Volanesorsen (previously known as ISIS 304801) is a 20-nucleotide partially 
2'-O-(2-methoxyethyl) (2'-MOE)-modified antisense oligonucleotide (ASO) gapmer, 
which was recently approved in the European Union as a novel, first-in-class 
treatment in the reduction of triglyceride levels in patients with familial 
chylomicronemia syndrome. We characterized the absorption, distribution, 
metabolism, and excretion characteristics of volanesorsen in mice, rats, 
monkeys, and humans, in either radiolabeled or nonradiolabeled studies. This 
also included the characterization of all of the observed ASO metabolite species 
excreted in urine. Volanesorsen is highly bound to plasma proteins that are 
similar in mice, monkeys, and humans. In all species, plasma concentrations 
declined in a multiphasic fashion, characterized by a relatively fast initial 
distribution phase and then a much slower terminal elimination phase following 
subcutaneous bolus administration. The plasma metabolite profiles of 
volanesorsen are similar across species, with volanesorsen as the major 
component. Various shortened oligonucleotide metabolites (5-19 nucleotides long) 
were identified in tissues in the multiple-dose mouse and monkey studies, but 
fewer in the [3H]-volanesorsen rat study, likely due to a lower accumulation of 
metabolites following a single dose in rats. In urine, all metabolites 
identified in tissues were observed, consistent with both endo- and 
exonuclease-mediated metabolism and urinary excretion being the major 
elimination pathway for volanesorsen and its metabolites. SIGNIFICANCE 
STATEMENT: We characterized the absorption, distribution, metabolism, and 
excretion (ADME) of volanesorsen, a partially 2'-MOE-modified antisense 
oligonucleotide, from mouse to man utilizing novel extraction and quantitation 
techniques in samples collected from preclinical toxicology studies, a 3H rat 
ADME study, and a phase 1 clinical trial.