MK-0616: an oral PCSK9 inhibitor for hypercholesterolemia treatment

References

• Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154–156. doi: 10.1038/ng1161
   PubMed Web of Science ®Google Scholar
• Cohen JC, Boerwinkle E, Mosley TH Jr., et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264–1272. doi: 10.1056/NEJMoa054013
   PubMed Web of Science ®Google Scholar
• Seidah NG, Prat A. The multifaceted biology of PCSK9. Endocr Rev. 2022;43(3):558–582. doi: 10.1210/endrev/bnab035
   PubMed Web of Science ®Google Scholar
• Ahamad S, Bhat SA. Recent update on the development of PCSK9 inhibitors for hypercholesterolemia treatment. J Med Chem. 2022;65(23):15513–15539. doi: 10.1021/acs.jmedchem.2c01290
   PubMedGoogle Scholar
• Rosenson RS, Hegele RA, Fazio S, et al. The evolving future of PCSK9 inhibitors. J Am Coll Cardiol. 2018;72(3):314–329. doi: 10.1016/j.jacc.2018.04.054
   PubMed Web of Science ®Google Scholar
• Rosenson RS, Hegele RA, Koenig W. Cholesterol-lowering agents. Circ Res. 2019;124(3):364–385. doi: 10.1161/CIRCRESAHA.118.313238
   PubMed Web of Science ®Google Scholar
• Nurmohamed NS, Navar AM, Kastelein JJP. New and emerging therapies for reduction of LDL-Cholesterol and apolipoprotein B: JACC focus seminar 1/4. J Am Coll Cardiol. 2021;77(12):1564–1575. doi: 10.1016/j.jacc.2020.11.079
   PubMed Web of Science ®Google Scholar
• Gill PK, Hegele RA. New biological therapies for low-density lipoprotein cholesterol. Can J Cardiol. 2023. doi: 10.1016/j.cjca.2023.08.003
   PubMedGoogle Scholar
• Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489–1499. doi: 10.1056/NEJMoa1501031
   PubMed Web of Science ®Google Scholar
• Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500–1509. doi: 10.1056/NEJMoa1500858
   PubMed Web of Science ®Google Scholar
• Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical Outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–1722. doi: 10.1056/NEJMoa1615664
   PubMed Web of Science ®Google Scholar
• Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular Outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097–2107. doi: 10.1056/NEJMoa1801174
   PubMed Web of Science ®Google Scholar
• Ridker PM, Tardif JC, Amarenco P, et al. Lipid-reduction variability and antidrug-antibody formation with Bococizumab. N Engl J Med. 2017;376(16):1517–1526. doi: 10.1056/NEJMoa1614062
   PubMed Web of Science ®Google Scholar
• Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of Bococizumab in high-risk patients. N Engl J Med. 2017;376(16):1527–1539. doi: 10.1056/NEJMoa1701488
   PubMed Web of Science ®Google Scholar
• Blom DJ, Marais AD, Moodley R, et al. RNA-based therapy in the management of lipid disorders: a review. Lipids Health Dis. 2022;21(1):41. doi: 10.1186/s12944-022-01649-3
   PubMed Web of Science ®Google Scholar
• Oostveen RF, Khera AV, Kathiresan S, et al. New approaches for targeting PCSK9: small-interfering ribonucleic acid and genome editing. Arterioscler Thromb Vasc Biol. 2023;43(7):1081–1092. doi: 10.1161/ATVBAHA.122.317963
   PubMed Web of Science ®Google Scholar
• Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2017;376(15):1430–1440. doi: 10.1056/NEJMoa1615758
   PubMed Web of Science ®Google Scholar
• Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of Inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382(16):1507–1519. doi: 10.1056/NEJMoa1912387
   PubMed Web of Science ®Google Scholar
• Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020;382(16):1520–1530. doi: 10.1056/NEJMoa1913805
   PubMed Web of Science ®Google Scholar
• Ray KK, Raal FJ, Kallend DG, et al. Inclisiran and cardiovascular events: a patient-level analysis of phase III trials. Eur Heart J. 2023;44(2):129–138. doi: 10.1093/eurheartj/ehac594
   PubMed Web of Science ®Google Scholar
• Raal F, Fourie N, Scott R, et al. Long-term efficacy and safety of lerodalcibep in heterozygous familial hypercholesterolaemia: the LIBerate-HeFH trial. Eur Heart J. 2023. doi:10.1093/eurheartj/ehad596
   Web of Science ®Google Scholar
• Raal F, Mehta V, Kayikcioglu M, et al. Randomized, open-label, cross-over phase-3 study to evaluate efficacy and safety of LIB003 compared with evolocumab in homozygous familial hypercholesterolemia patients on stable lipid-lowering therapy (LIBERATE-HoFH). O066. Presented at: EAS 2023, 2023 May 23, Mannheim, Germany; 2023.
