Merck & Co.'s oral PCSK9 inhibitor succeeds in dual Phase III trials侃侃而言 学以致用Merck & Co. 距离将首个口服 PCSK9 抑制剂推向市场又迈进一步！就在本周一，该公司宣布，其实验性药物 Enlicitide decanoate（原 MK-0616) 在两项 III 期试验中达到了主要目标，显著降低了低密度脂蛋白胆固醇水平，且其安全性与安慰剂和现有口服药物相当！此前，我曾分享 MK-0616的发现历程、以及工艺开发优化历程(1、2)，详见文末往期相关分享。本消息来自“FirstWord Pharma”，文末阅读原文可直达原址。"Enlicitide is a novel macrocyclic peptide that has the potential to deliver antibody-like efficacy and specificity for the validated PCSK9 mechanism in the form of a daily oral pill," said Dean Li, president of Merck Research Laboratories.默沙东研究实验室总裁 Dean Li 说：“ Enlicitide 是一种新型大环肽，有可能以每日口服药物的形式为经验证的 PCSK9 机制提供类似抗体的功效和特异性。”In the CORALreef HeFH study, the drug was tested in 303 heterozygous familial hypercholesterolaemia (HeFH) patients who have a history of or were at risk for a major atherosclerotic cardiovascular disease (ASCVD) event and are treated with a moderate or high intensity statin, with or without other lipid-lowering therapies. The CORALreef AddOn study compared it to ezetimibe, bempedoic acid, and their combination in 301 hypercholesterolaemia patients already on statin therapy.在 CORALreef HeFH研究中，该药物在 303 例杂合性家族性高胆固醇血症（HeFH）患者中进行了测试，这些患者有主要动脉粥样硬化性心血管疾病（ASCVD）事件的病史或风险，并接受中等或高强度他汀类药物治疗，同时有或没有其他降脂治疗。CORALreef AddOn 研究在 301 名已经接受他汀类药物治疗的高胆固醇血症患者中，将其与依折替米贝、苯甲多酸及其组合进行了比较。代谢疾病引擎Across both trials, Merck said the drug showed statistically significant and clinically meaningful results on the primary endpoint of LDL reductions and also significantly improved key secondary measures, which included non-HDL cholesterol, ApoB, and lipoprotein(a).在两项试验中，Merck 表示，该药物在降低低密度脂蛋白（LDL）这一主要指标方面显示出具有统计学意义且具有临床意义的结果，并且在关键的次要指标上也取得了显著改善，这些指标包括非高密度脂蛋白胆固醇、载脂蛋白 B 和脂蛋白(a)。The wins come as Merck looks to build out its cardiometabolic portfolio ahead of the 2028 patent cliff for its cancer immunotherapy juggernaut Keytruda (pembrolizumab). Both enlicitide and the already approved pulmonary arterial hypertension drug Winrevair (sotatercept) are two key assets the company hopes will drive sales in the space (see Spotlight On: How Merck & Co. plans to unlock $15B from its cardiometabolic pipeline). Analysts have suggested $5 billion in peak sales for enlicitide.这些胜利的取得正值 Merck 着手扩充其心血管代谢领域的产品组合之际，因为其癌症免疫疗法旗舰产品可瑞达（帕博利珠单抗）的专利将于 2028 年到期。恩利利德和已经获批的肺动脉高压药物维纳维尔（索特拉西特）都是该公司希望能在该领域推动销售的两大关键资产（详见——聚焦：默克公司计划从其心血管代谢产品线中获取 150 亿美元收入）。分析师们预计 Enlicitide 的峰值销售额可达 50 亿美元。Monday's topline readouts build on encouragingPhase II data, where enlicitide achieved LDL cholesterol reductions ranging from 41% to 61% depending on dosage in a 381-patient trial. Those findings suggested the drug may be able to match the efficacy of injectable PCSK9 inhibitors like Amgen's Repatha (evolocumab) and Regeneron's Praluent (alirocumab), which reduce LDL cholesterol by about 60%, but face barriers due to cost, coverage and injection hesitancy.