LDLRAP1

Hypercholesterolemia refers to a condition in which the cholesterol level in the blood is abnormally elevated. Cholesterol is a type of lipid substance that plays an important role in the human body, including the construction of cell membranes, hormone synthesis, and the production of bile acids, etc. When cholesterol levels in the blood persistently increase, it may increase the risk of cardiovascular diseases such as coronary heart disease, stroke, and atherosclerosis. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of hypercholesterolemia. Since cholesterol is not soluble in water, it is transported in blood plasma through lipoprotein particles. Lipoproteins are classified by density into: Very Low-Density Lipoproteins (VLDL), Low-Density Lipoproteins (LDL), Intermediate-Density Lipoproteins (IDL), and High-Density Lipoproteins (HDL). All lipoproteins carry cholesterol, higher levels of High-Density Lipoprotein cholesterol have a protective effect, whereas an increase in Low-Density Lipoprotein cholesterol is associated with an increased risk of atherosclerosis and coronary heart disease. High levels of Low-Density Lipoprotein Cholesterol (LDL-C) have become one of the major risk factors for mortality and morbidity worldwide. Under normal circumstances, low density lipoprotein receptors (LDLR) located on the surface of hepatic cells combine with APOB/LDL-C to form a complex, and through the interaction of LDLR and LDLRAP1, the complex is internalized into the cell. When the complex dissociates within the cell, LDLR are typically recycled to the cytoplasmic membrane, while free cholesterol is consumed within the cell. PCSK9 mediates the activity inhibition of LDLR through interactivity on the cell surface. In hereditary hypercholesterolemia, single mutations in LDLR, APOB, PCSK9, and LDLRAP1 can lead to varying phenotypes ranging from mild to severe.  Mutations in LDLR can disrupt the binding of LDL-C to LDLR, resulting in the accumulation of LDL-C in the bloodstream. Mutations in the APOB gene can cause protein dysfunction, limiting the binding of LDL-C with LDLR.  Mutations in the PCSK9 gene can cause: (1) increased PCSK9 activity, (2) lack of LDLR recycling, (3) accumulation of LDL-C levels in the plasma. In such cases, anti-PCSK9 therapy, including emerging PCSK9 inhibitors (e.g., alirocumab, evolocumab), can be used to reduce LDL-C and prevent cardiovascular diseases. Current Status of Drug Research Related to HypercholesterolemiaAccording to the Synapse database, hypercholesterolemia and its related metabolic diseases are popular research indications for global pharmaceutical companies. There are a total of 338 drugs for hypercholesterolemia, coming from 310 institutions, covering 72 targets, and conducting 1884 clinical trials.  Under the indication of hypercholesterolemia, HMG-CoA reductase is the most common clinical target, with 7 drugs already approved for marketing, and 20 drugs in the non-research stage. The second is PCSK9 target, with 4 approved drugs, 13 drugs in the preclinical stage, and 21 drugs in the non-research stage. Using targeted PCSK9 drugs as examples, including the Tafolecimab from Innovent Biologics, Inclisiran from Novartis, Alirocumab from Sanofi and Regeneron, and Evolocumab from Amgen, have all been approved for marketing for diseases related to hypercholesterolemia or lipid disorders. Additionally, several drugs are in the stages of market application. Novartis Company's small interfering RNA drug: InclisiranOn August 22, Novartis's Inclisiran, a long-acting lipid-lowering small interfering RNA (siRNA) cholesterol-lowering drug, was approved by China's National Medical Products Administration for the treatment of adult primary hypercholesterolemia or mixed dyslipidemia.  Inclisiran is currently the first and only siRNA therapy in the world used to lower low-density lipoprotein cholesterol (LDL-C), where patients need only two injections per year to reduce LDL-C levels. Thanks to the long-lasting effects of the drug, patients do not need to take medication every day, earning Inclisiran the nickname of a "vaccine" in the cardiovascular field.  On August 28, Novartis's official website released the latest long-term data from ORION-8, which is the phase III open-label extension trial of the ORION-9, ORION-10, ORION-11, and ORION-3 trials. These data suggest that Leqvio (Inclisiran) can sustainably reduce low-density lipoprotein cholesterol (LDL-C) in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolaemia (HeFH) by administering twice a year, on top of statin therapy, and can last for more than six years. Merck's Oral PCSK9 Inhibitor: MK-0616On August 25, Merck announced on its official website the official launch of a Phase 3 clinical programme, CORALreef. This programme aims to investigate MK-0616, an oral PCSK9 inhibitor under investigation, for the treatment of Hypercholesterolemia in adults. Reportedly, this is the first Phase 3 clinical programme for an oral PCSK9 inhibitor.  Currently, the first batch of participants are taking part in two registration Phase 3 studies evaluating MK-0616's ability to reduce Low-Density Lipoprotein (LDL-C): CORALreef Lipids and CORALreef HeFH. Furthermore, Merck plans to launch a Phase 3 cardiovascular outcomes study -- CORALreef Outcomes, by the end of 2023.

