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Oral PCSK9 Inhibitors

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Abstract

Purpose of Review

In this review, we will discuss the data from early clinical studies of MK-0616 and summarize clinical trials of other oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

Recent Findings

The success of PCSK9 inhibition with monoclonal antibody injections has fueled the development of additional therapies targeting PCSK9, including oral formulations, the most advanced of which is MK-0616. MK-0616 is a novel, orally administered macrocyclic peptide that binds to PCSK9 and inhibits binding of PCSK9 to the LDL receptor, thereby decreasing plasma levels of LDL-C.

Summary

Clinical trial data on the safety and efficacy of MK-0616 are promising and report LDL-C–lowering efficacy comparable to that provided by injectable PCSK9 inhibitors. Ongoing and future studies of oral PCSK9 inhibitors in development will evaluate the safety, efficacy, and effectiveness of these agents and their potential role in preventing cardiovascular disease events.

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Data Availability

No datasets were generated or analysed during the current study.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37(2):161–5. https://doi.org/10.1038/ng1509.

    Article  CAS  PubMed  Google Scholar 

  2. Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154–6. https://doi.org/10.1038/ng1161.

    Article  CAS  PubMed  Google Scholar 

  3. Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci U S A. 2004;101(18):7100–5. https://doi.org/10.1073/pnas.0402133101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264–72. https://doi.org/10.1056/NEJMoa054013.

    Article  CAS  PubMed  Google Scholar 

  5. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–22. https://doi.org/10.1056/NEJMoa1615664.

    Article  CAS  PubMed  Google Scholar 

  6. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097–107. https://doi.org/10.1056/NEJMoa1801174.

    Article  CAS  PubMed  Google Scholar 

  7. Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382(16):1507–19. https://doi.org/10.1056/NEJMoa1912387.

    Article  CAS  PubMed  Google Scholar 

  8. Ballantyne CM, Minhas AMK, Orringer CE. Inclisiran: where are we on safety, efficacy, and clinical effectiveness of siRNA therapies for prevention? J Am Coll Cardiol. 2023;82(24):2262–4. https://doi.org/10.1016/j.jacc.2023.10.020.

    Article  CAS  PubMed  Google Scholar 

  9. • Landmesser U, Makhmudova U. New chapter in the PCSK9 book: oral inhibition of PCSK9 binding to the LDL receptor with a macrocyclic peptide. Circulation. 2023;148(2):159–61. https://doi.org/10.1161/CIRCULATIONAHA.123.065407. This editorial describes the challenges of developing orally bioavailable PCSK9 inhibitors.

    Article  CAS  PubMed  Google Scholar 

  10. Johns DG, Campeau LC, Banka P, Bautmans A, Bueters T, Bianchi E, et al. Orally bioavailable macrocyclic peptide that inhibits binding of PCSK9 to the low density lipoprotein receptor. Circulation. 2023;148(2):144–58. https://doi.org/10.1161/CIRCULATIONAHA.122.063372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. • Alleyne C, Amin RP, Bhatt B, Bianchi E, Blain JC, Boyer N, et al. Series of novel and highly potent cyclic peptide PCSK9 inhibitors derived from an mRNA display screen and optimized via structure-based design. J Med Chem. 2020;63(22):13796–824. https://doi.org/10.1021/acs.jmedchem.0c01084. This article reports the iterative medical chemistry alterations and drug design enhancements involved in developing oral agents for PCSK9 inhibition.

    Article  CAS  PubMed  Google Scholar 

  12. Tucker TJ, Embrey MW, Alleyne C, Amin RP, Bass A, Bhatt B, et al. A series of novel, highly potent, and orally bioavailable next-generation tricyclic peptide PCSK9 inhibitors. J Med Chem. 2021;64(22):16770–800. https://doi.org/10.1021/acs.jmedchem.1c01599.

    Article  CAS  PubMed  Google Scholar 

  13. ClinicalTrials.gov. A study of MK-0616 in participants with moderate renal impairment (MK-0616-007). 2023. https://clinicaltrials.gov/study/NCT05070390. Accessed 12 Oct 2023.

  14. ClinicalTrials.gov. MK-0616 (Oral PCSK9 Inhibitor) renal impairment study 2 (MK-0616-020). 2023. https://clinicaltrials.gov/study/NCT05934292. Accessed 12 Oct 2023.

