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Review
. 2023 Apr 25;81(16):1633-1645.
doi: 10.1016/j.jacc.2023.02.033.

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

Waqas A Malick  1 , Sascha N Goonewardena  2 , Wolfgang Koenig  3 , Robert S Rosenson  4
Affiliations
Free article
Review

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

Waqas A Malick et al. J Am Coll Cardiol. .
Free article

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.

Keywords: Lp(a); Lp(a) clinical trials; olpasiran; pelacarsen.

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Conflict of interest statement

Funding Support and Author Disclosures Dr Malick is supported by a training grant from the New York Academy of Medicine. Dr Goonewardena has pending patents on analytical methods and systems for biocellular marker and detection using microfluidic profiling (PCT/US2019/026364) and compositions and methods relating to the identification and treatment of immunothrombotic conditions (PCT/US2020/63104926). Dr Koenig has received consulting fees from AstraZeneca, Novartis, Amgen, Pfizer, The Medicines Company, DalCor Pharmaceuticals, Kowa, Corvidia, Therapeutics, OMEICOS, Novo Nordisk, Esperion, LIB Therapeutics, New Amsterdam Pharma, TenSixteen Bio, Genentech, and Daiichi-Sankyo; has received lecture fees from AstraZeneca, Novartis, Amgen, Berlin-Chemie, Bristol Myers Squibb, and Sanofi; and has received grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics, and Dr Beckmann Pharma. Dr Rosenson has received research funding to his institution from Amgen, Arrowhead, Lilly, Novartis, and Regeneron; has received consulting fees from Amgen, Arrowhead, CRISPR Therapeutics, Lilly, Lipigon, Novartis, Precision Biosciences, and Verve; has received honoraria from nonpromotional educational activities from Amgen and Kowa; has received royalties from Wolters Kluwer; has stock holdings in MediMergent, LLC; and has pending patents on analytical methods and systems for biocellular marker and detection using microfluidic profiling (PCT/US2019/026364) and compositions and methods relating to the identification and treatment of immunothrombotic conditions (PCT/US2020/63104926), and quantification of Lp(a) vs non-Lp(a) apo B concentration novel validated equation (PCT/US2021/63248837).

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