Cangrelor tetrasodium

导致人类死亡最多的疾病是什么？ 提到这个问题，“癌症”也许是许多人脑海里想到的第一个答案。 事实上，癌症并非致死率最高的疾病，人类健康的“头号杀手”其实“另有其病”，那就是——心血管疾病。 过去20多年来，心脑血管疾病一直是全球疾病死亡的首要原因。根据WHO发布的《2019全球健康预测》报告，2019年，在全球5540万死亡病例中，其中，有近900万死于缺血性心脏病，与2000年相比，心脏病死亡人数增加了200多万。此外，中风患者死亡人数高达655万，包括缺血性心脏病和中风在内的心血管疾病成为全球疾病死亡的最主要原因。 目前，市场上也已研发出多款治疗药物，例如氯吡格雷、坎格雷洛、替格瑞洛等抗血小板药物，以及华法林、肝素等抗凝血药物。尽管已有众多治疗药物，但由于药物副作用以及不同个体对抗血小板药物的反应性不同，目前仍有患者对抗血小板药物存在抵抗，即治疗反应不足，其他替代药物又可能伴随着较高的出血风险。 药物抵抗问题摆在了科研、产业界的人士面前，如何为患者提供疗效更好、安全性更高的治疗药物成为当下的重点。上海柯君医药科技有限公司（以下简称“柯君医药”）便是一家致力于研发新一代抗血小板药物，以解决药物抵抗问题的创新药企。 柯君医药于2018年在上海创立，是一家聚焦于心脑血管和抗病毒领域治疗药物研发的初创企业，在研产品包括抗血小板、抗凝血、抗呼吸道病毒感染、抗乙肝药物等。成立至今，柯君医药自主构建了两大核心技术平台——靶向前药技术平台和核酸药物技术平台。依托团队优势和核心技术，公司在心脑血管和抗病毒领域布局了多条创新管线。值得一提的是，公司自主研发的抗血小板药物CG-0255已完成1期临床试验，目前正在推进关键注册临床研究，未来有望通过快速审评流程实现上市。 在短短5年时间里，柯君医药完成了团队组建、平台搭建、管线推进等重要事项，并且核心管线即将进入注册临床试验阶段，不日将迈入产品化阶段。公司快速且顺利的发展过程离不开一位核心人物的执掌——柯君医药创始人兼首席执行官何公欣博士。 何博士是一位深耕生物医药行业30年的科学家兼创业者。正式进入医药领域前，何博士在日本九州大学获得了合成化学博士学位，并在美国加州大学完成了博士后研究。1992年，何博士进入美国吉利德科学公司，先后担任吉利德美国总部科学家和研发高级总监等职位。 在吉利德任职期间，何博士曾参与并主导了多个国际best-in-class新药的研发工作，值得关注的是，他还是目前世界广泛使用的抗乙肝病毒药物替诺福韦新一代前药替诺福韦艾拉酚胺 (TAF) 的主要发明人和研发项目负责人。此外，何博士也是多个抗病毒疗法的共同发明人，在心脑血管、核酸药物和多种抗病毒治疗领域具有丰富研发经验。 2008年，何博士回国出任吉利德中国区首席代表及首任总经理，负责吉利德在国内搭建区域分部工作。在此期间，何博士从一位药物研发者逐渐成为一位负责生产运营、供应链管理以及企业发展的管理者。 2018年，何博士担任吉利德中国区负责人已整整10年，工作期间，对国内整体医药运行体系建立了深刻理解并积累了广泛资源。也正是在这个时候，“参与到中国生物医药领域的发展中，促进国内医药健康行业发展”的想法再次在何博士心里涌现。 “创办一家公司，将科学理论真正转化实际成果，为患者带来更好原研新药”怀着这样的愿景，2018年，何博士选择离开工作了26年的吉利德，在国内创立了柯君医药，并将研发重点聚焦在致死率最高的心血管疾病和抗病毒领域。 而后，何博士快速组建了一个具有相同价值理念、高度凝聚力以及专业实力的团队，团队成员超半数为何博士在吉利德的前同事们，其中包括首席运营官陈佳琳以及财务副总裁姚莉，他们共同见证了吉利德从一个小型公司发展成为一个跨国药企的过程，并且拥有低调务实的特性和专业认真的执行能力。 除此之外，公司的科学家团队也“众星云集”，包含多位药物研发领域的资深科学家。其中，化学研发副总裁陈小五博士拥有超25年的创新药研发经验，在吉利德参与了流感口服药达菲（奥司他韦）的后期研发，并在多个后来成为“重磅炸弹产品”的艾滋病和丙肝药物研发过程中做出了重要贡献． 同时，柯君医药还吸引了病毒学领域资深科学家聂玉春博士担任生物研发副总裁。聂博士深耕核酸药物抗病毒领域10余年，此前曾任罗氏研发中心和斯隆-凯特琳癌症中心担任高级研发职位。此外，医学方面的资深科学家严桦女士担任公司临床项目管理高级总监，她拥有近40年药物研发管理经验，曾先后在上海徐汇区中心医院、中美上海施贵宝、上海新生源医药负责临床、注册申报、药理毒理及新药研发管理等工作。 至此，柯君医药打造了一个在药物研发领域平均具有15年以上经验的专业化团队，核心成员的专业知识和经验覆盖新药研发的整个流程，为公司的运营发展和在研管线推进提供了充足动力。 基于核心团队的丰富经验和对临床需求的综合判断，柯君医药决定布局心脑血管疾病领域和抗病毒领域，并根据市场需求，重点研发新一代抗血小板药物以及广谱呼吸道抗病毒药物。明确发展规划和研发领域后，柯君医药迅速搭建了两大核心技术平台——靶向前药技术平台和核酸药物技术平台。 其中，靶向前药技术平台率先在2020年完成建构。简单而言，“前药”是一种需要经过体内的酶或非酶转化才能释放出活性药物、从而发挥药效的治疗药物。 值得关注的一点是，吉利德拥有成熟的前药技术，而何博士在吉利德工作期间就曾主导过替诺福韦前药TAF的研究。在何博士的带领以及团队的努力下，柯君医药在2年内搭建起了一个专有的靶向前药技术平台。 “靶向”是该平台的突出优势之一，它能够修饰改善药物的理化特性、递送转运效率、酶选择性、化合物稳定性等成药特性，从而实现针对不同疾病器官的靶向递送，即将有效成分更加高效地递送到特定治疗位置，从而在最小安全剂量下达到最佳药效。此外，该平台能够基于已验证活性物质靶点快速形成具有重大药代/药效或安全性改进的新型靶向前药，高效产生具有临床开发价值且成药性明确的候选化合物。 而核酸药物技术平台则由聂博士主导开发。该平台具备小核酸药物和信使RNA药物的序列设计和修饰标记能力，以及多元化先进的药物递送技术，能够针对肝靶向和肝外器官选择性使用药物递送平台，开发针对全身给药或局部给药等不同机制的临床候选产品。 在核心技术平台和团队两大“引擎”推动下，柯君医药目前在心脑血管和抗病毒领域共布局了4条在研管线。 其中，核心管线抗血小板药物CG-0255进展最快。CG-0255是新一代P2Y12类抗血小板药物，被开发用于心脑血管疾病的抗板治疗。 值得注意的是，CG-0255采用的是水解前药设计，基于深厚的前药技术功底做出了科学上的突破，设计出世界第一款硫醇前药，通过羧酸酯酶转化生成有抗血小板作用的活性代谢产物H4，完全绕过了抗板药物普遍依赖的氧化代谢途径。因此，它在体内可通过水解酶的作用快速产生活性代谢物，且由于水解酶的广泛分布几乎不存在个体代谢差异。另外，CG-0255也是世界上目前第一个既可以口服，也可以注射的P2Y12抑制剂，填补了国内注射针剂的空白。 氯吡格雷是目前最为常用的抗血小板药物之一，它是一种无活性前体药物，主要依赖细胞色素P450酶系统（CYP）中的酶，其中最主要的是CYP2C19，才能够被激活，从而转化为有抗血小板作用的活性代谢产物H4，进而发挥治疗作用。 但是，世界上很大一部分人口携带的是CYP2C19功能丧失的等位基因，这意味着，氯吡格雷在该类人群中代谢缺失或者代谢极其缓慢，继而导致服药后所产生的抗血小板作用弱，发生“氯吡格雷抵抗”。正因如此，FDA在批准的说明书上对氯吡格雷添加了黑框警告。 现有研究显示，CYP2C19等位基因功能丧失在所有族裔的患者中都十分常见。