Clinical Pharmacology of Olezarsen, a Novel ApoC-III Targeted Antisense Inhibitor, for Reducing Triglycerides in Patients with Familial Chylomicronemia Syndrome

• Published in: Journal of clinical lipidology Vol. 19; no. 3; pp. e108 - e109
• Main Authors: Yu, Rosie, Diep, John, Karwatowska-Prokopczuk, Ewa, Gao, Xiang
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.05.2025
• ISSN: 1933-2874
• DOI: 10.1016/j.jacl.2025.04.156

Olezarsen is a newly approved APOC-III-directed antisense oligonucleotide (ASO) GalNAc3 conjugate indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). We aimed to characterize the clinical pharmacology of olezarsen. Data were obtained from Phase 1, 2, and 3 studies (NCT02900027, NCT05337878, NCT03385239, NCT05579860, NCT05355402, NCT05130450) and in vitro using human materials. The absorption, distribution, elimination, metabolism, and excretion properties and QT prolongation potential of olezarsen were evaluated in healthy subjects and patients. Drug–drug interaction potential was assessed in vitro. Population pharmacokinetic/pharmacodynamic (PK/PD) models were developed, the impact of intrinsic/extrinsic factors were assessed. Exposure-response (E-R) relationships and immunogenicity were analyzed for PD, efficacy, and safety endpoints. Following subcutaneous administration, olezarsen was rapidly absorbed with Cmax at 2 hours post-dose and terminal elimination half-life of approximately 4 weeks. The primary elimination route of olezarsen is initial rapid hydrolysis of GalNAc conjugate following receptor-mediated uptake into tissues, then slow metabolism via endo- and exonucleases, with fragmented oligonucleotide metabolites subsequently excreted in urine. Urinary excretion of olezarsen within the first 24 hours was < 1% of administered dose. No clinically relevant changes in ECG parameters, including QT intervals, have been observed. There was a flat relationship between olezarsen plasma concentration and placebo-adjusted, change-from-Baseline QT interval corrected by Fredericia formula (ΔΔQTcF) across a wide dose range (including a supratherapeutic 120-mg dose). In vitro studies showed that olezarsen is not an inducer nor inhibitor of CYP-mediated metabolism, nor an inhibitor or substrate for major drug transporters. No drug-drug interaction was observed with regard to plasma protein-binding displacement. Intrinsic/extrinsic factors had no clinically meaningful effect on olezarsen exposure and PD response at 80 mg Q4W dose. Although higher exposures trended towards greater reductions in apoC-III and TG, no clinically meaningful differences in safety endpoints were observed across exposure tertiles (50 and 80 mg Q4W doses), in favor of 80 mg dose. Anti-olezarsen antibodies (ADA) had no impact on the peak plasma exposures but increased Ctrough. There was no clinically meaningful impact of ADA positivity on PD, efficacy, or safety, indicating ADA had no neutralizing activity and did not affect pharmacological response or compromise clinical benefit. The overall clinical pharmacology properties of olezarsen are favorable and support the recommended dosing regimen of 80 mg olezarsen subcutaneous injection once monthly as safe and effective treatment in adults with FCS. No dose adjustment is required for intrinsic/extrinsic factors.