‍最新资讯8月28日，信达生物制药集团 (信达生物) 官网发布公告称，抗PCSK9单克隆抗体信必乐®（托莱西单抗注射液）在获得国家药品监督管理局（NMPA）批准后，8月25日开始正式正式向全国各大医院和药房供药，并迅速在北京大学第一医院，复旦大学附属中山医院等医院开出了全国首批处方。 “PCSK9抑制剂作为一种新型降胆固醇药物，能强效降低LDL-C水平且安全性良好。托莱西单抗在多个注册III期研究中展现出强大的降脂疗效和良好的安全性，与国内已上市PCSK9单抗相比，具有更长的给药间隔。尽管目前临床上已有多种降脂药物，但中国患者血脂整体达标情况不佳，相信托莱西单抗的上市会提升PCSK9单抗在降脂治疗方面的可及性，为广大高胆固醇血症及混合型血脂异常患者提供优质的治疗选择。” 北京大学第一医院霍勇教授表示： 引此前8月中旬消息，信达生物的托莱西单抗注射液获得国家药品监督管理局（NMPA）批准，用于治疗原发性高胆固醇血症（包括杂合子型家族性和非家族性高胆固醇血症）和混合型血脂异常的成人患者。作为中国首个获批的本土自主研发PCSK9抑制剂，托莱西单抗注射液是信达生物布局心血管疾病领域的首款产品，也是信达生物成立12年来的第十款产品。 “与其他已获批的PCSK9单抗相比，托莱西单抗有更长给药间隔的优势，同时观察到脂蛋白a的明显下降。作为国内首个具有本土自主知识产权的PCSK9单抗，托莱西单抗的临床开发凝聚了国内多位心血管领域专家的心血，也证明了信达生物在心血管药物开发和临床开发领域的实力，以及监管机构对其疗效和安全性的认可。托莱西单抗的获批标志着信达生物在心血管及代谢（CVM）领域的前瞻布局开始进入收获期，信达生物将秉持着‘开发出老百姓用得起的高质量生物药’的使命，将为更广阔的慢病患者提供更多更优的治疗选择。” 信达生物制药集团临床开发副总裁钱镭博士表示： 高胆固醇血症高胆固醇血症(hypercholesterolemia)，是指血液中胆固醇水平异常升高的一种状况。胆固醇是一种脂质类物质，它在人体中扮演着重要的角色，包括细胞膜的构建、激素合成和胆汁酸的产生等。当血液中的胆固醇水平持续升高时，可能会增加心血管疾病（如冠心病、中风及动脉粥样硬化等）的风险。由于胆固醇不溶于水，它在血浆中通过脂蛋白颗粒运输。脂蛋白按密度分为：极低密度脂蛋白（VLDL）、低密度脂蛋白（LDL）、中密度脂蛋白（IDL）、和高密度脂蛋白（HDL）。所有脂蛋白都携带胆固醇，较高水平的高密度脂蛋白胆固醇具有保护作用，而低密度脂蛋白胆固醇水平升高与动脉粥样硬化和冠心病风险增加有关。根据此前文章推介，重磅解读：IQVIA 发布全球肥胖浪潮下心血管代谢创新药的复兴，IQVIA 发布的代谢性疾病相关市场调研，高水平低密度脂蛋白胆固醇 (LDL-C) 已经成为全球范围内死亡率和发病率的主要风险因素之一。在正常情况下，位于肝细胞表面的低密度脂蛋白受体(LDLR) 与 APOB/LDL-C 结合形成复合物，并通过 LDLR 与 LDLRAP1 的相互作用，复合物被内吞进入细胞。当复合物在细胞内解离时，LDLR 通常会回收到细胞质膜，游离胆固醇则会在细胞内消耗掉。PCSK9 通过细胞表面的相互作用介导 LDLR 的活性抑制。来源于，DOI: 10.3389/fgene.2020.572045在遗传性高胆固醇血症中，LDLR、APOB、PCSK9 和 LDLRAP1 的单个突变可导致从轻微到严重的多种表型。LDLR 突变会影响 LDL-C 与 LDLR 的结合，导致 LDL-C 在血液循环中蓄积。APOB 基因突变会导致蛋白质功能障碍，使 LDL-C 与 LDLR 的结合受到限制。PCSK9 基因突变可导致：(1) PCSK9 活性增加；(2) 没有 LDLR 循环；(3) 血浆中 LDL-C 水平累积。