Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a)

Nature Medicine volume 28, pages 96–103 (2022)Cite this article

Subjects

Abstract

Compelling evidence supports a causal role for lipoprotein(a) (Lp(a)) in cardiovascular disease. No pharmacotherapies directly targeting Lp(a) are currently available for clinical use. Here we report the discovery and development of olpasiran, a first-in-class, synthetic, double-stranded, N-acetylgalactosamine-conjugated small interfering RNA (siRNA) designed to directly inhibit LPA messenger RNA translation in hepatocytes and potently reduce plasma Lp(a) concentration. Olpasiran reduced Lp(a) concentrations in transgenic mice and cynomolgus monkeys in a dose-responsive manner, achieving up to over 80% reduction from baseline for 5–8 weeks after administration of a single dose. In a phase 1 dose-escalation trial of olpasiran (ClinicalTrials.gov: NCT03626662), the primary outcome was safety and tolerability, and the secondary outcomes were the change in Lp(a) concentrations and olpasiran pharmacokinetic parameters. Participants tolerated single doses of olpasiran well and experienced a 71–97% reduction in Lp(a) concentration with effects persisting for several months after administration of doses of 9 mg or higher. Serum concentrations of olpasiran increased approximately dose proportionally. Collectively, these results validate the approach of using hepatocyte-targeted siRNA to potently lower Lp(a) in individuals with elevated plasma Lp(a) concentration.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Identification of an siRNA with durable Lp(a) gene silencing activity in Lp(a) double transgenic mice and in cynomolgus monkeys.
Fig. 2: Olpasiran pharmacokinetics and pharmacodynamics in cynomolgus monkeys.
Fig. 3: Phase 1 single-ascending-dose study of olpasiran.
Fig. 4: Phase 1 study evaluation of mean (s.e.m.) lipid concentrations.

Similar content being viewed by others

Data availability

GENCODE data are available from the following gzipped file: http://ftp.ebi.ac.uk/pub/databases/gencode/Gencode_human/release_24/gencode.v24.annotation.gtf.gz. Other preclinical data that support the findings reported in this paper are available from the corresponding authors upon reasonable request.

Regarding the clinical trial portions of the paper, qualified researchers may request data from Amgen clinical studies. Complete details are available at https://wwwext.amgen.com/science/clinical-trials/clinical-data-transparencypractices/clinical-trial-data-sharing-request/.

References

  1. Schmidt, K., Noureen, A., Kronenberg, F. & Utermann, G. Structure, function, and genetics of lipoprotein (a). J. Lipid Res. 57, 1339–1359 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kronenberg, F. & Utermann, G. Lipoprotein(a): resurrected by genetics. J. Intern. Med. 273, 6–30 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Eckardstein, A. V. Lipoprotein(a). Eur. Heart J. 38, 1530–1532 (2017).

    Article  PubMed  Google Scholar 

  4. Langsted, A., Kamstrup, P. R. & Nordestgaard, B. G. High lipoprotein(a) and high risk of mortality. Eur. Heart J. 40, 2760–2770 (2019).

    Article  CAS  PubMed  Google Scholar 

  5. Clarke, R. et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 2518–2528 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Kamstrup, P. R., Tybjaerg-Hansen, A., Steffensen, R. & Nordestgaard, B. G. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 301, 2331–2339 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Nordestgaard, B. G. et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur. Heart J. 31, 2844–2853 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Helgadottir, A. et al. Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. J. Am. Coll. Cardiol. 60, 722–729 (2012).

    Article  CAS  PubMed  Google Scholar 

  9. Thanassoulis, G. et al. Associations of long-term and early adult atherosclerosis risk factors with aortic and mitral valve calcium. J. Am. Coll. Cardiol. 55, 2491–2498 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kamstrup, P. R., Tybjaerg-Hansen, A. & Nordestgaard, B. G. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J. Am. Coll. Cardiol. 63, 470–477 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Kral, B. G. et al. Relation of plasma lipoprotein(a) to subclinical coronary plaque volumes, three-vessel and left main coronary disease, and severe coronary stenoses in apparently healthy African-Americans with a family history of early-onset coronary artery disease. Am. J. Cardiol. 118, 656–661 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Thanassoulis, G. Lipoprotein (a) in calcific aortic valve disease: from genomics to novel drug target for aortic stenosis. J. Lipid Res. 57, 917–924 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tsimikas, S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J. Am. Coll. Cardiol. 69, 692–711 (2017).

