Highlights
- •Pelacarsen was studied in subjects of Japanese ancestry.
- •Single (20, 40, 80 mg) and multiple doses of pelacarsen 80 mg were used.
- •Maximal, placebo-corrected Lp(a) reduction was -106% with 80 mg monthly dose.
- •No serious adverse events were noted.
- •No clinically relevant abnormalities in any laboratory parameters were noted.
Abstract
Background
Pelacarsen is a liver-targeted antisense oligonucleotide that potently lowers lipoprotein(a)
[Lp(a)] levels. Its safety and efficacy in diverse populations has not been extensively
studied.
Objective
To assess the effect of pelacarsen, including monthly dosing of 80 mg, in subjects
of Japanese ancestry.
Methods
A randomized double-blind, placebo-controlled, study was performed in 29 healthy Japanese
subjects treated with single ascending doses (SAD) of pelacarsen 20, 40 and 80 mg
subcutaneously or multiple doses (MD) of pelacarsen 80 mg monthly for 4 doses. The
primary objective was to assess the safety and tolerability in healthy Japanese subjects;
secondary objectives to assess the pharmacokinetics of pelacarsen; and exploratory
objective to determine the effect of pelacarsen on plasma Lp(a) levels.
Results
No serious adverse events or clinically relevant abnormalities in any laboratory parameters
were noted. In the MD cohort, mean plasma concentrations of pelacarsen peaked at ∼4
hours and declined in a bi-exponential manner thereafter. In the SAD cohorts, the
placebo-corrected least-square mean (PCLSM) percent changes in Lp(a) at Day 30 were:
-55.4% (p=0.0008), -58.9% (p=0.0003) and -73.7% (p<0.0001) for the 20 mg, 40 mg, and
80 mg pelacarsen-treated groups, respectively. In the MD cohort, the PCLSM at Days
29, 85, 113, 176 and 204 were -84.0% (p=0.0003), -106.2% (p<0.0001), -70.0 (p<0.0001),
-80.0% (p=0.0104) and -55.8% (p=0.0707), respectively.
Conclusions
Pelacarsen demonstrates an acceptable safety and tolerability profile and potently
lowers plasma levels of Lp(a) in healthy Japanese subjects, including with the 80
mg monthly dose being evaluated in the Lp(a) HORIZON trial.
Keywords
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Article info
Publication history
Published online: December 07, 2022
Accepted:
December 1,
2022
Received:
September 10,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Author contributions: First manuscript draft (E K-P, ST), editing for critical content (EP-K, AL, ST), gathering of data (EP-K, AL), obtaining pharmacokinetic data (J-HY, EH, AH, and AM), and statistical analysis (SX).
Conflict of interest: EK-P and SX are employees of Ionis Pharmaceuticals, EH is former employee of Akcea Therapeutics. AL, J-HY, AH, and AM are employees of Novartis Pharma. ST is an employee of Ionis Pharmaceuticals and of the University of California San Diego and has received research support from the Fondation Leducq and NHLBI (R01HL159156). ST is a co-inventor and receives royalties from patents owned by UCSD on oxidation-specific antibodies and of biomarkers related to oxidized lipoproteins and are co-founder and have an equity interest in Oxitope, Inc and its affiliate, Kleanthi Diagnostics, LLC and Covicept Therapeutics. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies.
Financial Support: This study was funded by Akcea Therapeutics.
Identification
Copyright
© 2022 National Lipid Association. Published by Elsevier Inc. All rights reserved.