25%-30%的白人人群存在CYP2C19功能缺失等位基因，而这个比例在东亚人群中更是高达59%1。并且多项临床研究表明，氯吡格雷的疗效确实在这些患者中存在降低或丧失。这也意味着，“氯吡格雷抵抗”问题在国内心脑血管患者身上更加明显。另外，氯吡格雷仅可口服给药，无法静脉注射，起效时间约为2～8小时，限制了其在紧急状况下的临床应用。 与氯吡格雷不同的是，CG-0255可以完全绕过与其相关的CYP代谢问题。并且在靶向前药技术的支持下，CG-0255给药更加精准，能够以最小剂量达到更大效果。此外，CG-0255生物利用度高、起效快，可通过静脉注射和口服给药，有望作为氯吡格雷的替代药，全面解决患者潜在的药物抵抗问题，同时扩大了临床应用场景。 此前，陈小五博士在2023年度美国心脏协会（2023 AHA）年会的特色科学专场发表了CG-0255的1期临床研究结果。这是一项开放标签、阳性对照、剂量递增、1期临床试验，5个队列（每组6名参与者）通过推注或输注不同剂量的方式给予CG-0255，以坎格雷洛为阳性对照组，旨在评估健康受试者经静脉注射CG-0255的安全性、耐受性、药效学和药代动力学。 研究结果显示，CG-0255具备良好的安全性和耐受性，可快速、稳定转化为活性代谢产物H4，并且血小板聚集抑制效果呈明确剂量依赖关系且作用迅速，给药20分钟内血小板聚集抑制率超过90%。此外，CG-0255不可逆地结合P2Y12受体，抗血小板作用持久，给药24小时后IPA仍在持续。重要的是，CG-0255 的血小板聚集抑制作用无显著个体差异。 作为一家核心团队皆从吉利德走出的初创企业，柯君医药同样布局了抗病毒领域，但并非模仿复刻吉利德，而是在形成核心技术的基础上，希望像吉利德研发出治疗丙肝的“神药”索磷布韦一样，在抗病毒领域有所建树。因此，柯君医药专注于广谱呼吸道和乙肝抗病毒药物领域的研发。 其中，RNA聚合酶抑制剂CG-0980是公司针对广谱呼吸道RNA病毒感染适应症研发，它是一款具有广谱抗病毒活性的小分子直接抗病毒药物，与仅针对某一特定感染源的药物不同的是，它对于多种常见呼吸道RNA病毒，如呼吸道合胞病毒（RSV）、偏肺病毒（hMPV）、副流感病毒、普通冠状病毒、鼻病毒等均有明确的抗病毒活性，适用于大部分人群对于呼吸道病毒感染的治疗及密接暴露后预防的临床潜在需求。 其临床前研究显示，CG-0980具有良好的安全性特征，有潜力覆盖最广泛的患者群体，填补广谱呼吸道抗病毒药物这一空白市场。目前，CG-0980正处于临床前研究阶段，预计将在今年年底申请IND。 在柯君医药公布CG-0255的1期临床试验的积极数据后不久，在今年年初，公司再次宣布，顺利完成亿元B轮融资。本轮融资由泰珑投资旗下泰鲲基金领投，其他主要投资方包括骊宸投资、泰煜投资等，原有投资方宏海创健、汉康资本等也持续加持。 新的资金加持也进一步支持了持续推进中的CG-0255关键注册临床研究，同时推动其他核心在研管线加速向临床阶段推进。 快速推进CG-0255的临床开发和商业化进程成为柯君医药短期内的重要目标。“今年将快速完成CG-0255的关键注册临床研究工作，后续有望通过快速审评流程实现上市，届时，也期待能够为国内外患者提供更好的治疗选择。”陈小五博士说道。 “柯君医药希望探索中国生物医药发展的新模式”怀着这个伟大愿景，陈小五博士表示，尽管目前柯君医药是一家小型初创公司，但在未来，柯君医药将继续研发针对心脑血管疾病的联合疗法，同时，推进抗病毒领域管线的进一步研发，并实现候选产品的商业化，为患者提供更多有效的治疗药物，为社会创造广泛的价值，这也是柯君团队大多数科学家踏入生物医药行业的初心。 * 参考资料：1. Ellithi M, Baye J, Wilke RA. CYP2C19 genotype-guided antiplatelet therapy: promises and pitfalls. Pharmacogenomics. 2020 Aug;21(12):889-897. doi: 10.2217/pgs-2020-0046. Epub 2020 Jul 29. PMID: 32723143; PMCID: PMC7444625. 内容来源于网络，如有侵权，请联系删除。

On March 18th, Cell published online a research paper about a new mechanism involving the gut in regulating cholesterol metabolism. The researchers discovered a gut-derived hormone called Cholesin, which is triggered by cholesterol intake and produced within intestinal cells. Cholesin achieves inhibition of the PKA-ERK1/2 signaling pathway in the liver by binding to the GPR146 receptor there, thereby downregulating the cholesterol synthesis process regulated by SREBP2. This means that when the gut absorbs cholesterol, the Cholesin-GPR146 axis acts to suppress cholesterol production in the liver, helping to maintain stable blood cholesterol levels and combat hypercholesterolemia and atherosclerosis.  DOI: 10.1016/j.cell.2024.02.024To investigate the interaction between intestinal cholesterol absorption and hepatic cholesterol synthesis, the researchers designed experiments to induce mice to consume diets with varying cholesterol content (regular diet and high-cholesterol Western diet) and observed changes in cholesterol levels in the intestine and liver. Under a high-cholesterol diet, intestinal cholesterol content increased, accompanied by downregulated expression of the cholesterol biosynthesis marker HMGCR in the intestine, suggesting a negative feedback mechanism where absorbed cholesterol can influence its own synthesis. Against this backdrop, the researchers identified a new gut-derived hormone induced by cholesterol – Cholesin. Cholesin is triggered by cholesterol absorption mediated by NPC1L1, with its gene encoded in humans as C7orf50 and in mice as 3110082I17Rik. After secretion by intestinal cells, Cholesin binds to a specific orphan GPCR member, GPR146, and suppresses the PKA-ERK1/2 signaling pathway, reducing the hepatic cholesterol synthesis activity regulated by SREBP2. To further confirm the relationship between Cholesin and its receptor GPR146, researchers employed a variety of experimental approaches, including but not limited to binding assays on frozen tissue sections, genome-wide CRISPR-Cas9 screenings, and immunohistochemistry techniques. Ultimately, it was established that GPR146 is an effective receptor for Cholesin, and the interaction between Cholesin and GPR146 directly influences the regulation of cholesterol metabolism. Through CRISPR screenings, protein expression purification, and a range of experimental validations, Cholesin's mechanism of action was elucidated, and it was demonstrated that both the sole use of Cholesin and its combination with statin drugs significantly reduce total plasma cholesterol levels and alleviate atherosclerotic lesions. Moreover, Cholesin can also decrease body weight gain, lower triglyceride levels, and improve hepatic lipid accumulation and inflammation markers. About AtherosclerosisAtherosclerosis is a chronic inflammatory disease, primarily characterized by the accumulation of substantial amounts of cholesterol and other lipid substances on the vessel walls, forming plaques. These plaques gradually enlarge and can lead to the narrowing of the arterial lumen, impeding blood flow. Additionally, these plaques may become unstable and rupture, causing thrombosis, which in turn can trigger serious events such as myocardial infarction or stroke. Cholesterol is an essential lipid for the human body, involved in the construction of cell membranes, hormone synthesis, and various other physiological functions. However, when cholesterol levels in the blood are too high, especially when low-density lipoprotein cholesterol (LDL-C) concentrations are excessive, the risk for cardiovascular diseases increases, with the most notable being the onset and progression of atherosclerosis. Studies have shown that an excess of cholesterol, particularly oxidized LDL cholesterol, penetrating beneath endothelial cells, can trigger an inflammatory response through a complex series of biochemical processes. This stimulates smooth muscle cell migration and proliferation, causes macrophages to engulf lipids and become foam cells, forming what are called fatty streaks, which then evolve into mature atherosclerotic plaques. In addition to the abnormal accumulation of lipids, the state of imbalance between immune responses and their clearance is also believed to be primarily shaped by the migration and homeostasis of leukocytes, which are regulated by chemokines and their receptors. In recent years, new pro-inflammatory and anti-inflammatory pathways that link lipid biology with inflammation have been discovered, and gene expression profiling studies have revealed various factors involved in human coronary artery disease. Cardiovascular diseases are the leading