    Article  CAS  PubMed  Google Scholar 

  14. Gudbjartsson, D. F. et al. Lipoprotein(a) concentration and risks of cardiovascular disease and diabetes. J. Am. Coll. Cardiol. 74, 2982–2994 (2019).

    Article  CAS  PubMed  Google Scholar 

  15. Patel, A. P. et al. Lp(a) (lipoprotein[a]) concentrations and incident atherosclerotic cardiovascular disease: new insights from a large national biobank. Arterioscler. Thromb. Vasc. Biol. 41, 465–474 (2021).

    CAS  PubMed  Google Scholar 

  16. Yahya, R. et al. Statin treatment increases lipoprotein(a) levels in subjects with low molecular weight apolipoprotein(a) phenotype. Atherosclerosis 289, 201–205 (2019).

    Article  CAS  PubMed  Google Scholar 

  17. Artemeva, N. V. et al. Lowering of lipoprotein(a) level under niacin treatment is dependent on apolipoprotein(a) phenotype. Atheroscler. Suppl. 18, 53–58 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Baum, S. J. et al. Effect of evolocumab on lipoprotein apheresis requirement and lipid levels: results of the randomized, controlled, open-label DE LAVAL study. J. Clin. Lipidol. 13, 901–909 (2019).

    Article  PubMed  Google Scholar 

  19. Nugent, A., Gray, J., Gorby, L. & Moriarty, P. Lipoprotein apheresis: first FDA indicated treatment for elevated lipoprotein (a). J. Clin. Cardiol. 1, 16–21 (2019).

    Google Scholar 

  20. Shen, X. & Corey, D. R. Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs. Nucleic Acids Res. 46, 1584–1600 (2018).

    Article  CAS  PubMed  Google Scholar 

  21. Watts, J. K. & Corey, D. R. Silencing disease genes in the laboratory and the clinic. J. Pathol. 226, 365–379 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Roberts, T. C., Langer, R. & Wood, M. J. A. Advances in oligonucleotide drug delivery. Nat. Rev. Drug Discov. 19, 673–694 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Varvel, S., McConnell, J. P. & Tsimikas, S. Prevalence of elevated Lp(a) mass levels and patient thresholds in 532 359 patients in the United States. Arterioscler. Thromb. Vasc. Biol. 36, 2239–2245 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. Marcovina, S. M. et al. Differences in Lp[a] concentrations and apo[a] polymorphs between black and white Americans. J. Lipid Res. 37, 2569–2585 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Burgess, S. et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 3, 619–627 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lamina, C. & Kronenberg, F. Lp(a)-GWAS-Consortium. Estimation of the required lipoprotein(a)-lowering therapeutic effect size for reduction in coronary heart disease outcomes: a Mendelian randomization analysis. JAMA Cardiol. 4, 575–579 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Madsen, C. M., Kamstrup, P. R., Langsted, A., Varbo, A. & Nordestgaard, B. G. Lipoprotein(a)-lowering by 50 mg/dL (105 nmol/L) may be needed to reduce cardiovascular disease 20% in secondary prevention: a population-based study. Arterioscler. Thromb. Vasc. Biol. 40, 255–266 (2020).

    Article  CAS  PubMed  Google Scholar 

  28. Tsimikas, S. et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N. Engl. J. Med. 382, 244–255 (2020).

    Article  CAS  PubMed  Google Scholar 

  29. Chi, X., Gatti, P. & Papoian, T. Safety of antisense oligonucleotide and siRNA-based therapeutics. Drug Discov. Today 22, 823–833 (2017).

    Article  CAS  PubMed  Google Scholar 

  30. Judge, D. P. et al. Phase 3 multicenter study of revusiran in patients with hereditary transthyretin-mediated (hATTR) amyloidosis with cardiomyopathy (ENDEAVOUR). Cardiovasc. Drugs Ther. 34, 357–370 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Springer, A. D. & Dowdy, S. F. GalNAc-siRNA conjugates: leading the way for delivery of RNAi therapeutics. Nucleic Acid Ther. 28, 109–118 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kenski, D. M. et al. siRNA-optimized modifications for enhanced in vivo activity. Mol. Ther. Nucleic Acids 1, e5 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Frankish, A. et al. GENCODE reference annotation for the human and mouse genomes. Nucleic Acids Res. 47, D766–D773 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Kozomara, A., Birgaoanu, M. & Griffiths-Jones, S. miRBase: from microRNA sequences to function. Nucleic Acids Res. 47, D155–D162 (2019).

