Luspatercept-AAMT

//   激活素II受体通过对肌肉代谢这个调控回路的机理研究，揭示了对其干预所引起的下游生物效应，发展成了一个热门新药靶点。无论是礼来制药的比马格鲁单抗，还是来凯医药的“激活素管线组合拳”，我们都期待在这个领域能够诞生下一个重磅大药，造福全球的肥胖症患者。 迷失在翻译中 肥胖症一词的英文是“obesity”，来自拉丁词语 “obesitas”，意思是“脂肪”或“肥胖”，所以中文翻译成“肥胖症”准确明了，是没问题的。但是，“肥胖（fat）”一词在中西文化中一般都是贬义的，甚至还带有一定的侮辱性，所以在英文语境中，大家都选择了更为中性的“超重（overweight）”来形容肥胖症患者。对肥胖症患者的治疗也就顺理成章地被称为“减重（weight loss）”。虽然这样的说法顾及到了患者的感受，但却不符合“信、达、雅”的翻译原则，因为它并不准确。 在中文的语境里，本来应该被准确地翻译成“减重”的“weight loss”，却又被阴差阳错地翻译成了“减肥”（对应的英文词应该是“fat loss”），也是不符合“信、达、雅”翻译原则的。但是这样一来，“减肥”对于肥胖症患者的治疗却又是非常准确的，因为肥胖症患者所面临的问题正是脂肪过量，而不是肌肉过量，这两者之间并没有必然的联系。 如果“减重”不当，减掉了脂肪的同时也减掉了不该被减掉的肌肉，对健康生活的影响其实是相当负面的；只有减掉了脂肪，才能有效降低包括2型糖尿病在内的多种健康风险，同时必须增强肌肉才能保证生活质量。 肥胖到底是不是病？ 虽然这在学术界早有定论，但是老百姓的心里，多少还是有些疑问的。 在中国改革开放之前，肥胖症就像2型糖尿病一样，绝大多数人没有听说过。只有那些关注发达国家新闻轶事的人才有可能读到只言片语，多半也会认为那是西方人吃饱了撑的。改革开放40多年之后，中国人的饮食结构已经有了巨大的变化。中国疾病预防控制中心的最新数据显示，2018年中国成年人肥胖率估计超过8.1%（8500万中国成年人），是2004年的3倍。【1】 在一篇2023年发表的题为“中国肥胖及相关并发症的患病率：一项针对 1580 万成年人的横断面真实世界研究”的研究论文中，中国学者得出的结论是：“超重/肥胖及相关并发症在该人群中非常普遍。”具体说来，根据中国体重指数（ Body Mass Index，缩写BMI）分类，在受试的成年人中，超重的占比为34.8%，肥胖的占比为14.1% 。【2】换一种更直观的说法：在每6个成年人中，大概会有2名超重者和1名肥胖症患者。 图1  BMI与几种疾病发病率的相关性 以高血压为例（见图1，红色曲线），体重超重（BMI在25~29.9）人群的高血压发病率在10年里是正常体重人群的2倍，而肥胖症患者更是高达2.5~3倍！当然2型糖尿病就更不用说了。还有许多看似并不相关的疾病，比如胆结石，肥胖症患者的风险是正常人群的3倍多；另外，癌症（图1显示肠癌）和心血管的发病率也都有所上升。 很显然，肥胖症患者所消耗的医疗资源是远超正常人群的，而我们需要思考的问题则是如何更有效地分配有限的医疗资源：是把肥胖定义成“病”，然后花钱治疗肥胖症呢，还是不把肥胖定义成“病”，然后花钱治疗肥胖所带来的其它各种疾病？ 根据大数据的分析结果，目前医疗的提供方（医院、药企等）和医疗的支付方（保险公司、个人等）都认为，把肥胖定义成“病”，花钱治疗肥胖症，对于有效利用医疗资源是更合理的选择。 脂肪与肌肉 你也许会问，既然脂肪过量对于健康有诸多不良影响，为啥现代人这么容易长胖？为啥人类在长期的进化过程中没有淘汰那些容易长胖的基因？这就要从人类在这颗星球上的生存环境说起了。 从古猿直立行走开始，人类在地球上已经度过了20多万年。在这20多万年里，前95%的时间人类都是依靠狩猎和采摘过日子的。所以现代人类的基因依然保留着狩猎采摘时代的印记，不会有大的改变。 从获取食物的角度看，在整个狩猎采摘时代里，食物没有保障，进食没有规律，吃了上顿没下顿应该是常态。由此我们可以得出两个推论： 第一，提高储能效率的基因对生存是十分有利的——1克脂肪所能提供的能量大约是9卡路里，超过葡萄糖的2倍！在那样的生活环境中，容易长胖的人是有生存优势的；第二，能够提高狩猎和采摘能力的基因对生存也是十分有利的——如果想成功猎取食物，我们的祖先还必须有发达的肌肉。但肌肉是耗能的，为了有效地降低能耗，我们的身体会及时减少没有用的肌肉，把摄取的能量用于增强那些被反复使用的肌肉。 综上所述，基因决定了我们的身体一定会把多余的能量转化成脂肪储存起来，以防日后食物短缺带来的饥饿；与此同时，如果我们停止使用某些肌肉，它们很快就会发生萎缩。即使是年轻人，如果长期卧床不起，就算有吃有喝，仍会流失很多肌肉。这也是在食物匮乏的环境中长期进化的结果。 对于老年人来说，肌肉流失与骨质疏松一样是严重影响生活质量的退行性疾病，甚至威胁生命。肌肉流失会导致日常活动减少，由此将进一步加快骨质流失和肌体退化，跌倒和骨折的风险也将大大增加。在美国，老年人因为跌倒和骨折导致的住院人数比心脏病发作、中风和乳腺癌的总和还要多。【3】 激活素与抑制素调控的肌肉代谢 通过锻炼，我们可以提高增强肌肉，这是众所周知的。但是，我们必须考虑到很多老年人的具体情况，仅靠“锻炼”确实还不够。老年患者的一大特征就是同时患有几种不同的退行性疾病，其中有不少会限制运动和锻炼。比如，有一个很普遍的老年病是骨关节炎，而这些骨关节炎的患者的活动就受到了很大的限制；再比如心脏病的患者，同样也不能承受大运动量的锻炼，否则风险也会大大增加。 那么有没有可能通过药物来增强肌肉的？当然也是可以的，要不然奥运会也不必有药检了。类固醇和生长激素都可以促进肌肉的生长，那是另外一个话题。如何能更加安全有效地介入肌肉代谢的生物调控呢？在目前已知的相关信号回路里，激活素（Activin）与抑制素（Inhibin）调控回路是研究得比较深入的。【4】 1986 年，美国索尔克生物研究所（Salk Institute for Biological Studies）的 Wylie Vale 和 Roger Guillemin 首次从猪卵泡液中分离出了一种新的蛋白质。他们研究发现，该蛋白能够通过一种不依赖促性腺激素分泌的机制来诱导促卵泡激素 (FSH) 分泌。于是Roger Guillemin 的团队将这种新的蛋白质命名为“激活素”这一术语，以表示该蛋白与早些年发现的竞争性拮抗剂“抑制素”的作用相反。 研究结果显示，激活素的几种亚型——激活素A、激活素B和激活素AB具有生理相关性，也是迄今为止被研究最多的。最近有报告提出了其他变体的作用，例如激活素C在性腺或肝脏病理学中的作用以及激活素E（βE βE）在葡萄糖稳态中的作用 ，等等。 研究结果显示，激活素和抑制素都是通过激活素受体复合物的调控回路而起作用的，享有共同的机制；激活素受体复合物是这些配体的枢纽，激活下游的通路。