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

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. (J Am Coll Cardiol 2023;81:1633-1645) (c) 2023 by the American College of Cardiology Foundation.

Automated summary

Lp(a) is a residual risk factor in patients with atherosclerotic cardiovascular disease (ASCVD). Clinical trials using monoclonal antibodies targeting proprotein convertase subtilisin kexin 9 have shown that lowering Lp(a) concentrations can reduce cardiovascular events. Novel therapies such as antisense oligonucleotides, small-interfering RNA, and gene editing are being tested to lower Lp(a) and potentially reduce ASCVD. Challenges in trial design need to be addressed for optimal patient selection and outcomes as these therapies enter clinical trials.