Lepodisiran sodium

*仅供医学专业人士阅读参考 最新捷报！ 近两年，多种降低脂蛋白(a)（Lp[a]）的药物临床试验已经进入白热化阶段。今天，又是谁带着成果上台呢？ 前日，两款Lp(a)降脂药的II期临床结果同时于《美国医学会杂志》期刊惊艳亮相。 一款是Lp(a)的首个口服降脂药muvalaplin[1]，此次II期临床结果显示，相比于安慰剂，12周、每日一次240 mg的muvalaplin治疗可以使Lp(a)水平≥175 nmol/L、具有较高心血管事件风险的患者Lp(a)水平降低达85.8%。 另一款是腹部皮下注射的小干扰 RNA（siRNA）药物zerlasiran[2]，相比于安慰剂，以450 mg、每24周两次的给药方式进行治疗36周后，zerlasiran使Lp(a)水平≥125 nmol/L、动脉粥样硬化性心血管疾病患者的Lp(a)平均水平降低85.6%，且药效持久，治疗结束半年内Lp(a)水平稳定较低。 两个药物的安全性都可靠。 脂蛋白(a)（Lp[a]）已被证明是动脉粥样硬化和主动脉瓣狭窄心血管疾病独立危险因素，高于50mg/dL（125nmol/L）通常被认为属于较高水平，临床上尚无获批药物进行治疗。 很多研究喜欢拿Lp(a)和另一个心血管“杀手”进行掰头，也就是低密度脂蛋白（LDL）或者说低密度脂蛋白胆固醇（LDL-C）。结果发现，虽说LDL水平高在人群中更普遍存在，但是Lp(a)的毒性可谓是一节更比六节强，每颗粒Lp(a)是LDL的致动脉粥样硬化性的大约6.6倍[3]。即使求救“神奇海螺”他汀，将LDL-C降至较低水平也无法完全抵消由Lp(a)增加的疾病风险[4]。 还有件棘手的事情，Lp(a)这东西难以通过改变生活饮食习惯来改变，几乎是刻在DNA里的（80%-90%由基因决定），于生命早期就已达到一定水平，随后基本保持稳定[5]。这么一比，LDL-C竟好似温柔了些。 不能用他汀，不能靠改善饮食，现有的法子行不通，那就另寻他路了。 Lp(a)由载脂蛋白(a) (apo[a])与含有apo B100蛋白的LDL样颗粒结合通过非共价结合形成。针对它的结构和诱导心血管疾病的病理机制，应对之策主要有两个大方向： 一是限制apo(a)的合成。apo(a)由LHA基因编码，在肝脏中合成。对LHA做手脚，可以开发靶向LHA的小干扰 RNA（siRNA）药物，代表有lepodisiran、olpasiran、zerlasiran；或者是靶向LHA的反义寡核苷酸（ASO）药物，代表有pelacarsen。 二是限制Lp(a)的组装，代表有muvalaplin。不同于上述几种药物的注射疗法，muvalaplin是首个口服药，通过阻断apo(a)与apoB结合、抑制Lp(a)形成。 脂蛋白（a）以及当前临床药物的主要研发方向[9] 截至目前，lepodisiran的I期临床试验[6]、olpasiran的II期临床试验[7]、pelacarsen的II期临床试验[8]已完成，数据喜人、优势不同。今天为大家献上的是zerlasiran和muvalaplin的最新临床结果。 澳大利亚莫纳什大学维多利亚心脏研究所的Stephen J. Nicholls团队，领衔完成了Lp(a)口服降脂药muvalaplin的II期临床试验。 试验共招募233名来自多个国家Lp(a)水平≥175 nmol/L、年龄≥40岁的患者，中位年龄为66岁，33%为女性。患者的心血管事件风险高，患有冠状动脉疾病或缺血性卒中、外周动脉疾病、2型糖尿病、家族性高胆固醇血症。 患者被随机分配至四个治疗组，包括三个不同剂量的muvalaplin治疗组和一个安慰剂对照组，每天口服一次药物。 12周治疗后，muvalaplin在所有剂量组中均显著降低了Lp(a)浓度，且呈现明显的剂量依赖性，而安慰剂组未观察到明显变化。与安慰剂相比，使用完整Lp(a)测定法时，10 mg/天、60 mg/天、240 mg/天剂量的muvalaplin治疗分别使Lp(a)水平降低47.6%、81.7%、85.8%；使用基于apo(a)的测定法时，分别降低40.4%、70.0%、68.9%。 次要终点中，完整Lp(a)测定法显示，接受60 mg/天或240 mg/天剂量治疗的患者里，超过95%的人在12周内将Lp(a)水平降低至125 nmol/L以下。 另外，接受60 mg/天或240 mg/天剂量治疗的患者LDL-C水平在治疗12周后分别降低16%、21.3%，任何剂量均未观察到高超敏C反应蛋白（hs-CRP）的变化，也没有安全性或耐受性问题。 zerlasiran的II期临床试验由美国克利夫兰医学中心的Steven E. Nissen团队完成。 试验共招募178名Lp(a)水平≥125 nmol/L、年龄在18-80岁之间的患者，均患有动脉粥样硬化性心血管疾病。患者的中位年龄63.7岁，女性占25.8%，被随机分配至五个治疗组，包括两个安慰剂组和三个不同剂量的zerlasiran治疗组，均通过腹部皮下注射给药。 36周治疗后，将两个安慰剂组的数据进行合并，发现zerlasiran各治疗组均可显著降低Lp(a）水平。相比于合并安慰剂组，接受450 mg、每24周两次治疗的患者Lp(a)平均水平降低85.6%、中位水平降低94.5%；接受300 mg每16周三次治疗的患者Lp(a)平均水平降低82.8%，中位水平降低96.4%；接受300mg、每24周两次治疗的患者Lp(a)水平降低81.3%、中位水平降低90.0%。 每24周450 mg、每16周300 mg、每24周300 mg的zerlasiran治疗，还可以使患者的LDL-C水平在为期36周的疗程后平均降低25.1%、31.9%、29.7%。 研究者们对患者进行后续随访。结果显示，zerlasiran在不同剂量组中均表现出较长的持续疗效，首次给药后48周时患者Lp(a)水平仍相较于合并安慰剂组降低78.7%-83.0%，60周时降低幅度可维持在71.8%-79.2%。 zerlasiran治疗最常见的不良事件是轻度注射部位反应，给药后第一天有2.3%-7.1%的参与者反映轻度疼痛，无治疗相关严重不良反应。 新的风暴已经出现，怎么能够停滞不前？Lp(a)的恶行被陆续揭露，靶向Lp(a)的降脂药走向临床也指日可待了。 参考文献： [1]Nicholls, S. J., Ni, W., Rhodes, G. M., Nissen, S. E., Navar, A. M., Michael, L. F., Haupt, A., & Krege, J. H. (2024). Oral Muvalaplin for Lowering of Lipoprotein(a): A Randomized Clinical Trial. JAMA, 10.1001/jama.2024.24017. Advance online publication. https://doi.org/10.1001/jama.2024.24017 [2]Nissen, S. E., Wang, Q., Nicholls, S. J., Navar, A. M., Ray, K. K., Schwartz, G. G., Szarek, M., Stroes, E. S. G., Troquay, R., Dorresteijn, J. A. N., Fok, H., Rider, D. A., Romano, S., Wolski, K., & Rambaran, C. (2024). Zerlasiran-A Small-Interfering RNA Targeting Lipoprotein(a): A Phase 2 Randomized Clinical Trial. JAMA, 10.1001/jama.2024.21957. Advance online publication. https://doi.org/10.1001/jama.2024.21957 [3]Björnson E, Adiels M, Taskinen M-R, et al. Lipoprotein(a) is markedly more atherogenic than LDL: an apolipoprotein B-based genetic analysis. J Am Coll Cardiol. 