因为它首先被用激活素来描述，由此得名。 激活素受体复合物是一种膜结合的异源二聚体，存在两种I型受体和两种II型受体，其中I型受体不能单独结合配体，只负责传递信号；而II型受体的细胞外域会与配体结合，随后激活 I 型受体。激活素II 型受体主要有A型（ActRIIA）和B型（ActRIIB），它们对激活素和抑制素有大致相同的亲和力，但在调控效应上的区别和协同作用尚在进一步研究中。 比利时蓝牛   图片来源|网络 肌肉生长抑制素是骨骼肌生长的主要调节剂之一，它是在哺乳动物的调控回路上研究最广泛的激活素受体信号激动剂。肌肉生长抑制素的敲除或拮抗都会在表型上使肌肉质量显著增加。目前已经发现，肌生长抑制素功能丧失性基因突变存在于多种动物，其中最著名的例子就是比利时蓝牛，肌肉异常发达（见上图）。这种抑制素功能丧失突变也发生于人类，与超常肌脂比的报道相吻合，同时没有明显的健康相关的并发症。 基于这些基础研究结果，激活素受体拮抗剂在畜牧业、体育和医学科学领域的应用潜力受到了广泛的关注和大量的资源投入。 激活素受体拮抗剂成药可期 2019年11月，生物医药公司Acceleron与新基公司（Celgene，后被BMS收购）联合开发的新药利布洛泽（Reblozyl）在美国获批上市，通用名为注射用罗特西普（luspatercept），用于治疗输血依赖性β地中海贫血症。 利布洛泽就是一种激活素II型受体的融合蛋白，通过与转化生长因子β超家族的配体结合，增加红细胞数量，促进红细胞前体的成熟。地中海贫血症虽然是一个罕见病，药物市场相对小众，但利布洛泽的成功上市证明了激活素介导的调控回路和激活素II型受体的可成药性（druggable）。 所谓融合蛋白（Fusion Proteins），就是通过连接由不同基因编码的 2 个或多个结构域而产生的新型蛋白质。融合蛋白的目的是结合基因的不同属性，以提高蛋白质治疗疾病的能力，并改善单个天然蛋白质所缺乏的特性。当两个蛋白质结构域发生融合时，一部分充当结合的受体，另一部分则可用于增加稳定性或新的靶向途径等功能。融合蛋白与单克隆抗体相似，因为它们具有单一的均质特异性，并且可以由人类或人源化成分组成，从而规避了免疫清除，可用于长期治疗。目前已经上市的融合蛋白药物被用于治疗癌症、免疫和炎症等疾病。 2024年3月，Acceleron（2021年被默沙东以115亿美元高价收购）另一款名为Winrevair（sotatercept）的融合蛋白药物获FDA批准上市，用于肺动脉高压的治疗。sotatercept也是一款激活素II型受体的融合蛋白。 利布洛泽和sotatercept这两个药物的区别是：用于治疗贫血症的利布洛泽是激活素IIB型受体（ActRIIB）的融合蛋白；而用于治疗肺动脉高压的Sotatercept则是激活素IIA型受体（ActRIIA）的融合蛋白，将ActRIIA的胞外域与抗体的Fc端融合在一起，可以阻断激活素与细胞膜上的ActRIIA受体结合，从而降低激活素介导的信号传导。 与罕见病地中海贫血症不同，肺动脉高血压是老年人中的常见病，而全球老龄化趋势推动了市场的发展。2023 年，肺动脉高压药物市场规模已经达到了77亿美元，预计到 2032 年市场规模将达到116亿美元，复合年增长率为 4.6%。 ActRIIA的拮抗剂已经成药了，现在ActRIIB的拮抗剂也成药了，而且很有可能将是一个重磅大药，那么对ActRIIA和ActRIIB都有拮抗作用的“双抗”呢？好像应该也能成药的。那么它的适应症又将是什么呢？ 2023年7月礼来公司官宣，将以高达约19亿美元的款项收购生物医药公司Versanis Bio。这是一家专注于开发治疗心血管代谢疾病新药的生物制药公司，其唯一核心资产也是一个激活素II型受体拮抗剂的人源抗体，叫“比马格鲁单抗”（bimagrumab），正在进行II期临床试验。 与前文提到的两个已经上市的激活素II型受体拮抗剂不同，比马格鲁单抗是对ActRIIA和ActRIIB都有拮抗作用的双靶点抗体，它是一个具有增肌减脂潜力的候选药物。 比马格鲁单抗的前世今生 比马格鲁单抗最早“出生”在制药巨头诺华的旗下。 诺华的早期临床前动物药效学研究结果显示，如果分别使用特异性（只是对ActRIIA或者ActRIIB有中和作用，而没有交叉活性）的抗体拮抗激活素II受体两个亚型中的一个，并不能完全阻断信号的传递，只能将信号传导减弱；只有使用两个特异性的抗体，同时阻断激活素 II 型受体A和B，才能完全阻断调节信号的传递。虽然ActRIIA特异性抗体和ActRIIB特异性抗体在单独用药时也观察到了一定程度上的骨骼肌增强，但它们联合用药的效果超过了两种抗体分别使用的简单加和，展示了协同效应，与双靶点的比马格鲁单抗相类似。于是，诺华开发了双靶点的比马格鲁单抗并将它推进到了临床。 也许是出于谨慎，诺华首选的适应症是散发性包涵体肌炎（sporadic inclusion body myositis，简称sIBM）。这是一种老年人中很常见的炎症性肌肉疾病，在男性中比女性更常见。其特异性症状是近端肌肉（位于或靠近躯干）和远端肌肉（靠近手或脚）的慢性萎缩，导致手臂和腿部肌肉严重虚弱，对老年人的起居有严重影响。但是，该病的发病原因目前尚不明确，也没有发现该病的患者在激活素受体调控方面出现异常。 彼时，比马格鲁单抗虽然获得了FDA突破性疗法的认证，但是致病机理的相关性却是存疑的。果然，到了2016年4月，诺华突然宣布比马格鲁单抗治疗sIBM的临床IIb/III期研究失败，该药物没有达到主要临床终点，需要重新评估完整的数据集。业界有一些专家认为，这个临床试验的失败并不是对这个调节回路的否定，而是因为散发性包涵体肌炎并不是比马格鲁单抗所针对的适应症。 于是，诺华在2017至2019期间又进行了一项II期临床试验，在超重或肥胖的 2 型糖尿病受试者中研究比马格鲁单抗增肌减脂的疗效。这项随机分组对照的临床试验结果显示，超重或肥胖的 2 型糖尿病受试者在连续 48 周使用比马格鲁单抗后，体脂（Fat Mass）、肌肉（Lean Mass）和其它代谢相关指标都有改善，从概念上验证了对ActRII通路的抑制有可能成为一种治疗过度肥胖和伴随代谢紊乱的新方法。但诺华也许是认为它单独用药的疗效还不够显著，在公司重组和管线清理时，将它转让给了生物医药公司Versanis。 从诺华获得比马格鲁单抗授权之后，Versanis继续推进临床试验。在诺华临床数据的基础上，他们决定与司美格鲁肽联合用药，试图搭上GLP-1激动剂的顺风车，在超重或肥胖的 2 型糖尿病领域里后来居上。想到这一策略的显然不止Versanis一家，刚刚在双靶点的替尔泊肽（tirzepatide）上尝到了甜头的礼来，在这项临床试验的结果发表之前便果断下注，将Versanis收入囊中。 就这样，在经历了短暂的沉寂之后，比马格鲁单抗的开发又成了大家关注的热点。 