    Article  CAS  PubMed  Google Scholar 

  35. Kozomara, A. & Griffiths-Jones, S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 42, D68–D73 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Kozomara, A. & Griffiths-Jones, S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 39, D152–D157 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Griffiths-Jones, S., Saini, H. K., van Dongen, S. & Enright, A. J. miRBase: tools for microRNA genomics. Nucleic Acids Res. 36, D154–D158 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Griffiths-Jones, S. The microRNA registry. Nucleic Acids Res. 32, D109–D111 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang, G., Budker, V. & Wolff, J. A. High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA. Hum. Gene Ther. 10, 1735–1737 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Wooddell, C. I., Reppen, T., Wolff, J. A. & Herweijer, H. Sustained liver-specific transgene expression from the albumin promoter in mice following hydrodynamic plasmid DNA delivery. J. Gene Med. 10, 551–563 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Dati, F. et al. First WHO/IFCC international reference reagent for lipoprotein(a) for immunoassay—Lp(a) SRM 2B. Clin. Chem. Lab. Med. 42, 670–676 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Marcovina, S. M., Albers, J. J., Gabel, B., Koschinsky, M. L. & Gaur, V. P. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a). Clin. Chem. 41, 246–255 (1995).

    Article  CAS  PubMed  Google Scholar 

  43. Marcovina, S. M. et al. Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a). Clin. Chem. 46, 1956–1967 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Yeang, C., Witztum, J. L. & Tsimikas, S. ‘LDL-C’ = LDL-C + Lp(a) − C: implications of achieved ultra-low LDL-C levels in the proprotein convertase subtilisin/kexin type 9 era of potent LDL-C lowering. Curr. Opin. Lipidol. 26, 169–178 (2015).

    Article  CAS  PubMed  Google Scholar 

  45. Willeit, P. et al. Low-density lipoprotein cholesterol corrected for lipoprotein(a) cholesterol, risk thresholds, and cardiovascular events. J. Am. Heart Assoc. 9, e016318 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Langlois, M. R. et al. Quantifying atherogenic lipoproteins for lipid-lowering strategies: consensus-based recommendations from EAS and EFLM. Clin. Chem. Lab. Med. 58, 496–517 (2020).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Amgen, Inc. and Arrowhead Pharmaceuticals, Inc. funded this work. J. Murray, H. Hamilton, M. Stolina, D. Dwyer and P. Denis supported the in vitro screening and preclinical data. J. Hegge performed some of the preclinical work (mouse and monkey) and supported data preparation for the manuscript. P. Yamaguchi assisted in drafting the preclinical section of the manuscript. J. Wang and the Amgen Clinical Biomarker and Diagnostics group supported Lp(a) assay evaluation and selection. N. Shah and Z. Atter provided statistical support for the clinical study. W. Krall of Wanda Krall Medical Communications, funded by Amgen, and E. Stoltzfus of Amgen provided editorial support.

