Antisense drug IONIS-APO(a)-LRX cuts Lp(a) by 90% in a phase 2 trial, a review of Lp(a) and atherosclerotic disease (Cardiovasc Drugs Ther 2019)

Original title: Lipoprotein(a) and Atherosclerotic Cardiovascular Disease: Current Understanding and Future Perspectives

Cardiovasc Drugs Ther · 1 December 2019 · 6

Wu MF, Xu KZ, Guo YG, Yu J, Wu Y, Lin LM

This review by Wu, Xu, Guo, Yu, Wu and Lin surveys current understanding of lipoprotein(a) [Lp(a)] in atherosclerotic cardiovascular disease (ASCVD), covering its structure, metabolism, atherogenic mechanisms, laboratory measurement and prognostic value. Elevated Lp(a) is a heritable, independent, and possibly causal risk factor for ASCVD through proatherogenic, proinflammatory and prothrombotic properties, and current guidelines recommend Lp(a) measurement in patients with intermediate-high ASCVD risk, familial hypercholesterolaemia, family history of early ASCVD or elevated Lp(a), or progressive ASCVD despite optimal therapy. Traditional Lp(a)-lowering approaches, niacin, PCSK9 inhibitors, mipomersen, lomitapide and lipoprotein apheresis, offer only limited, non-specific reduction with tolerability or cost drawbacks. A phase 2 randomised controlled trial of the antisense oligonucleotide IONIS-APO(a)-LRX showed it specifically reduced Lp(a) by 90% with good tolerability. The authors conclude Lp(a) measurement should be used to reclassify ASCVD risk, especially given the promise of IONIS-APO(a)-LRX for future treatment.

Original abstract

Purpose: To review current knowledge of elevated lipoprotein(a) [Lp(a)] levels in relation to atherosclerotic cardiovascular disease (ASCVD) and discuss their potential use as biomarkers and therapeutic approaches in clinical practice.

Methods: We summarized the current understanding and recent advances in the structure, metabolism, atherogenic mechanisms, standardized laboratory measurement, recommended screening populations, and prognostic value of Lp(a), with a special focus on the current potential treatment approaches for hyperlipoprotein(a)emia in patients with ASCVD.

Results: Lp(a) is composed of LDL-like particle and characteristic apolipoprotein(a) [apo(a)] connected by a disulfide bond. Substantial evidence shows that elevated plasma Lp(a) level is a heritable, independent, and possibly causal risk factor for ASCVD through its proatherogenic, proinflammatory, and potentially prothrombotic properties. Current guidelines recommend Lp(a) measurement for patients with an intermediate-high risk of ASCVD, familial hypercholesterolemia, a family history of early ASCVD or elevated Lp(a), and progressive ASCVD despite receiving optimal therapy. Traditional Lp(a)-lowering approaches such as niacin, PCSK9 inhibitors, mipomersen, lomitapide, and lipoprotein apheresis were associated with a non-specific and limited reduction of Lp(a), intolerable side effects, invasive procedure, and high expense. The phase 2 randomized controlled trial of antisense oligonucleotide against the apo(a) encoding gene LPA mRNA showed that IONIS-APO(a)-LRX could specifically reduce the level of Lp(a) by 90% with good tolerance, which may become a promising candidate for the prevention and treatment of ASCVD in the future.

Conclusions: It is reasonable to measure Lp(a) levels to reclassify ASCVD risk and manage individuals with elevated Lp(a) to further reduce the residual risk of ASCVD, especially with IONIS-APO(a)-LRX.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.