cause of death globally, with an estimated 17.8 million people dying each year. Inflammation is considered to be one of the main driving forces in the development of atherosclerosis and is recognized as one of the major etiologies of cardiovascular disease. Despite the increasing body of research evidence over the past three decades showing that immune components play an indispensable role in the formation and chronicity of atherosclerosis, through a series of immunotherapeutic targets, the benefits and challenges brought about by targeting inflammation and the immune system in cardiovascular diseases have been demonstrated. DOI: 10.1038/s41569-021-00668-4DOI: 10.1038/nm.2538Using the diagram above as an example, chemokines and their receptors also play an important role in the pathogenesis of atherosclerosis. The process of leukocyte recruitment includes rolling, firm adhesion, lateral migration, and transendothelial migration, which are finely regulated by chemokines. On the one hand, soluble chemokines directly mediate the recruitment of leukocytes; on the other hand, chemokines immobilized by glycosaminoglycans (GAGs) on the surface of activated endothelial cells can trigger the docking of leukocytes through GPCRs and activate leukocyte integrins, thus achieving firm adhesion. The cell-specific and lesion stage-specific utilization of chemokines and their receptors underscores the robustness and complexity of the chemokine system, ensuring the formation of specific chemokine combinations at each stage of the lesion that attract specific subtypes of leukocytes. Synergistic effects among chemokines in the recruitment of leukocytes can lead to cooperative interactions, potentially mediating the process between leukocytes and atherosclerotic lesions. According to statistics from the Synapse database, as of now, there are more than 500 therapeutic drug pipelines globally, originating from over 400 institutions, encompassing over 200 targets, and involving 4095 clinical trials. The therapeutic drugs for this disease have a diverse range of Mechanisms of Action (MOA). At present, the primary therapeutic drugs for the treatment of atherosclerosis include statins, which function primarily by inhibiting the key enzyme in cholesterol biosynthesis—hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. Examples include Lovastatin (Merck, approved in 1987), Fluvastatin (Novartis, approved in 1993), Atorvastatin (Pfizer, approved in 1996), Rosuvastatin (AstraZeneca, approved in 2002). P2Y12 receptor antagonists are another class of therapeutic drugs for atherosclerosis, acting by selectively blocking the function of the P2Y12 receptor to inhibit excessive activation and aggregation of platelets. This is crucial because platelets play a key role in the development of atherosclerosis and thrombosis, especially in the progression of cardiovascular diseases. Common drugs in this category include Clopidogrel (Sanofi, approved in 1997), Ticagrelor (AstraZeneca, approved in 2010), Cangrelor (CHIESI, approved in 2015). Additionally, in recent years, PCSK9 has emerged as a therapeutic candidate for the treatment of hypercholesterolemia and atherosclerosis-related diseases. The primary