Emerging RNA Therapeutics to Lower Blood Levels of Lp(a): JACC Focus Seminar 2/4.

Lipoprotein(a) [Lp(a)] has risen to the level of an accepted cardiovascular disease risk factor, but final proof of causality awaits a randomized trial of Lp(a) lowering. Inhibiting apolipoprotein(a) production in the hepatocyte with ribonucleic acid therapeutics has emerged as an elegant and effective solution to reduce plasma Lp(a) levels. Phase 2 clinical trials have shown that the antisense oligonucleotide pelacarsen reduced mean Lp(a) levels by 80%, allowing 98% of subjects to reach on-treatment levels of <125 nmol/l (∼50 mg/dl). The phase 3 Lp(a)HORIZON (Assessing the Impact of Lipoprotein(a) Lowering With TQJ230 on Major Cardiovascular Events in Patients With CVD) outcomes trial is currently enrolling approximately 7,680 patients with history of myocardial infarction, ischemic stroke, and symptomatic peripheral arterial disease and controlled low-density lipoprotein cholesterol to pelacarsen versus placebo. The co-primary endpoints are major adverse cardiovascular events in subjects with Lp(a) >70 mg/dl and >90 mg/dl, in which either of the two being positive will lead to a successful trial. Additional ribonucleic acid-targeted therapies to lower Lp(a) are in preclinical and clinical development. The testing of the Lp(a) hypothesis will provide proof whether Lp(a)-mediated risk can be abolished by potent Lp(a) lowering.
Competing Interests: Funding Support and Author Disclosures Dr.Tsimikas has received research support from the Fondation Leducq and partial support from National Institutes of Health grants HL136275, HL106579, HL108735, HL136098, HL128550, and HL135737. Dr. Tsimikas is an employee of the University of California-San Diego and of Ionis Pharmaceuticals; is a co-inventor and receives royalties from patents owned by the University of California San Diego on diagnostic and therapeutic applications; and is a co-founder and has an equity interest in Oxitope and its affiliates (“Oxitope”) as well as in Kleanthi Diagnostics (“Kleanthi”) (although these relationships have been identified for conflict-of-interest management based on the overall scope of the project and its potential benefit to Oxitope and Kleanthi, the research findings included in this particular publication may not necessarily relate to the interests of Oxitope and Kleanthi; 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). Dr. Moriarty has served as an advisor, consultant, and received research support from Regeneron, Sanofi, Amgen, Esperion, Kaneka, Amarin, Stage II Innovations/Renew, Novartis, Ionis, Akcea, FH Foundation, GB Life Sciences, Aegerion, Gemphire, and Pfizer. Dr. Stroes has received fees paid to his institution from Amgen, Akcea, Athera, Sanofi-Regeneron, Esperion, Novo Nordisk, Lily, and Novartis.
(Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)