A population pharmacokinetic and pharmacokinetic‐pharmacodynamic analysis of vupanorsen from phase I and phase II studies

Vupanorsen (PF‐07285557) is a second‐generation ligand‐conjugated 2′O‐methoxyethyl modified antisense oligonucleotide designed to target angiopoietin‐like 3 (ANGPTL3) mRNA expressed by the liver, shown to reduce lipids and apolipoproteins in subjects with dyslipidemia. Using pooled data from two phase I studies of participants with elevated triglycerides (Western: n = 48 and Japanese: n = 12), and two phase II studies of patients with hypertriglyceridemia, diabetes, and nonalcoholic fatty liver disease (n = 105), and statin‐treated patients with dyslipidemia (n = 286), we developed population pharmacokinetic (PK) and PK/pharmacodynamic (PK/PD) models. Efficacy target values were set a priori to −75%, −60%, and −35% for ANGPTL3, triglyceride (TG), and non‐high‐density lipoprotein‐cholesterol (non‐HDL‐C), respectively. Covariates evaluated via a full model approach included baseline body weight, age, estimated glomerular filtration rate (eGFR), anti‐drug antibody (ADA) status, sex, and race. Vupanorsen population PK was well‐characterized by a two‐compartment model with first‐order absorption and elimination. Apparent clearance (CL/F) for ADA‐positive, female, and Asian participants was estimated to be about 62% (relative standard error 12%), 18% (9%), and 30% (20%) lower than ADA‐negative, male, and non‐Asian participants, respectively. The associations between CL/F and Black race, age, and eGFR were negligible. The developed population PK/PD model was robust to predict the dose–response relationships. The model predicted that ANGPTL3 target reduction of 75% can be sufficiently achieved with a 320‐mg monthly dose of vupanorsen, but target values for TG and non‐HDL‐C were not expected to be achieved at doses up to 320 mg monthly in patients with dyslipidemia.