Trial design challenges for Lp(a)-lowering therapies take center stage as pelacarsen and olpasiran enter phase 3 outcomes trials, a JACC Focus Seminar (J Am Coll Cardiol 2023)

Original title: Clinical Trial Design for Lipoprotein(a)-Lowering Therapies: JACC Focus Seminar 2/3

J Am Coll Cardiol · 25 April 2023 · 7

Malick WA, Goonewardena SN, Koenig W, Rosenson RS

This JACC Focus Seminar examines clinical trial design challenges for the new generation of Lp(a)-lowering therapies. PCSK9 monoclonal antibody trials have suggested that Lp(a) reduction may itself predict cardiovascular event reduction with that drug class. Selective Lp(a)-targeted therapies, antisense oligonucleotides, small interfering RNAs and gene editing, are now being tested directly: the phase 3 Lp(a)HORIZON outcomes trial is evaluating pelacarsen, an antisense oligonucleotide, and olpasiran, a small interfering RNA, is also in phase 3. The authors discuss the trial-design challenges these programs must address, particularly around patient selection and outcome measures, as Lp(a)-specific therapies move toward potential approval.

Original abstract

Lipoprotein(a) [Lp(a)] is a source of residual risk in patients with atherosclerotic cardiovascular disease (ASCVD). Clinical trials of fully human monoclonal antibodies targeting proprotein convertase subtilisin kexin 9 have shown that reductions in Lp(a) concentrations may be a predictor of event reduction with this class of cholesterol-lowering therapy. With the advent of selective therapies targeting Lp(a) such as antisense oligonucleotides, small-interfering RNA-based therapies, and gene editing, lowering of Lp(a) may lead to reduction in ASCVD. 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 testing the effect of pelacarsen, an antisense oligonucleotide, on ASCVD risk. Olpasiran is a small-interfering RNA that is in a phase 3 clinical trial. As these therapies enter clinical trials, challenges in trial design will have to be addressed to optimize patient selection and outcomes.

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