   Google Scholar
• Alleyne C, Amin RP, Bhatt B, 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):13796–13824. doi: 10.1021/acs.jmedchem.0c01084
   PubMed Web of Science ®Google Scholar
• Tucker TJ, Embrey MW, Alleyne C, et al. A series of novel, highly potent, and orally bioavailable next-generation tricyclic peptide PCSK9 inhibitors. J Med Chem. 2021;64(22):16770–16800. doi: 10.1021/acs.jmedchem.1c01599
   PubMed Web of Science ®Google Scholar
• Johns DG, Campeau LC, Banka P, et al. Orally bioavailable macrocyclic peptide that inhibits binding of PCSK9 to the low density lipoprotein receptor. Circulation. 2023;148(2):144–158. doi: 10.1161/CIRCULATIONAHA.122.063372
   PubMed Web of Science ®Google Scholar
• Ballantyne CM, Banka P, Mendez G, et al. Phase 2b randomized trial of the oral PCSK9 inhibitor MK-0616. J Am Coll Cardiol. 2023;81(16):1553–1564. doi: 10.1016/j.jacc.2023.02.018
   PubMed Web of Science ®Google Scholar
• Merck initiates phase 3 clinical program for oral PCSK9 inhibitor candidate MK-0616. [cited 2023 Aug 29]. Available from: https://www.merck.com/news/merck-initiates-phase-3-clinical-program-for-oral-pcsk9-inhibitor-candidate-mk-0616/
   Google Scholar
• Koren MJ, Hofherr A, Schumi J, et al. Etesian: a phase 2B study of the efficacy, safety and tolerability of AZD8233, a PCSK9-targeted antisense oligonucleotide, in patients with dyslipidemia. J Am Coll Cardiol. 2022;79(9):1475. doi: 10.1016/S0735-1097(22)02466-4
   Web of Science ®Google Scholar
• Ionis provides update on development program evaluating PCSK9 antisense medicine for the treatment of hypercholesterolemia. [cited 2023 Aug 28]. Available from: https://www.prnewswire.com/news-releases/ionis-provides-update-on-development-program-evaluating-pcsk9-antisense-medicine-for-the-treatment-of-hypercholesterolemia-301631819.html
   Google Scholar
• Gennemark P, Walter K, Clemmensen N, et al. An oral antisense oligonucleotide for PCSK9 inhibition. Sci Transl Med. 2021;13(593). doi: 10.1126/scitranslmed.abe9117
   PubMed Web of Science ®Google Scholar
• CiVi 008. [cited 2023 Aug 28]. Available from: https://www.civibio.com/pipeline/civi-008/
   Google Scholar
• Zeitlinger M, Bauer M, Reindl-Schwaighofer R, et al. A phase I study assessing the safety, tolerability, immunogenicity, and low-density lipoprotein cholesterol-lowering activity of immunotherapeutics targeting PCSK9. Eur J Clin Pharmacol. 2021;77(10):1473–1484. doi: 10.1007/s00228-021-03149-2
   PubMed Web of Science ®Google Scholar
• Chadwick AC, Wang X, Musunuru K. In vivo base editing of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a therapeutic alternative to genome editing. Arterioscler Thromb Vasc Biol. 2017;37(9):1741–1747. doi: 10.1161/ATVBAHA.117.309881
   PubMed Web of Science ®Google Scholar
• Musunuru K, Chadwick AC, Mizoguchi T, et al. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature. 2021;593(7859):429–434. doi: 10.1038/s41586-021-03534-y
   PubMed Web of Science ®Google Scholar
• Rothgangl T, Dennis MK, Lin PJC, et al. In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels. Nat Biotechnol. 2021;39(8):949–957. doi: 10.1038/s41587-021-00933-4
   PubMed Web of Science ®Google Scholar
• Lee RG, Mazzola AM, Braun MC, et al. Efficacy and safety of an investigational single-course CRISPR base-editing therapy targeting PCSK9 in nonhuman primate and mouse models. Circulation. 2023;147(3):242–253. doi: 10.1161/CIRCULATIONAHA.122.062132
   PubMed Web of Science ®Google Scholar