周一发布的总体数据进一步巩固了此前令人鼓舞的二期试验结果。在一项涉及 381 名患者的试验中，依利替德（enlicitide）在不同剂量下分别实现了 41%至 61%的低密度脂蛋白胆固醇降低率。这些发现表明，该药物或许能够达到与注射型 PCSK9 抑制剂（如安进公司的瑞帕他韦（依洛尤单抗）和再生元公司的普拉卢恩（阿利罗单抗））相当的疗效，这些注射型药物能将低密度脂蛋白胆固醇降低约 60%，但它们因成本、覆盖范围和注射顾虑等问题而面临障碍。对决 AstraZenecaHowever, Merck faces competition from AstraZeneca, which is developing its own oral PCSK9 inhibitor, AZD0780, currently in mid-stage testing. The compound recently showed a nearly 51% LDL reduction in the PURSUIT trial and doesn't require the fasting period that enlicitide demands – no food eight hours before or 30 minutes after dosing.然而，Merck 公司面临着来自 AstraZeneca 的竞争。AstraZeneca 正在研发其自身的口服 PCSK9 抑制剂——AZD0780，该药物目前正处于中期测试阶段。该化合物在“PURSUIT”试验中显示，其能将低密度脂蛋白（LDL）水平降低近 51%，而且无需像Enlicitide 那样在服用药物前 8 小时或服用后 30 分钟内禁食。A recent FirstWord physician survey found that nearly two-thirds of cardiologists would choose AZD0780 over Merck & Co.'s drug. SeePhysician Views Results: Keen on oral PCSK9s, cardiologists see AstraZeneca's as most palatable.最近的一项 FirstWord 医生调查发现，近三分之二的心脏病专家会选择 AZD0780，而非Merck 的同类药物。详情如下——医生观点结果：热衷于口服 PCSK9 药物的医生认为，AstraZeneca 的药物是最易接受的。Cleveland Clinic cardiologist Leslie Cho, who has worked with injectable PCSK9 inhibitors, told FirstWord that oral versions could address a large underserved population. "The issue has been the cost of the drug. It continues to be quite expensive and pose coverage issues in some of our patients," Cho said, adding that competitive pricing between oral options could drive broader adoption. However, she emphasised the importance of cardiovascular outcomes data before widespread prescribing. See KOL Views Q&A: Cardiovascular outcomes data and competitive pricing will be needed to drive oral PCSK9 uptake.克利夫兰诊所的心脏病专家莱斯利·乔斯曾研究过可注射的 PCSK9 抑制剂。她向 FirstWord表示，口服药物能够惠及大量未得到充分治疗的患者群体。“问题在于药物的成本。其价格一直很高，而且在一些患者中还存在报销问题。”乔斯说道，并补充说，口服药物之间的竞争定价可能会推动其更广泛的使用。不过，她强调在广泛开处方之前，必须先有心血管结果数据。详见专家观点问答：心血管结果数据和竞争定价将推动口服 PCSK9 的使用。Merck's Phase III CORALreef programme aims to enroll approximately 17,000 patients across multiple trials. The company expects to present detailed results from the completed CORALreef HeFH and CORALreef AddOn studies at a future scientific congress. The programme includes two larger ongoing trials–CORALreef Lipids, expected to enrol 2760 patients and complete this August, and CORALreef Outcomes, which is looking to recruit 14,550 patients and wrap towards the end of 2029.Merck 的 III 期 “CORALreef” 项目计划在多个试验中招募约 17,000 名患者。该公司预计将在未来的科学大会上公布已完成的 “CORALreef” 高胆固醇血症（HeFH）和 “CORALreef” 附加研究的详细结果。该项目包括两个正在进行的更大规模的试验——“CORALreef” 脂质试验，预计将招募 2,760 名患者，并于今年 8 月完成；以及“CORALreef”结果试验，旨在招募 14,550 名患者，并于 2029 年年底结束。声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号 粉丝群/投稿/授权/广告等请联系公众号助手 觉得本文好看，请点这里↓
