Abstract
Volanesorsen (previously known as ISIS 304801) is a 20-nucleotide partially 2′-O (2 methoxyethyl) (2′ MOE) modified antisense oligonucleotide (ASO) gapmer and was recently approved in the European Union as a novel, first in class treatment for 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 non-radiolabeled studies. This also included the characterization of all the observed ASO metabolite species excreted in urine. Volanesorsen is highly bound to plasma proteins, 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 a 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 exo-nuclease 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′-O (2 methoxyethyl) 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.
- The American Society for Pharmacology and Experimental Therapeutics