  15. • Ballantyne CM, Banka P, Mendez G, Garcia R, Rosenstock J, Rodgers A, et al. Phase 2b randomized trial of the oral PCSK9 inhibitor MK-0616. J Am Coll Cardiol. 2023;81(16):1553–64. https://doi.org/10.1016/j.jacc.2023.02.018. This article reports significant, dose-dependent LDL-C reduction with good tolerability with the oral PCSK9 inhibitor MK-0616 in 381 patients with hypercholesterolemia.

    Article  CAS  PubMed  Google Scholar 

  16. ClinicalTrials.gov. A research study looking at how NNC0385-0434 tablets work to lower blood cholesterol in people with heart disease or a high risk of heart disease. 2023. https://clinicaltrials.gov/study/NCT04992065. Accessed 13 Oct 2023.

  17. ClinicalTrials.gov. A study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD0780 in healthy subjects. 2023. https://clinicaltrials.gov/study/NCT05384262. Accessed 16 Oct 2023.

  18. ClinicalTrials.gov. A study of MK-0616 (Oral PCSK9 Inhibitor) in adults with hypercholesterolemia (MK-0616-013): CORALreef lipids. 2023. https://clinicaltrials.gov/study/NCT05952856. Accessed 13 Oct 2023.

  19. ClinicalTrials.gov. A study of MK-0616 (Oral PCSK9 Inhibitor) in adults with heterozygous familial hypercholesterolemia (MK-0616-017): CORALreef HeFH. 2023. https://clinicaltrials.gov/study/NCT05952869. Accessed 13 Oct 2023.

  20. ClinicalTrials.gov. MK-0616 (Oral PCSK9 Inhibitor) cardiovascular outcomes study (MK-0616-015) CORALreef outcomes. 2023. https://clinicaltrials.gov/study/NCT06008756. Accessed 13 Oct 2023.

  21. Gennemark P, Walter K, Clemmensen N, Rekic D, Nilsson CAM, Knochel J, et al. An oral antisense oligonucleotide for PCSK9 inhibition. Sci Transl Med. 2021;13(593). https://doi.org/10.1126/scitranslmed.abe9117.

  22. Kosmas CE, Papakonstantinou EJ, Carreño J, EchavarriaUceta R, Guzman E, Sourlas A. PCSK9 targeting in the management of hypercholesterolaemia. EMJ Cardiol. 2023;11(1):87–97. https://doi.org/10.33590/emjcardiol/10303462.

    Article  Google Scholar 

  23. Koren MJ, Descamps O, Hata Y, Hengeveld EM, Hovingh GK, Ikonomidis I, et al. PCSK9 inhibition with orally administered NNC0385–0434 in hypercholesterolaemia: a randomised, double-blind, placebo-controlled and active-controlled phase 2 trial. Lancet Diabetes Endocrinol. 2024;12(3):174–183. https://doi.org/10.1016/S2213-8587(23)00325-X.

  24. ClinicalTrials.gov. A study to assess the effect of AZD0780 on the pharmacokinetics of rosuvastatin. 2023. https://clinicaltrials.gov/study/NCT05787002. Accessed 16 Oct 2023.

  25. ClinicalTrials.gov. An ADME study of [14C]AZD0780 in healthy male subjects. 2023. https://clinicaltrials.gov/study/NCT05817461. Accessed 16 Oct 2023.

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Authors and Affiliations

  1. Center for Cardiovascular Disease Prevention, Cardiovascular Division, Baylor Scott and White Health Heart Hospital Baylor Plano, Plano, TX, USA

    Anandita Agarwala

  2. College of Osteopathic Medicine, Kansas City University, Kansas City, MO, USA

    Ramsha Asim

  3. Section of Cardiovascular Research and Center for Cardiometabolic Disease Prevention, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, MS BCM285, Houston, TX, 77030, USA

    Christie M. Ballantyne

Authors
  1. Anandita Agarwala
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  2. Ramsha Asim
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  3. Christie M. Ballantyne
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Contributions

C.M.B. outlined the manuscript and expanded and updated the text and table. A.A. and R.A. drafted the original text. All authors reviewed the manuscript.

Corresponding author

Correspondence to Christie M. Ballantyne.

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Conflict of Interest

Dr. Ballantyne reports receiving consulting fees and research grants to his institution from Abbott Diagnostics, Akcea, Amgen, Arrowhead, Esperion, Ionis, Novartis, Novo Nordisk, Merck, Regeneron, and Roche Diagnostics. The other authors report that they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Agarwala, A., Asim, R. & Ballantyne, C.M. Oral PCSK9 Inhibitors. Curr Atheroscler Rep (2024). https://doi.org/10.1007/s11883-024-01199-2

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