Potential Novel RNA-Targeting Agents for Effective Lipoprotein(a) Lowering: A Systematic Assessment of the Evidence From Completed and Ongoing Developmental Clinical Trials

Supplemental Digital Content is Available in the Text. Abstract An increase in blood lipoprotein (a) [Lp(a)] levels, mostly genetically determined, has been identified as an independent risk factor of atherosclerotic cardiovascular disease. No drug has yet been approved that markedly lowers Lp(a) and thereby reduces residual cardiovascular risk. The aim of this article was to critically review the evidence from clinical development studies to date on the efficacy and safety of new RNA-based therapeutics for targeted lowering of Lp(a). PubMed/MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov were searched without any language or date restriction up to November 5, 2022, and a total of 12 publications and 22 trial records were included. Several drugs were found that are currently in various stages of clinical development, such as the antisense oligonucleotide pelacarsen and the small interfering RNA molecule olpasiran and drugs coded as SLN360 and LY3819469. Among them, pelacarsen has progressed the most, currently reaching phase 3. All these drugs have so far shown satisfactory pharmacokinetic properties, consistently high and stable, dose-dependent efficacy in lowering Lp(a) even by more than 90%, with an acceptable safety profile in subjects with highly elevated Lp(a). In addition, reports of early clinical trials with pelacarsen imply a promising suppressive effect on key mechanisms of atherogenesis. Future research should focus on confirming these beneficial clinical effects in patients with lower average Lp(a) levels and clearly demonstrating the association between lowering Lp(a) and reducing adverse cardiovascular outcomes.

[1]  N. Nurmohamed,et al.  Lp(a): a New Pathway to Target? , 2022, Current Atherosclerosis Reports.

[2]  F. Kronenberg,et al.  Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement , 2022, European heart journal.

[3]  M. Sabatine,et al.  Lipoprotein(a) does not have a clinically significant arterial or venous prothrombotic effect , 2022, Atherosclerosis.

[4]  A. Curcio,et al.  Antisense Oligonucleotides and Small Interfering RNA for the Treatment of Dyslipidemias , 2022, Journal of clinical medicine.

[5]  E. Stroes,et al.  Considerations for routinely testing for high Lp(a) , 2022, Current opinion in lipidology.

[6]  S. Virani,et al.  Highlights of Cardiovascular Disease Prevention Studies Presented at the 2022 American College of Cardiology Scientific Sessions , 2022, Current Atherosclerosis Reports.

[7]  R. Hegele,et al.  Lipid-Modifying Therapies and Stroke Prevention , 2022, Current Neurology and Neuroscience Reports.

[8]  M. Boffa,et al.  Oxidized phospholipid modification of lipoprotein(a): Epidemiology, biochemistry and pathophysiology. , 2022, Atherosclerosis.

[9]  A. Scrimgeour,et al.  Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels. , 2022, JAMA.

[10]  Nada Bejar,et al.  RNA Therapeutics: the Next Generation of Drugs for Cardiovascular Diseases , 2022, Current Atherosclerosis Reports.

[11]  J. Witztum,et al.  THE EFFECT OF LONG-TERM USE OF ASPIRIN ON THE OUTCOMES OF COVID-19 INFECTION IN PATIENTS WITH A HISTORY OF CORONARY ARTERY DISEASE AND CHRONIC KIDNEY DISEASE , 2022, Journal of the American College of Cardiology.

[12]  Saptarsi M. Haldar,et al.  Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a) , 2022, Nature Medicine.

[13]  E. Stroes,et al.  Emerging RNA Therapeutics to Lower Blood Levels of Lp(a): JACC Focus Seminar 2/4. , 2021, Journal of the American College of Cardiology.

[14]  J. Witztum,et al.  Prevalence and influence of LPA gene variants and isoform size on the Lp(a)-lowering effect of pelacarsen. , 2021, Atherosclerosis.

[15]  B. Okopień,et al.  Pleiotropic Effects of PCSK-9 Inhibitors , 2021, International journal of molecular sciences.

