days reduced LDL-C levels by 26.3%, TC by 20.1%, and ApoB by 17.4% in participants with elevated LDL-C levels in the phase Ib study (CTR20160744). 88 In order to assess the effectiveness and safety of CVI-LM001 (1) in people with hypercholesterolemia, CVI Pharmaceuticals is currently recruiting participants for a phase II clinical trial (NCT04438096).…”

“…88 A 300 mg dose of CVI-LM001 (1) for 28 days reduced LDL-C levels by 26.3%, TC by 20.1%, and ApoB by 17.4% in participants with elevated LDL-C levels in the phase Ib study (CTR20160744). 88 In order to assess the effectiveness and safety of CVI-LM001 (1) in people with hypercholesterolemia, CVI Pharmaceuticals is currently recruiting participants for a phase II clinical trial (NCT04438096). Following a strategic business decision, Pfizer discontinued the phase I clinical development of PF-06815345 ( 2) in 2016 (NCT02654899).…”