Rosuvastatin Zinc

​New late-breaking clinical trial data presented at ACC and published simultaneously in JACC show benefit of investigational medicine AZD0780 on top of standard of care WILMINGTON, DE, USA I March 31, 2025 I Positive results from the PURSUIT Phase IIb trial for AstraZeneca’s AZD0780 demonstrated a statistically significant low-density lipoprotein cholesterol (LDL-C) reduction when administered on top of standard-of-care statin therapy, as compared with placebo. 1,2 AZD0780 is an investigational once-daily oral PCSK9 inhibitor for patients currently not reaching their LDL-C lowering goal despite standard-of-care-lipid lowering therapies such as statins. 1,2 These new data were presented today at the American College of Cardiology’s (ACC) Annual Scientific Session & Expo in Chicago, Illinois, US and published simultaneously in JACC . 1,2 At 12 weeks, AZD0780 30mg taken once-daily (when added to the standard-of-care statin therapy and administered without any fasting or food restrictions) led to a 50.7% reduction in LDL-C [95% CI: -59.0%, -42.4%, p<0.001]. Similar efficacy was observed regardless of whether trial participants received moderate- or high- intensity statin doses at baseline. 1,2 In addition, AZD0780 30mg enabled 84% [95%CI: 74.4%-90.7%] of trial participants to meet their American Heart Association/American College of Cardiology guideline-recommended LDL-C target (<70 mg/dL), compared to 13% [95%CI: 7.2%-22.3%] of participants on background statin therapy alone. 1,2 High LDL-C (≥70 mg/dL), a common type of dyslipidemia, is a key risk factor for atherosclerotic cardiovascular disease, including stroke and heart attack, and a significant public health concern. 3 It is estimated that more than 70% of patients worldwide are currently not reaching guideline-recommended LDL-C targets. 4-7 Dr. Michael J Koren, MD, CEO & Medical Director of Jacksonville Center for Clinical Research, Florida, US and PURSUIT Principal Investigator, said: “The PURSUIT Phase IIb trial demonstrates the potential of AZD0780 to provide a much-needed once-daily oral treatment option to deliver greater LDL cholesterol lowering on top of standard of care for millions of patients who remain at risk for serious cardiovascular events including premature death. These results are particularly important because the majority of patients with atherosclerotic disease today do not reach their LDL-C goals, despite availability of lipid-lowering therapies such as statins and injectable PCSK9 inhibitors.” Sharon Barr, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “These new data reflect AZD0780’s ability to reduce LDL cholesterol in patients who need more options to manage their cholesterol and related risks when standard-of-care therapy is not enough. As a novel small molecule oral PCSK9 inhibitor that can be taken without fasting restrictions, AZD0780 has the potential to be a game changer that could offer LDL-C lowering with greater convenience for patients. Our work in dyslipidemia builds on our strong heritage in cardiovascular, renal and metabolic diseases where we are advancing novel therapies, alone or in combination with other molecules in our extensive portfolio, that could redefine treatment standards and patient outcomes.” AZD0780 was generally well tolerated, and adverse events (AEs) were comparable between the total AZD0780 treatment groups (38.2%) and placebo (32.6%). 