螳螂捕蝉，黄雀在后 在增肌减脂这个赛道上，礼来的比马格鲁单抗一马当先，II期临床试验结果将在近期内揭晓，整个制药界都在期待。 比马格鲁单抗是对ActRIIA和ActRIIB都有拮抗作用的双靶点抗体，与ActII结合的解离常数KD大约400 pM，而结合ActIIB的解离常数KD大约2 pM。两个活性都很高，但是相差约200倍。【5】换句话（不严格地）说，当血液中该抗体的浓度达到400 pM时，受体亚型B的活性完全被抑制，但受体亚型A的活性还剩50%呢。 目前还没有进一步临床数据说明这两个受体亚型之间是如何协调工作，以及分别拮抗这两个受体亚型对疗效和不良反应的影响。要想找到这两个亚型之间最为理想的协同工作状态，光有一个双靶点抗体是做不到的，必须有高特异性的单靶点药物进行不同组合的优化研究。生物技术公司来凯医药（Laekna）的“组合拳”，就有可能“黄雀在后”，找到两个亚型之间更为理想的协同效应，为其后续药的开发拓展出足够的空间。 这个所谓的“组合拳”包括：LAE102，一种ActRIIA特异性的抗体；LAE103，一种针对ActRIIB的特异性抗体；LAE123，一种同时针对ActRIIA/IIB的双靶点抗体。通过它们之间的多种灵活组合，完全有可能获得干预这个调控回路更优的疗效与安全比，还有可能扩展到其他更多的疾病适应症，比如肌肉缺少适应症、癌症以及肺动脉高压等。 这个策略有点像打牌坐在下家，不管上家出什么牌，你最好都要跟得上，所以保证手里牌型的灵活性是非常重要的。在疗效方面，来凯医药的临床前研究结果显示，在肥胖（DIO）小鼠模型的三周试验中，LAE102作为单药有增肌减脂效果，当跟司美格鲁肽联用时，可以看到更多脂肪的减少以及肌肉保护作用，可能足以弥补司美格鲁肽导致肌肉流失的不足；而LAE102与LAE103联合用药合又要优于LAE102单药，但同时抑制两个靶点也可能会引起更多不良反应，因为ActRIIA-IIB双基因敲除的小鼠胚胎是无法存活的。 开发一款以增肌减脂为适应症的药物，在安全性方面的考量至关重要。只有尽可能地扩大药物的安全窗口，提高患者的依从性，才能最终获得商业成功。目前马格鲁单抗在II期临床中最常见的不良事件是腹泻和肌肉痉挛，这也让部分专家担心它和GLP-1胃肠道不良反应叠加有可能导致安全性风险上升。如果要想提高干预这个调节回路的安全窗口，“组合拳”显然也是有优势的，可以在不同的方向上进行优化，找到最佳组合，满足增肌减脂的临床需求。 以调节回路为平台的药物靶点研究 发现和验证可成药的新型靶点，一直是新药研发的瓶颈之一。 2005年，时任诺华生物医学研究所（Novartis Institutes for BioMedical Research）所长菲什曼（Mark Fishman）在《自然》杂志上，以“药物研发的新语法”为题撰文指出：“只有当靶点能够令人信服地与疾病相关时，它们才对药物发现有价值……验证通常也不是一步到位的过程，而是在流行病学和疾病生理学方面，以及动物模型的研究结果。”【6】 对此，他提出了以调节回路为平台的药物靶点研究，认为基于路径的临床分类法的一个优点是它为疾病描述提供了机制基础。当通路的多个元素受到影响时，这些测定的结果变得更容易解释。单个蛋白质的细微变化可能低于检测阈值，但可以通过包含多个通路成分的复杂计算方法进行放大。菲什曼根据这种“新语法”，以调节回路为导向对诺华生物医学研究所进行了重组，以期提高新型靶点发现和验证的成功率。 激活素II受体正是在这样的平台上，通过对肌肉代谢这个调控回路的机理研究，揭示了对其干预所引起的下游生物效应，发展成了一个热门新药靶点。无论是礼来制药的比马格鲁单抗，还是来凯医药的“激活素管线组合拳”，我们都期待在这个领域能够诞生下一个重磅大药，造福全球的肥胖症患者。 2024年8月于新泽西 参考文献（向下滑动查看） 【1】Jing Li, Qingyang Shi, Qingyang Gao, Xiong-Fei Pan, Li Zhao, Yazhou He, Haoming Tian, Zhiming Zhu, and Sheyu Li, “Obesity pandemic in China: epidemiology, burden, challenges, and opportunities”, Chinse Med. J., 2022, 135, 1328. 【2】Kang Chen, Zewei Shen, Weijun Gu, Zhaohui Lyu, Xuan Qi, Yiming Mu, Yi Ning, “Prevalence of obesity and associated complications in China: A cross-sectional, real-world study in 15.8 million adults”, Diabetes Obes Metab, 2023, 11, 3390. 【3】D. Hansen, C. Bazell, P. Pelizzari, B. Pyenson, “Medicare Cost of Osteoporotic Fractures, The clinical and cost burden of an important consequence of osteoporosis”Commissioned by the National Osteoporosis Foundation, 2019. 【4】Lodberg A. Principles of the activin receptor signaling pathway and its inhibition. Cytokine Growth Factor Rev. 2021 Aug;60:1-17. doi: 10.1016/j.cytogfr.2021.04.001. Epub 2021 Apr 20. PMID: 33933900. 【5】Lach-Trifilieff, E., Minetti, G. C., Sheppard, K., Ibebunjo, C., Feige, J. N., Hartmann, S., … Glass, D. J. (2014). An Antibody Blocking Activin Type II Receptors Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy. Molecular and Cellular Biology, 34(4), 606–618. 【6】Mark C. Fishman, Jeffery A. Porter, “A new grammar for drug discovery”, Nature, 2002, Vol 437, 491. 作者简介 贵柏曾在默沙东新药研究院工作多年，潜心钻研药物化学，颇有建树。几年前回国加入药明康德，从事业务开发、项目管理和驻美运营。梁博士是《新药的故事》一书的作者。他以长期的积累、独特的视角和生动的文字，通过《老梁说药》栏目讲述新药研发“背后的故事”，令人耳目一新，脑洞大开。梁贵柏博士目前是偕怡制药联合创始人兼首席科学家，欢迎读者通过邮箱gbliang55@hotmail.com与梁博士联系。 编辑 | 姚嘉 yao.jia@PharmaDJ.com  总第2189期 访问研发客网站，深度报道和每日新闻抢鲜看 www.PharmaDJ.com

