An investigational in vivo base editing medicine targeting ANGPTL3, VERVE-201, achieves potent and LDLR-independent liver editing in mouse models

Abstract Background VERVE-201 is an investigational medicine composed of a messenger RNA for an adenine base editor and a guide RNA that targets the ANGPTL3 gene packaged in a GalNAc lipid nanoparticle (LNP). Delivered via a one-time intravenous infusion, VERVE-201 is designed to inactivate ANGPTL3 in the liver and thereby lower low-density lipoprotein cholesterol (LDL-C) concentrations to treat atherosclerotic cardiovascular disease (ASCVD). VERVE-201 is initially being developed for the treatment of homozygous familial hypercholesterolemia—a rare genetic disorder in which severe or complete low-density lipoprotein receptor (LDLR)-deficiency leads to marked elevations in LDL-C and premature ASCVD. Purpose We first evaluated the potential of VERVE-201 to achieve on-target ANGPTL3 editing in human liver cells in vitro and humanized ANGPTL3 mice in vivo. Second, while standard LNPs are taken up into hepatocytes primarily by the LDLR, the GalNAc targeting ligand included in the VERVE-201 LNP is expected to enable LDLR-independent delivery via an alternate receptor (ASGPR). We test the hypothesis that VERVE-201mu (mouse surrogate of VERVE-201) can achieve comparable degree of Angptl3 editing in wild-type mice and those with partial (Ldlr+/-) or complete (Ldlr-/-) LDLR-deficiency. Methods VERVE-201 was first assessed in primary human hepatocytes at a range of doses in vitro. To assess whether VERVE-201 edits the human ANGPTL3 gene in vivo, a human ANGPTL3 mouse model was generated and VERVE-201 was evaluated at 7 dose levels ranging from 0.1 to 3.0 mg/kg (n=4 in each group). Next, one of four doses of VERVE-201mu ranging from 0.25 to 2.0 mg/kg or a vehicle control was administered to wild type, Ldlr+/−, and Ldlr−/− mice (n=5 in each genotype treatment group). In mouse experiments, tissue and blood samples were collected 7 days following dosing for evaluation. Results In primary human hepatocytes, VERVE-201 achieved potent and dose-responsive ANGPTL3 editing in cells from each of three donors. In human ANGPTL3 mice, VERVE-201 treatment resulted in dose-responsive liver ANGPTL3 editing. In mice treated with the highest dose of 3 mg/kg, mean liver editing of 64% and reduction in blood ANGPTL3 protein of 98% were observed. In wild type, Ldlr+/−, and Ldlr−/− mice, VERVE-201mu was similarly well-tolerated and achieved highly consistent potency across the doses studied (Figure). In mice treated with the highest dose of 2.0 mg/kg, mean liver Angptl3 editing of 60% and reductions in blood ANGPTL3 protein of 99% were observed, with no detectable differences across wild-type, Ldlr+/−, and Ldlr−/− mice. Conclusions These nonclinical data support the potential of VERVE-201 to enable precise and potent ‘once-and-done’ ANGPTL3 inactivation in the context of the severe or complete LDLR deficiency that occurs in homozygous familial hypercholesterolemia, a patient population that struggles to achieve adequate LDL-C reduction even on multiple lipid-lowering therapies.