Clinical Pharmacology of Eplontersen, the First Approved GalNAc-Conjugated Antisense Oligonucleotide

Abstract

Eplontersen is a GalNAc-conjugated antisense oligonucleotide (ASO) approved for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN). GalNAc conjugation enables targeted hepatic delivery and improved potency compared with unconjugated ASOs. The clinical pharmacology of eplontersen was characterized by using in vitro studies and data from three Phase 1 studies in healthy participants and one pivotal Phase 3 study in patients with ATTRv-PN. Following subcutaneous administration, eplontersen was rapidly absorbed and exhibited a biphasic pharmacokinetic (PK) profile with a terminal half-life of approximately 3 weeks, supporting once-monthly dosing. Eplontersen is highly plasma protein‑bound, distributes predominantly within the plasma compartment before receptor‑mediated tissue uptake, and is eliminated mainly via nuclease‑mediated metabolism, with minimal renal excretion of intact drug. Across integrated population PK/PKPD and exposure–response analyses at 45 mg Q4W, eplontersen exhibits predictable PK, robust PD, exposure-independent efficacy within the achieved range, and no exposure-dependent safety signals. Albeit some covariates were identified as statistically significant for population PK and population PKPD models, they were not considered clinically meaningful when taking into account the overall variability in PK, their minimal impact on TTR reduction, and the therapeutic window for eplontersen. These findings support that 45 mg Q4W is appropriate for patients with ATTRv-PN without the need for dose modification. In vitro and model-based analyses indicate low potential for clinically relevant plasma protein binding displacement and CYP- or transporter-mediated drug–drug interactions, and demonstrate no clinically meaningful effects on the QT prolongation and a predominantly non-neutralizing anti-drug antibody profile without impact on efficacy or safety.