As major multinational corporations (MNC) report their financial results for the second quarter of 2024, pharmaceutical industry leaders such as Astrazeneca, Roche, Sanofi, Johnson & Johnson and Novartis have announced their financial results for the first half of 2024 (H1). As of August 6, according to the operating income data of the first half of the year, the ranking of the top ten enterprises in the global pharmaceutical industry has been settled, and the specific ranking is as follows: Quarterly and Half-Yearly Revenue and Year-Over-Year Growth Rate Chart for the Second Quarter and Full Year 2024 Rank Company 2024 Q2 Revenue (Billion USD) YoY Growth 2024 H1 Revenue (Billion USD) YoY Growth 1 Johnson & Johnson 224.5 4.3% 438 3.3% 2 Roche 178.19 13.9% 337.19 5.0% 3 Merck 161.12 7.2% 318.87 8.0% 4 Pfizer 132 2.0% 281.62 -11.0% 5 AbbVie 144.62 4.3% 267.72 3.7% 6 AstraZeneca 129.38 13.3% 256.17 18.0% 7 Novartis 125.1 11.0% 243 11.0% 8 Bristol-Myers Squibb 122.01 9.0% 240.66 7.0% 9 Sanofi 117.22 10.2% 230.20 8.4% 10 GlaxoSmithKline 100.38 13.0% 194.12 12.0%   With the gradual fading of the novel coronavirus epidemic in 2023, the revenue pattern of the global large pharmaceutical companies has ushered in a new round of change. Entering 2024, the impact of the epidemic on business operations has significantly weakened, and pharmaceutical companies have gradually returned to the normal development track. From the performance point of view, in the first half of 2024, in addition to Pfizer, the revenue of the remaining nine pharmaceutical companies generally showed an increase.   Against this backdrop, Johnson & Johnson has solidified its position as the top global pharmaceutical and medical device company in terms of revenue. According to the financial data for the first half of 2024, Johnson & Johnson's overall revenue reached $43.83 billion, an increase of 3.3%. From the perspective of treatment segment segmentation, the tumor segment is particularly strong, and its revenue has surpassed the autoimmune diseases segment to become the largest revenue contribution of Johnson & Johnson. Specifically, revenue from the oncology segment reached $5.09 billion in the second quarter, up 15.7% year over year; In the autoimmune diseases segment, revenue in the same period was $4.722 billion, a growth rate of only 5%.   In terms of product lines, Darzalex in oncology, with its $5.57 billion in sales, successfully surpassed Stelara in autoimmune diseases ($5.536 billion in sales) to become the top-selling product in the first half of 2024. In addition, two new oncology drugs, BCMA CAR-T therapy Carvykti and dual antibody product Tecvayli, also showed strong growth momentum, with sales reaching $343 million and $268 million, respectively, with year-on-year growth rates of 81.5% and 70.2%.   