2024;83:385-395. [4]Harpreet S. Bhatia, Simon Wandel, Peter Willeit, et al. Independence of Lipoprotein(a) and Low-Density Lipoprotein Cholesterol–Mediated Cardiovascular Risk: A Participant-Level Meta-Analysis. Circulation. DOI: 10.1161/CIRCULATIONAHA.124.069556. [5]Wilson DP, Jacobson TA, Jones PH, et al. Use of lipoprotein(a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association. J Clin Lipidol.2022;16:e77–e95. [6]Nissen SE, Linnebjerg H, Shen X, et al. Lepodisiran, an Extended-Duration Short Interfering RNA Targeting Lipoprotein(a): A Randomized Dose-Ascending Clinical Trial. JAMA. 2023;330(21):2075–2083. doi:10.1001/jama.2023.21835 [7]O'Donoghue, M. L., Rosenson, R. S., Gencer, B., López, J. A. G., Lepor, N. E., Baum, S. J., Stout, E., Gaudet, D., Knusel, B., Kuder, J. F., Ran, X., Murphy, S. A., Wang, H., Wu, Y., Kassahun, H., Sabatine, M. S., & OCEAN(a)-DOSE Trial Investigators (2022). Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease. The New England journal of medicine, 387(20), 1855–1864. https://doi.org/10.1056/NEJMoa2211023 [8]Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med 2020;382:244-255. [9]Nicholls SJ, Nissen SE, Fleming C, et al. Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation: A Randomized Clinical Trial. JAMA. 2023;330(11):1042–1053. doi:10.1001/jama.2023.16503 本文作者 | 张艾迪

Muvalaplin, an oral, once-daily treatment that inhibits lipoprotein(a) formation via a novel mechanism, achieved positive results in a 12-week Phase 2 study These data were published in the Journal of the American Medical Association (JAMA) and simultaneously presented today at the American Heart Association (AHA) Scientific Sessions 2024 INDIANAPOLIS, IN, USA I November 18, 2024 I Eli Lilly and Company (NYSE: LLY ) today announced positive Phase 2 results for muvalaplin, an investigational once-daily, orally administered selective inhibitor of lipoprotein(a) [Lp(a)], a genetically inherited risk factor for heart disease. The study demonstrated that muvalaplin significantly reduced elevated Lp(a) levels in adults, meeting its primary endpoint of percent change in Lp(a) from baseline to week 12. At the 12-week primary endpoint, muvalaplin (10 mg, 60 mg and 240 mg) showed significant reductions in Lp(a) levels compared to placebo. The placebo-adjusted reductions were up to 85.8% using an intact Lp(a) assay and up to 70.0% using an apo(a) assay. Specifically, the reductions were 47.6% (10 mg), 81.7% (60 mg) and 85.8% (240 mg) with the intact Lp(a) assay, and 40.4% (10 mg), 70.0% (60 mg) and 68.9% (240 mg) with the apo(a) assay. “High levels of Lp(a) have been shown to be a significant risk factor for atherosclerotic