在这种情况下，抗 PCSK9 疗法，包括新出现的 PCSK9 抑制剂（如 alirocumab、evolocumab），可用于降低 LDL-C，预防心血管疾病。高胆固醇血症相关药研现状根据 智慧芽新药情报中心 统计，高胆固醇血症及其相关的代谢性疾病是全球药企的热门研究适应症，共有337个高胆固醇血症药物，来自311个机构，覆盖71个靶点，开展1872个临床试验。在适应症高胆固醇血症下，HMG-CoA reductase 是最常见的临床靶点，有7个药物已经获得批准上市，还有20个药物处于非在研阶段。其次是PCSK9靶点，有4个药物获得批准上市，13个药物处于临床前阶段，21个药物处于非在研阶段。以靶向 PCSK9 的药物为例，包括开篇提到的信达生物的托莱西单抗 (Tafolecimab)、Novartis的英克司兰钠 (Inclisiran)、Sanofi 和 Regeneron 的阿利西尤单抗 (Alirocumab) 以及安进公司的依洛尤单抗 (Evolocumab) 均已获批上市用于高胆固醇血症或血脂障碍等相关疾病。另有多款药物处于申请上市阶段。在GPCR 类靶点方面，热门靶点包括NIACR1、AT1R、HCAR3、LTRs、PGD2R、GPR120等，成为治疗高胆固醇血症的临床治疗靶点。其中，NIACR1 激动剂 Acipimox、H1/H3 受体双重拮抗剂 Betahistine、HCAR3/NIACR1 双重激动剂 Niacin 均已获批上市用于治疗高胆固醇血症、动脉粥样硬化、脂质代谢紊乱等相关疾病。诺华公司的小干扰核酸药物: Inclisiran8月22日，诺华公司 (Novartis）的英克司兰钠宣布其长效降脂小干扰核酸（siRNA）降胆固醇药物英克司兰钠（Inclisiran）注射液获得中国国家药监局批准，用于成人原发性高胆固醇血症或混合性血脂异常患者的治疗。据悉，Inclisiran是目前全球首款也是唯一一款用于降低低密度脂蛋白胆固醇（LDL-C）的siRNA疗法，患者每年进行两次注射即可降低LDL-C。由于这款药物的长效性，患者无需每天服药，因此inclisiran也被称为心血管领域的“疫苗”。8月28日，诺华官网再次重磅公布 ORION-8 的最新长期数据，ORION-8 是 ORION-9、ORION-10、ORION-11 和 ORION-3 试验的 III 期开放标签扩展试验。这些数据表明，Leqvio (Inclisiran) 在他汀类药物治疗的基础上，通过每年两次给药，可在动脉粥样硬化性心血管疾病 (ASCVD) 或杂合性家族性高胆固醇血症 (HeFH)1 患者中持续降低低密度脂蛋白胆固醇 (LDL-C)，并可持续六年以上。Merck 公司的口服PCSK9 抑制剂: MK-06168月25日，默克公司 (Merck) 官网发布公告称，正式启动公司的一项3期临床项目CORALreef。该项目旨在研究MK-0616，一款正在研究的口服 PCSK9 抑制剂，用于治疗成人高胆固醇血症。据悉，这是首个口服 PCSK9 抑制剂的 3 期临床项目。目前，首批参与者正在参加两项评估 MK-0616 降低低密度脂蛋白（LDL-C) 的注册 3 期研究：CORALreef Lipids 和 CORALreef HeFH。默克还计划在2023年底前启动一项3期心血管结果研究--CORALreef Outcomes。下图为 www.clinicaltrials.gov 上关于 MK-0616 的临床研究情况: 以上文章来源于GPCR drug diacovery，作者段思研‍       本文仅作信息交流之目的，文中观点不代表相关疾病治疗立场，也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。