Author information

Author notes

  1. These authors contributed equally: Michael J. Koren, Monica Florio.

Authors and Affiliations

  1. Jacksonville Center for Clinical Research, Jacksonville, FL, USA

    Michael J. Koren

  2. University of Kansas Medical Center, Kansas City, KS, USA

    Patrick Maurice Moriarty

  3. Excel Medical Clinical Trials, Boca Raton, FL, USA

    Seth J. Baum

  4. Orange County Research Center, Tustin, CA, USA

    Joel Neutel

  5. QPS MRA, Miami, FL, USA

    Martha Hernandez-Illas

  6. NYU Langone Medical Center, New York, NY, USA

    Howard S. Weintraub

  7. Amgen, Inc., Thousand Oaks, CA, USA

    Monica Florio, Helina Kassahun, Winnie Sohn & Huei Wang

  8. Arrowhead Pharmaceuticals, Inc, Pasadena, CA, USA

    Stacey Melquist

  9. Amgen, Inc., Cambridge, MA, USA

    Tracy Varrieur

  10. Amgen, San Francisco, CA, USA

    Saptarsi M. Haldar, Brooke M. Rock, Oliver Homann & Jennifer Hellawell

  11. Amgen, Ltd., Cambridge, UK

    Mary Elliott-Davey

  12. Arrowhead Pharmaceuticals, Inc., Madison, WI, USA

    Tao Pei

  13. University of Western Australia and Royal Perth Hospital, Perth WA, Australia

    Gerald F. Watts

Authors
  1. Michael J. Koren
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrick Maurice Moriarty
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seth J. Baum
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joel Neutel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Martha Hernandez-Illas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Howard S. Weintraub
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Monica Florio
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Helina Kassahun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stacey Melquist
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tracy Varrieur
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Saptarsi M. Haldar
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Winnie Sohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Huei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Mary Elliott-Davey
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Brooke M. Rock
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Tao Pei
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Oliver Homann
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Jennifer Hellawell
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Gerald F. Watts
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.J.K., P.M.M., S.J.B., J.N., M.H.-I., H.S.W. and G.F.W. enrolled participants in the clinical study and supervised the clinical components of the trial (clinical review, safety and dose monitoring). M.J.K., P.M.M., S.J.B. and G.F.W. additionally interpreted results and critically revised the manuscript. H.W. and M.E.-D. performed statistical planning and analysis of the clinical study, interpreted the results and critically revised the manuscript. W.S. oversaw the clinical pharmacokinetic and pharmacodynamic data analyses, interpreted the results and critically revised the manuscript. J.H. was involved in the oversight of the clinical study (for example, eligibility, protocol amendments and safety monitoring), study data analysis, interpreting results and revision and drafting of the manuscript. T.V. was involved in safety monitoring, study data analysis, interpreting results and revision of the manuscript. S.M.H. was involved in conceptualization and drafting and revision of the manuscript and interpreting results. H.K. was involved in study data analysis, interpreting results and revision and drafting of the manuscript. B.M.R. oversaw the cynomolgus monkey study and data analysis and interpreted results. M.F. and S.M. were involved in the design and interpretation of the preclinical studies and prepared the preclinical portion of the manuscript. M.F. directed additional safety and manufacturability assessments to select the clinical candidate olpasiran. T.P. designed the siRNA molecules for the in vitro and in vivo screening. O.H. conducted the bioinformatics analysis. All authors reviewed the manuscript, approved the final version and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Michael J. Koren.

Ethics declarations

Competing interests

M.J.K. is an employee of Jacksonville Center for Clinical Research, an organization that has received research grant funds from Amgen and multiple other manufacturers of lipid-lowering agents. M.J.K. has no direct personal financial relationship with Amgen, the manufacturer of olpasiran, and is an unpaid member of the Northeast Florida AHA Board. P.M.M. reports speaker and consulting fees from Amgen and Regeneron; consulting/advisory fees and grant research support from Esperion; grant research support from Ionis, Aegerion and the FH Foundation; speaker fees from Amarin; consulting fees from Stage II Innovations/Renew and Kaneka; advisor fees from Novartis; and fees for genetic testing kits from GB Life Sciences. S.J.B. reports Scientific Advisory Board/Consultant/Speaker for Amgen; and Scientific Advisory Board/Consultant for Sanofi Regeneron, Akcea and Novartis. J.N. and M.H.-I. have nothing to disclose. H.S.W. reports research funding from Amgen and Novo Nordisk; research funding and scientific advisory fees from Novartis; and speaker fees from Esperion. S.M. and T.P. are employees of Arrowhead Pharmaceuticals and have received Arrowhead stock options. M.F., H.K., T.V., W.S., H.W., M.E.D., B.M.R., O.H. and J.H. are employees of Amgen and own Amgen stock. S.M.H. is an officer, executive and shareholder in Amgen; a scientific founder of and shareholder in Tenaya Therapeutics; and serves on the Scientific Advisory Board of the German Centre for Cardiovascular Research. G.F.W. has received honoraria for lectures or advisory boards and research grants from Sanofi, Regeneron, Amgen, Arrowhead, Novartis and Kowa.

Reviewer recognition statement Nature Medicine thanks Kosh Ray, Kathy Wolski and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Editor recognition statement Michael Basson was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1

Phase 1 study schema.

Supplementary information

Supplementary Information

Supplementary Tables 1, 2 and 4

Reporting Summary

Supplementary Table 3

Transcript sequences were derived from the GENCODE version 24 (BASIC; https://www.gencodegenes.org/) gene model and the human GRCh38 reference genome, downloaded from the OmicSoft Studio software platform (Qiagen). Olpasiran guide and passenger sequences were aligned to the transcript sequences using a simple custom gapless aligner, employing a brute force approach in which the siRNA query sequence was exhaustively scanned as a sliding window across all transcript sequences. miRNA sequences were downloaded from miRBase (version 21; https://www.mirbase.org), and seed sequences (positions 2–7) were checked for human miRNA seed sequences matching the six-nucleotide seed region of the olpasiran guide sequences.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Koren, M.J., Moriarty, P.M., Baum, S.J. et al. Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a). Nat Med 28, 96–103 (2022). https://doi.org/10.1038/s41591-021-01634-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41591-021-01634-w

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research