function of PCSK9 is to regulate the number of low-density lipoprotein cholesterol (LDL-C) receptors on the membrane of liver cells. When PCSK9 binds to LDL receptors, it leads to their degradation within lysosomes, thereby reducing the uptake and clearance of circulating LDL-C by the liver, resulting in elevated levels of LDL-C in the blood. Therapeutic drugs related to this mechanism include Evolocumab (Amgen, approved in 2015), Alirocumab (Sanofi, approved in 2015), Inclisiran (Novartis, approved in 2020). Factor Xa inhibitors are a class of drugs that specifically inhibit the activity of coagulation factor Xa (FXa). FXa plays a crucial role in the blood coagulation process, as it acts as a key enzyme in the coagulation cascade, facilitating the conversion of prothrombin to thrombin, which in turn catalyzes the transformation of fibrinogen into fibrin, leading to the formation of a stable clot. By binding to FXa and preventing its activity, Factor Xa inhibitors can effectively suppress the formation of thrombi and are widely used in clinical practice to prevent and treat various thrombotic diseases, such as deep vein thrombosis, pulmonary embolism, and stroke prevention in patients with atrial fibrillation. Therapeutic candidates in this category include Rivaroxaban (Bayer, approved in 2008), Edoxaban Tosylate (Daiichi Sankyo, approved in 2012), Apixaban (Bristol-Myers Squibb, approved in 2011). Additionally, SGLT2 inhibitors were initially developed for the treatment of type 2 diabetes by inhibiting the SGLT2 transporter protein in the renal proximal convoluted tubules, reducing the reabsorption of glucose and thereby promoting the excretion of glucose in the urine, leading to decreased blood glucose levels. In recent years, multiple large-scale clinical trials have revealed the significant therapeutic effect of SGLT2 inhibitors in reducing the risk of cardiovascular events, especially in patients with type 2 diabetes who have atherosclerotic cardiovascular diseases. Therapeutic candidates related to this include Tofogliflozin (Kowa, approved in 2014) and Ertugliflozin (Pfizer, approved in 2017). Besides the classical P2Y12 receptor, potential therapeutic targets within the GPCR family include AT1R, PAR-1R, CXCR4, CCR2, NIACR1, TBXA2R, PGI2R, ADRA1, and EP3. However, the progress in the drug pipeline related to these targets is not promising. Only Vorapaxar, a tricyclic compound derived from camptothecin that acts as a selective inhibitor on thrombin-activated receptor (PAR-1), has been approved for reducing the incidence of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral artery disease (PAD). The first antibody drug candidate developed targeting an immunomodulatory factor associated with GPCRs for treating atherosclerosis is the humanized monoclonal antibody Plozalizumab, an antagonistic monoclonal antibody targeting CCR2 developed by Takeda Pharmaceutical in Japan. CCR2 plays a critical role in the migration of monocytes and macrophages to sites of inflammation. The recruitment of macrophages to the arterial wall is considered a key step in the development of atherosclerosis. The first nanobody drug candidate is BI-655088, targeting the CX3CR1 receptor.