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27.03.2024 | Review

Oral PCSK9 Inhibitors

verfasst von: Anandita Agarwala, Ramsha Asim, Christie M. Ballantyne

Erschienen in: Current Atherosclerosis Reports

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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.

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

• 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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

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.

Titel: Oral PCSK9 Inhibitors
verfasst von: Anandita Agarwala
Ramsha Asim
Christie M. Ballantyne
Publikationsdatum: 27.03.2024
Verlag: Springer US
Erschienen in: Current Atherosclerosis Reports
Print ISSN: 1523-3804
Elektronische ISSN: 1534-6242
DOI: https://doi.org/10.1007/s11883-024-01199-2

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