In order to further strengthen its competitiveness in the field of oncology and immunization, Johnson & Johnson continues to increase investment in innovative drugs. In the first half of 2024, J&J completed a number of important acquisitions. Among them, the $2 billion acquisition of AmbrxBiopharma brought several ADC pipelines to the company; The $850 million acquisition of Proteologix and the $1.25 billion acquisition of a subsidiary of NumabTherapeutics further strengthen the company's portfolio of dual antibody products in the field of autoimmune diseases.   Roche showed solid growth in the first half of 2024, with total revenues of CHF 29.848 billion (US $33.719 billion), up 5% year-on-year. Among them, the pharmaceutical business, as the core driver, contributed 22.637 billion Swiss francs (about $25.573 billion) in revenue, and China revenue achieved double-digit growth to reach 1.609 billion Swiss francs (about $1.818 billion).   In pharmaceuticals, the oncology segment continued to play a leading role, contributing 9.619 billion Swiss francs ($10.867 billion), or 42.5% of total revenue, to Roche, which remained at 4% despite a slight slowdown in year-on-year growth. In contrast, the ophthalmology business showed strong growth with revenues of CHF 1.891 billion, up 54% year on year, and although it currently accounts for only 8.4% of total revenues, its potential cannot be ignored.   Specific to the product level, the ophthalmological double antibody Vabysmo (Pharisimumab) performance is particularly outstanding, the first half of the sales revenue of up to 1.794 billion Swiss francs (about 2.027 billion US dollars), an increase of 93%, almost doubled, successfully ranked among Roche's top 5 best-selling drugs. In addition, Ocrevus (Orizumab), Hemlibra (Emetzizumab), Evrysdi (Rispran), Phesgo (Trastuzumab + pertuzumab), Polivy (Vipostuzumab), Xolair (Omazumab), Alecensa (Aletinib) and other drugs also remained strong Growth trend.   On the other hand, Merck also achieved impressive results in the first half of 2024. The company's total revenue reached $31.887 billion, an increase of 8%, and pharmaceutical revenue reached $28.415 billion, an increase of 9%. Revenue in the second quarter was $16.1 billion, up 7 percent from a year earlier. This increase was mainly due to the excellent performance of K-drug (Pabolizumab) and HPV vaccine.   As a star product of Merck, K drug sales reached 14.217 billion US dollars in the first half of this year, achieving a double-digit high growth of 18%, and is expected to break through the 30 billion US dollars mark for the whole year. At the same time, HPV vaccines also maintained a stable sales performance, Gardasil/Gardasil 9 sales reached $4.727 billion, an increase of 7%.   