Department of Clinical Biochemistry, PathWest Laboratory Medicine, Perth, Western Australia.
Royal Perth Hospital & Fiona Stanley Hospital Network, Perth, Western Australia.
Expert Opin Investig Drugs. 2023 Jul-Dec;32(10):873-878. doi: 10.1080/13543784.2023.2267972. Epub 2023 Nov 6.
Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of morbidity and mortality worldwide. Lowering LDL-cholesterol, by lifestyle modification or therapeutically, reduces the risk of ASCVD. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein which binds to the LDL-receptor and induces degradation, is a clinically validated target to lower LDL-cholesterol. Injectable PCSK9 inhibitor therapies have demonstrated substantial reductions in LDL-cholesterol with associated decreased risk of ASCVD events.
MK-0616 is an orally bioavailable, renally excreted, macrocyclic peptide inhibitor of PCSK9. The article provides an understanding of the chemistry and development, pharmacokinetic and pharmacodynamic characteristics of MK-0616 and insight into its clinical efficacy and safety. In clinical trials, MK-0616 produced dose-dependent reductions in LDL-cholesterol, non-HDL-cholesterol, and apolipoprotein (apo) B levels. Furthermore, MK-0616 modestly lowered lipoprotein (a) [Lp(a)].
MK-0616 is a potent, oral macrocyclic peptide inhibitor of PCSK9 that is not only able to reduce LDL-cholesterol, non-HDL-cholesterol, and apoB, but can also lower Lp(a). Safety and tolerability studies reported to date are promising. MK-0616 may offer advantages over injectable anti-PCSK9 therapies in terms of ease of dosing, patient preference and cost. The results from phase III trials of MK-0616 on cardiovascular outcomes are awaited with interest.
动脉粥样硬化性心血管疾病（ASCVD）是全球发病率和死亡率的主要原因。通过生活方式改变或治疗降低 LDL 胆固醇可降低 ASCVD 的风险。前蛋白转化酶枯草溶菌素/糜蛋白酶 9 型（PCSK9）是一种与 LDL 受体结合并诱导其降解的蛋白，是降低 LDL 胆固醇的临床验证靶点。可注射的 PCSK9 抑制剂疗法已证明可显著降低 LDL 胆固醇，同时降低 ASCVD 事件的风险。
MK-0616 是一种口服生物可利用的、经肾脏排泄的、PCSK9 的大环肽抑制剂。本文介绍了 MK-0616 的化学和开发、药代动力学和药效学特征，并深入了解其临床疗效和安全性。在临床试验中，MK-0616 可使 LDL 胆固醇、非 HDL 胆固醇和载脂蛋白（apo）B 水平呈剂量依赖性降低。此外，MK-0616 可适度降低脂蛋白（a）[Lp(a)]。
MK-0616 是一种有效的、口服大环肽 PCSK9 抑制剂，不仅能降低 LDL 胆固醇、非 HDL 胆固醇和 apoB，还能降低 Lp(a)。迄今为止报告的安全性和耐受性研究结果令人鼓舞。MK-0616 在给药方便性、患者偏好和成本方面可能优于可注射的抗 PCSK9 疗法。人们对 MK-0616 对心血管结局的 III 期临床试验结果充满期待。