1,2 The frequency of treatment discontinuations due to AEs was similar across AZD0780 (1.5%) and placebo (2.3%) groups. 1,2 Data from PURSUIT are consistent with Phase I findings presented at European Atherosclerosis Society ( EAS ) 2024. 8 Notes About Dyslipidemia Elevated LDL-C levels in plasma is a key risk factor for cardiovascular disease and is estimated to cause 4.4 million deaths worldwide annually. 3 Despite current treatment options, the global burden of dyslipidemia is on the rise. 4 More than 70% of patients with atherosclerotic cardiovascular disease (ASCVD) are still not achieving their LDL-C target, so there remains a vast unmet need among high-risk patients for more varied and effective treatment options. 4-7 PURSUIT PURSUIT is a Phase IIb, multicenter, randomized, parallel-group, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy, safety and tolerability of AZD0780 in participants with dyslipidemia. 2 PURSUIT assessed the efficacy, safety and tolerability of different doses of AZD0780 on LDL-C levels in patients with hypercholesterolemia. 428 patients on stable standard-of-care therapy with moderate- or high-intensity statins with or without ezetimibe with LDL-C levels ≥70 and <190 mg/dL were randomized (1:1:1:1:1) to receive AZD0780 (1 mg, 3 mg, 10 mg and 30 mg daily) or matching placebo. 426 patients started treatment. 2 The primary objective of the study was to measure the effect of different doses of AZD0780 given once daily on LDL-C levels in patients with dyslipidemia receiving standard-of-care statins. The effect of AZD0780 versus placebo on other lipid parameters and inflammatory markers was also investigated. The concentration of AZD0780 in blood at specific timepoints was measured, and the safety and tolerability of AZD0780 evaluated. 2 AZD0780 AZD0780 is an oral, small molecule PCSK9 inhibitor that is being developed by AstraZeneca as an innovative therapy for patients with elevated low-density lipoprotein cholesterol (LDL-C) levels which cannot be controlled by statins alone. 2 PCSK9 is a well-known and validated target in LDL-C metabolism and inhibiting PCSK9 signalling has shown to be effective in reducing LDL-C levels in plasma. 2 Lower LDL-C levels are associated with a reduction in the risk of long-term cardiovascular disease and major cardiovascular events. 9 AstraZeneca is investigating the potential of AZD0780 as an oral small-molecule for use as a monotherapy or in fixed-dose combinations with other therapies in our extensive portfolio. Data from PURSUIT are consistent with Phase I findings for AZD0780 which demonstrated a statistically significant reduction of 51% in LDL-C levels on top of rosuvastatin treatment, with 80% total reduction from baseline, in treatment-naive participants with hypercholesterolemia. 