In addition, the company's oncology products such as Welireg (HIF-2α inhibitor) and Reblozyl (Rottsip), as well as the anti-cytomegalovirus infection drug Prevymis (Lytamovir) and 15-valent pneumococcal vaccine Vaxneuvance, also achieved double-digit or higher growth.   However, it is worth noting that Merck's main revenue is still highly dependent on K drugs and HPV vaccines. Among them, K drug sales accounted for nearly half of the company's total revenue. Although K-drug is still in a period of rapid growth, its patent will expire in 2028, when it will face the risk of declining sales. At the same time, the HPV vaccine market is increasingly competitive, and Merck's HPV vaccine sector revenue is not indestructible.   As a result, MSD is actively pursuing a second growth curve. Since the beginning of this year, the company has continuously introduced new potential products and pipelines through acquisitions, including pneumonia conjugate vaccine, the new drug Sotatercept for pulmonary hypertension, a new generation of RSV neutralizing antibodies, TL1A antibodies, and neoantigen mRNA vaccines, with a view to achieving more diversified revenue sources in the future.   Among the world's top 10 multinational pharmaceutical companies, Pfizer has been the most affected by the COVID-19 pandemic. In 2023, due to the sharp decline in sales of new coronavirus vaccine Comirnaty and anti-new coronavirus drug Paxlovid, the company failed to continue the brilliant performance of over 100 billion dollars in 2022, not only lost the top position in the industry, but also withdrew from the top three ranks. Entering 2024, although the first half of the revenue decline is still as high as 11%, showing that the company has not completely rid of the negative impact of the fading of the new coronavirus dividend, but the second quarter performance has shown signs of recovery. Financial data show that in the first half of 2024, the company's total revenue was 28.162 billion US dollars, down 11% year-on-year; In the second quarter, revenue reached $13.2 billion, up 2% from the same period last year and exceeding market analysts' expectations ($12.96 billion). If the contribution of COVID-19 vaccines and oral COVID-19 drugs is not included, the revenue growth in the second quarter was more significant, reaching 14%, which is the first time since the global coronavirus epidemic gradually eased in the fourth quarter of 2022, Pfizer achieved positive quarterly revenue growth, marking the company has adjusted to a good state and embarked on a new journey.   