[16]  P. Natarajan,et al.  Apolipoprotein B is an insufficient explanation for the risk of coronary disease associated with lipoprotein(a). , 2021, Cardiovascular research.

[17]  ESC / EAS Guidelines for the Treatment of Dyslipidemias: Lipid Modification to Reduce Cardiovascular Risk , 2020, Digital Doctor.

[18]  R. Langer,et al.  Advances in oligonucleotide drug delivery , 2020, Nature Reviews Drug Discovery.

[19]  N. Wong,et al.  The Evolving Understanding and Approach to Residual Cardiovascular Risk Management , 2020, Frontiers in Cardiovascular Medicine.

[20]  D. Boulay,et al.  Lipoprotein(a) Cellular Uptake Ex Vivo and Hepatic Capture In Vivo Is Insensitive to PCSK9 Inhibition With Alirocumab , 2020, JACC. Basic to translational science.

[21]  E. Stroes,et al.  Gene-based therapy in lipid management: the winding road from promise to practice , 2020, Expert opinion on investigational drugs.

[22]  E. Stroes,et al.  Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a) , 2020, European heart journal.

[23]  Lawrence A Leiter,et al.  Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. , 2020, The New England journal of medicine.

[24]  J. Purnell,et al.  Unusual responses to PCSK9 inhibitors in a clinical cohort utilizing a structured follow-up protocol , 2020, American journal of preventive cardiology.

[25]  J. Tardif,et al.  Lipoprotein(a) Reduction in Persons with Cardiovascular Disease. , 2020, The New England journal of medicine.

[26]  G. Hindricks,et al.  2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. , 2019, Atherosclerosis.

[27]  M. Boffa,et al.  Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis[S] , 2019, Journal of Lipid Research.

[28]  Odyssey Outcomes Investigators Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome , 2018 .

[29]  F. Kronenberg,et al.  Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials , 2018, The Lancet.

[30]  Suzanne G. Orchard,et al.  Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly , 2018, The New England journal of medicine.

[31]  P. Rothwell,et al.  Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial , 2018, The Lancet.

[32]  A. Keech,et al.  Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk: Insights From the FOURIER Trial , 2019, Circulation.

[33]  B. Nordestgaard,et al.  Antiplatelet therapy: Pharmacogenomic approach to tailor drug therapy , 2018, Nature Reviews Cardiology.

[34]  J. Witztum,et al.  Relationship between "LDL-C", estimated true LDL-C, apolipoprotein B-100, and PCSK9 levels following lipoprotein(a) lowering with an antisense oligonucleotide. , 2018, Journal of clinical lipidology.

[35]  B. Nordestgaard,et al.  High Lipoprotein(a) and Low Risk of Major Bleeding in Brain and Airways in the General Population: a Mendelian Randomization Study. , 2017, Clinical chemistry.

[36]  J. Minnier,et al.  Discordant response of low-density lipoprotein cholesterol and lipoprotein(a) levels to monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9. , 2017, Journal of clinical lipidology.

[37]  U. Laufs,et al.  Pleiotropic Effects of Statins on the Cardiovascular System , 2017, Circulation research.

[38]  S. Crooke,et al.  Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials , 2016, The Lancet.

[39]  M. Graham,et al.  Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans , 2016, Journal of Lipid Research.

[40]  J. Witztum,et al.  Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study , 2015, The Lancet.

[41]  B. Nordestgaard,et al.  Lipoprotein(a) concentrations, isoform size, and risk of type 2 diabetes: a Mendelian randomisation study. , 2013, The lancet. Diabetes & endocrinology.

[42]  L. Lerman,et al.  Personalized Medicine in Cardiovascular Diseases , 2012, Korean circulation journal.

[43]  J. Borén,et al.  Lipoprotein(a) as a cardiovascular risk factor: current status , 2010, European heart journal.

[44]  S. Tsimikas A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. , 2017, Journal of the American College of Cardiology.