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.