From the perspective of business structure, in the first half of 2024, the revenue of COVID-19 product Paxlovid was 2.286 billion US dollars, down 46% year-on-year; Comirnaty's revenue was $548 million, down 88% year over year. Despite the continued decline in revenue from COVID-19 products, the company's oncology business has achieved rapid growth, reaching $7.505 billion in revenue in the first half of the year, up 23% year-on-year. Among them, the breast cancer blockbuster CDK4/6 inhibitor Ibrance (Pipercilil), despite a slight decline in sales (-8%), still topped oncology drug sales with $2.184 billion in revenue. Androgen receptor signaling inhibitor Xtandi (Enzaluamide) and third-generation ALK inhibitor Lorbrena (Loratinib) also saw growth of 20% and 46%, respectively, with revenues of $913 million and $332 million, respectively.   In addition, ADCs such as Vyndaqel (chlorobenzolic acid), Eliquis (Apoxaban) and Nurtec ODT/Vydura, which were acquired through the Seagen acquisition, also began to contribute to the company's revenue. Abbvie also showed solid growth in the first half of 2024, with total revenue of $26.772 billion, up 3.7% year-on-year. In terms of therapeutic areas, autoimmune diseases, neuroscience, and oncology were the three pillars of the company's revenue, generating $12.342 billion (+0.6%), $4.127 billion (+15.6%), and $3.177 billion (+11%), respectively.   In the autoimmune diseases segment, although Humira (Adalimumab) has failed to reverse the downward trend in performance, with a decline of about 32% to $5.084 billion, full-year revenue is expected to fall below the $10 billion mark. However, the company's two star products in the field, Skyrizi (Lisencizumab) and Rinvoq (Upatinib), have maintained strong growth momentum, achieving revenue of $4.735 billion (+46.6%) and $2.523 billion (+60.4%), respectively, of which Skyrizi is expected to break the $10 billion revenue mark by the end of the year. In the oncology segment, Imbruvica continued to lose market share, with first-half revenue down 6.4% year-on-year to $1.671 billion; Venclexta, on the other hand, maintained steady growth, with first-half sales of $1.251 billion (+16%). In addition, the new blood cancer product CD3/CD20 dual antibody Epkinly since the FDA approved the market in May last year, sales have also doubled, from $31 million in the first half of 2023 to $63 million in the first half of this year. At the same time, the FRα ADC drug Elahere (Somituximab) acquired by the company in the acquisition of ImmunoGen late last year also contributed $192 million to the company's revenue in six months.   In the neuroscience segment, with the exception of Duodopa, a drug for Parkinson's disease, which showed negative growth, all products achieved steady growth. Although Qulipta's sales volume is not large ($281 million in revenue in the first half of the year), the growth rate is as high as 73.2%, becoming the fastest growing product in the field. Other products such as Ubrelvy, Botox Therapeutics and Vraylar also saw varying degrees of growth. Looking ahead, as AbbVie's pipeline in neuroscience continues to advance and its layout is optimized, the company is expected to continue to expand its market advantage in this field.   