cardiovascular disease, affecting over one billion adults globally,” said Stephen J. Nicholls, MBBS, Ph.D., director of the Victorian Heart Hospital and Institute, and professor of cardiology at Monash University, Australia. “Current cholesterol-lowering therapies are not approved to lower Lp(a) levels, highlighting an unmet need for people living with cardiovascular disease. These data represent a needed scientific advancement with the potential to reduce the risk of cardiovascular events such as heart attacks or strokes with a once-daily pill.” Lilly is evaluating muvalaplin, a potent, multivalent, small molecule that inhibits the formation of Lp(a) by blocking the initial interaction between apolipoprotein(a) [apo(a)] and apolipoproteinB (apoB). In the U.S., about 20% of people, or approximately 63 million individuals, have high levels of Lp(a). 1,2 Elevated Lp(a) levels can double or even triple the risk of a heart attack and are associated with other cardiovascular issues. 3 “While injectable approaches for Lp(a) are currently in Phase 3 development, including Lilly’s own lepodisiran program, these are the first positive Phase 2 data for an oral approach,” said Ruth Gimeno, Ph.D., group vice president, Diabetes and Metabolic Research, Lilly Research Laboratories. “We are very pleased to see these promising results and look forward to further exploring next steps for muvalaplin.” Muvalaplin also met secondary endpoints for all three tested doses (10 mg, 60 mg and 240 mg). The three tested doses achieved statistical significance for Lp(a) thresholds, and the 60 mg and 240 mg doses also achieved statistical significance for apoB reductions. These data also demonstrated: Adverse events were similar in both the muvalaplin and placebo groups. Treatment-emergent adverse events related to the study drug occurred in 14.9% of the placebo group, 5.9% of the 10 mg group, 14.3% of the 60 mg group and 14.7% of the 240 mg group. The incidence of adverse events leading to discontinuation of study drug varied from 0 to 8.8% across treatment groups and were single events spread across system organ classes. No deaths were reported in the study. About Lilly Lilly is a medicine company turning science into healing to make life better for people around the world. We’ve been pioneering life-changing discoveries for nearly 150 years, and today our medicines help tens of millions of people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world’s most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer’s disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we’re motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/news , or follow us on Facebook , Instagram , and LinkedIn . P-LLY References 1. Family Heart Foundation. Lipoprotein(a) – Family Heart Foundation . Last accessed Nov. 13, 2024. 2. Family Heart Foundation. Diagnosing High Lipoprotein(a) – Family Heart Foundation . Last accessed Nov. 13, 2024. 3. Harvard Medical School. Heart Health: The Latest on Lipoprotein(a), an Inherited Cause of Early Heart Disease . Last accessed Nov. 13, 2024. SOURCE: Eli Lilly