2 AstraZeneca in CVRM Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms one of AstraZeneca’s main disease areas and is a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys, liver and pancreas, AstraZeneca is investing in a portfolio of medicines for organ protection by slowing or stopping disease progression, and ultimately paving the way towards regenerative therapies. The Company’s ambition is to improve and save the lives of millions of people, by better understanding the interconnections between CVRM diseases and targeting the mechanisms that drive them, so we can detect, diagnose and treat people earlier and more effectively. AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 125 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on social media @AstraZeneca . References SOURCE: AstraZeneca

今日，阿斯利康（AstraZeneca）在欧洲动脉粥样硬化学会（EAS）公布其在研口服PCSK9抑制剂AZD0780于1期临床试验中取得积极结果。当AZD0780与他汀类药物瑞舒伐他汀（rosuvastatin）联用时，可降低患者低密度脂蛋白胆固醇（LDL-C）水平近80%。AZD0780已在今年1月进入2b期临床试验用于治疗血脂异常患者。 血浆中LDL-C水平升高是心血管疾病的主要风险因素，估计每年导致全球约260万人死亡。尽管目前有多种获批疗法，但全球血脂异常负担仍在增加。超过70%的动脉粥样硬化性心血管疾病（ASCVD）患者仍未达到其LDL-C目标值，因此高风险患者对于更多样化和更有效治疗方案的需求仍未得到满足。 此次公布的1期试验旨在评估AZD0780作为单药及与瑞舒伐他汀联合使用时，对未经治疗的高胆固醇血症患者血浆中LDL-C水平的药效学、药代动力学、安全性及耐受性。受试者每天服用安慰剂、30毫克或60毫克AZD0780（每组n=15）持续四周。 另一队列则包括35名受试者持续服用20毫克瑞舒伐他汀三周，然后服用30毫克AZD0780或安慰剂，持续四周。图片来源：123RF分析显示，在未经治疗的高胆固醇血症患者中，AZD0780在基于瑞舒伐他汀治疗的基础上，显示出52%（95% CI：-57，-45）的LDL-C水平显著下降，与基线相比患者的LDL-C总体下降幅度达78%。此外，比较进食与空腹服药的初步数据表明AZD0780对进食具有灵活性。未报告严重不良事件，AZD0780显示良好的耐受性。 AZD0780是一种口服、潜在“first-in-class"的PCSK9小分子抑制剂，开发用于治疗无法通过他汀类药物控制的血脂异常患者。 PCSK9是一个经过临床验证用于降低LDL-C水平的靶点。PCSK9蛋白的作用是抑制低密度脂蛋白受体（LDLR）的回收和再利用。因此，降低PCSK9蛋白的水平可以让更多LDL受体回到肝细胞表面，与更多LDL结合，将它们从血液中清除。 目前，靶向PCSK9以降低胆固醇的开发管线主要可分为两个大方向。第一大类为口服小分子，以阿斯利康的AZD0780与默沙东（MSD）的MK-0616为代表。MK-0616是一种与PCSK9结合并抑制PCSK9与LDLR相互作用的大环分子，可通过每日片剂形式给药。在一项2b期临床试验中，高胆固醇血症患者随机接受4种不同剂量（6 mg-30 mg）的MK-0616或安慰剂的治疗。试验结果显示，在第8周，所有剂量的MK-0616与安慰剂相比，均显著降低患者的LDL-C。降低幅度为41.2%（6 mg）到60.9%（30 mg）。患者在服药两周后疗效就接近峰值，并且在为期8周的治疗中得到维持。目前，MK-0616已进入3期临床研究阶段。去年年底，默沙东在中国启动了MK-0616的两项国际多中心3期临床研究，针对适应症包括动脉粥样硬化、高胆固醇血症。值得一提的是，该疗法获选为猎药人网站（drughunter.com）2023年度十大“明星”小分子之一。 ▲MK-0616显著降低患者LDL-C（图片来源：参考资料[2]） 另一类PCSK9靶向疗法则是利用基因编辑方式来抑制PCSK9的表达，这类疗法有望做到一次给药，长期维持患者低胆固醇的目标。Verve Therapeutics所开发的在研单碱基编辑器VERVE-101便是其中一例。在2023年11月所公布VERVE-101的1期试验数据显示，接受高剂量治疗的一位受试者在半年内维持了55%的LDL-C降低，这也是人体内基因编辑的首次概念验证。VERVE-101预计将在2024年下半年公布更多数据，而同样靶向PCSK9但与VERVE-101设计不同的VERVE-102将在2024年上半年启动1期临床试验。 诺华（Novartis）所开发的PCSK9靶向siRNA疗法Leqvio（inclisiran）在单次注射后的基因沉默效果亦显示可维持长达半年。去年8月所公布的ORION-8临床3期试验长期数据显示，每年两次给药Leqvio加上他汀类药物治疗，可使ASCVD、ASCVD或杂合体家族性高胆固醇血症（HeFH）风险增加患者的LDL-C持续降低超过6年。此外，RNAi疗法初创公司圣因生物的主打产品SGB-3403也已在中国和澳大利亚进入临床试验阶段。SGB-3403是一种靶向肝细胞PCSK9的siRNA-GalNAc结合物，采用了圣因生物的新一代GalNAc偶联技术递送到肝脏细胞，通过RNAi抑制肝脏PCSK9蛋白的合成。 参考资料： [1] AZD0780, an oral PCSK9 inhibitor demonstrated significant LDL-C reduction on top of statin in Phase I trial. Retrieved May 29, 2024 from https://www.astrazeneca.com/media-centre/medical-releases/azd0780-an-oral-pcsk9-inhibitor-demonstrated-significant-ldl-c-reduction-on-top-of-statin-in-phase-i-trial.html [2] Ballantyne et al., (2023). Efficacy and safety of the oral PCSK9 inhibitor MK-0616: a phase 2b randomized controlled trial. Journal of the American College of Cardiology, DOI: 10.1016/j.jacc.2023.02.018 内容来源于网络，如有侵权，请联系删除。