Novartis continues to deepen its commitment to nuclear medicine and invests in small nucleic acids and gene therapy. In the first half of 2024, Novartis achieved total revenue of $24.3 billion, an increase of 11%, of which sales in the China market reached $2.1 billion, an increase of 29%.   In the therapeutics segment, Novartis is showing strong growth. Oncology revenue reached $6.984 billion, up 14% year-over-year; Cardiovascular/renal metabolism revenue of $4.111 billion, up 37% year-over-year; Immunization revenue was $4.403 billion, up 21% year on year; Revenue in the neuroscience segment was $2.234 billion, up 39% from a year earlier.   Within these areas, several of Novartis's core products performed well, such as Entresto (sacubactril valsartan) revenue of $3.777 billion, up 30% year-over-year; Kesimpta (Oftolumab) revenue of $1.436 billion, an increase of 64%; Cosentyx revenue of $2.852 billion, up 21% year-over-year; Kisqali (Ribosili) revenue of $1.344 billion, an increase of 48%.   In addition, Novartis's layout in the field of nuclear drugs has also achieved significant results. In the first half of the year, Pluvicto and Lutathera generated revenue of $655 million (+45%) and $344 million (+16%), respectively, for a combined revenue of nearly $1 billion. Meanwhile, sales of Leqvio, a long-acting PCSK9 siRNA lipd-lowering drug, reached $333 million, up 135% year-over-year, making it Novartis' fastest growing new drug category. Gene therapy products also performed well, with Zolgensma, which treats spinal muscular atrophy (SMA), reporting first-half revenue of $644 million, up 6 percent year-on-year.   It is worth noting that Novartis has shown a unique vision in product development and M&A strategy. Unlike other multinational pharmaceutical companies (MNC), Novartis's products and research pipeline are less involved in ADC, PD-1, GLP-1 and other hot tracks. Instead, Novartis prefers to focus on the development of cutting-edge technologies and innovative therapies, such as nuclear drugs, small nucleic acids, cell and gene therapies (CGT). Although the combined revenue of these emerging areas is still less than 10% of total revenue, Novartis's future development prospects will be broader as the market matures in the future.   In addition, the top 10 MNCS such as Astrazeneca, Sanofi, GlaxoSmithKline, Bristol-Myers Squibb also achieved positive revenue growth in the first half of 2024. With the intensification of market competition, each MNC is actively adjusting its strategy, some grasp the hot spots of The Times to expand the advantages of the field, some choose to avoid homogenized competition, and some focus on the core business by cutting off non-core assets. All these efforts are in order to stand out in the fierce market competition, looking forward to the second half of the MNC can continue to bring wonderful performance.