Luspatercept-AAMT

地中海贫血是一组常染色体隐性遗传性疾病，其特征是血红蛋白生成减少或缺失，以及程度各异的慢性贫血。地中海贫血携带状态与对疟疾的抵抗力之间的进化关联，解释了其从撒哈拉以南非洲、中东、地中海盆地到东南亚这一广阔地域的高流行率。人口迁徙也将地中海贫血引入了欧洲和美洲，在这些地区该病以往相对罕见。预防计划实施面临的挑战以及新生儿存活率的提高，导致在资源有限地区以及发达国家多民族城市中，新发病例负担持续存在。治疗的进步提高了成年地中海贫血患者的预期寿命，但相关的资源消耗也很高。根据地中海贫血根据潜在的基因突变和血红蛋白四聚体中受影响珠蛋白链亚基的不同，分为α-地中海贫血和β-地中海贫血。α-地中海贫血先前已在《期刊》中综述。本综述重点讨论β-地中海贫血。 从基础到临床 血红蛋白合成在胚胎期、胎儿期和成人期会表达多种形式的血红蛋白，这些形式的组合可能在人类发育的不同时期出现。血红蛋白四聚体由两条α-珠蛋白链或α样（ζ）珠蛋白链以及两条β-珠蛋白链或β样（ε, γ, δ）珠蛋白链组成，分别由16号和11号染色体上的多基因簇编码。这些基因簇上的基因表达和转换与人类在不同部位的红细胞生成过程平行。在妊娠早期，胚胎血红蛋白（ζ2ε2, α2ε2, ζ2γ2）在卵黄囊的红系细胞中占主导地位。在胎儿期的其余阶段，胎儿血红蛋白（HbF, α2γ2）是红细胞的主要成分，最初由脾脏和肝脏产生，后期由骨髓产生。从γ-珠蛋白到β-珠蛋白基因表达的关键转换大约始于妊娠12周，并在出生后6个月完成，此后红细胞中大部分（>95%）的血红蛋白是成人血红蛋白（HbA, α2β2），以及少量HbA2（α2δ2）和HbF。 分子发病机制β-地中海贫血是由导致单个核苷酸替换、β-珠蛋白基因或其紧邻侧翼序列内小片段缺失或插入的突变引起，少数情况下由大片缺失引起。这些突变导致β-珠蛋白链和HbA生成减少。目前已描述超过350种β-地中海贫血突变，通常根据严重程度指数进行分类：β+表示导致β-珠蛋白链合成相对减少的轻度突变，β0表示可导致β-珠蛋白链产物完全缺失的严重突变。 β-地中海贫血的贫血严重程度、输血需求和临床发病率与α-珠蛋白链和β-珠蛋白链之间的失衡程度密切相关。β-珠蛋白链生成不足导致红系细胞中过量、不稳定的α-珠蛋白四聚体积聚。游离的α-珠蛋白不稳定，会产生细胞毒性的活性氧化物质和细胞沉淀物，损害红系前体细胞的成熟和存活，导致无效红细胞生成和循环红细胞过早溶血。因此，在纯合或复合杂合状态下具有严重β-地中海贫血突变的患者往往有更严重的临床表现，而同时遗传了α-地中海贫血的患者则病情较轻。在通常无症状的杂合子患者中，若同时遗传了额外的α-珠蛋白基因（重复），由于游离α-珠蛋白量增加，可能发展为显性疾病。此外，β-地中海贫血中的红系前体细胞能够解毒并耐受一定量的游离α-珠蛋白，这部分α-珠蛋白由分子伴侣α-血红蛋白稳定蛋白（AHSP）稳定，并通过泛素-蛋白酶体系统和自噬清除。AHSP表达水平的改变影响β-地中海贫血的严重程度，而编码自噬激活激酶Unc-51-like kinase 1（Ulk1）的基因缺失会降低红系前体细胞中α-珠蛋白的自噬清除能力，从而增加疾病严重程度。 α-珠蛋白链和β-珠蛋白链之间的失衡程度也可以通过出生后更有效地合成γ-珠蛋白链和HbF来降低。有几个基因参与调节γ-珠蛋白链反应；一些编码在β-珠蛋白基因簇内，另一些位于不同染色体上。检查HbF水平常见变异的全基因组关联研究已确定BCL11A（一种多锌指转录调节因子）是从胎儿血红蛋白向成人血红蛋白转换以及HbF沉默的关键调节因子。BCL11A抑制编码HbF的基因，并被认为通过RNA结合蛋白LIN28B在信使RNA翻译水平受到调控。BCL11A表达的遗传变异和持续的HbF产生已被证明可以降低β-地中海贫血的临床严重程度。 图1：展示了β-地中海贫血的表型分类，将传统表型（沉默携带者、轻型/特征、中间型、重型）与临床表现、输血需求（从不/很少、偶尔、频繁、终身定期）以及基因型（包括α-地中海贫血、γ链（HbF）产生增加、α-珠蛋白基因重复等修饰因素）关联起来。 基因型-表型关联三种主要的β-地中海贫血表型通常根据临床表现来划分，同时认识到某些遗传谱通常（但非绝对）与特定表型相关联。β-地中海贫血特征，或称β-地中海贫血轻型，源于β-地中海贫血突变的杂合遗传，其特征是处于临界状态的无症状贫血，伴有小细胞低色素性贫血（图1）。最近一项研究显示，具有这种β-地中海贫血表型的患者住院率和发病率高于健康对照，但原因尚待探索。患者可能遗传完全不表现出血液学异常的β-地中海贫血沉默突变（β-地中海贫血沉默携带者）。如果父母双方都是地中海贫血突变携带者，则需要进行关于子女患有β-地中海贫血风险的遗传咨询。 β-地中海贫血突变纯合或复合杂合的患者可能患有β-地中海贫血重型或中间型。β-地中海贫血重型患者通常在生命早期出现严重贫血和症状，而β-地中海贫血中间型患者则倾向于在生命后期出现轻度至中度贫血和症状。β-地中海贫血突变的严重程度、是否共遗传α-地中海贫血以及持续或增加HbF产生的遗传能力，是决定β-地中海贫血表现为中间型还是重型表型的一些因素。β-地中海贫血中间型也可能由与α-珠蛋白基因三重或四重重复基因型导致α-珠蛋白链产生增加相关的杂合状态、显性（包含体）β-地中海贫血、或δβ-地中海贫血缺失形式（涉及δ和β珠蛋白基因缺失）以及遗传性持续性胎儿血红蛋白（HPFH）引起。 血红蛋白E（HbE）是由β-珠蛋白基因单点突变产生的一种异常血红蛋白，其行为类似于β+突变。当此突变与β-地中海贫血突变共同遗传时，患者被归类为HbE-β-地中海贫血，其严重程度可从轻度或中度（类似β-地中海贫血中间型）到重度（类似β-地中海贫血重型）不等。疾病严重程度也受上述遗传修饰因子影响。HbE-β-地中海贫血儿童适应低血红蛋白水平的显著能力——这归因于生命早期比后期更强的促红细胞生成素反应——可能延迟或减少输血需求。 表型再认识过去十年，一种新的表型分类已开始取代前述的传统表型分类，旨在强调个体患者在疾病全过程中的输血需求，因为这一需求对相关病理生理特征和实际管理有重大影响。输血依赖性β-地中海贫血患者（β-地中海贫血重型或重度HbE-β-地中海贫血）需要终身定期输血才能生存，而非输血依赖性β-地中海贫血患者（β-地中海贫血中间型或轻度至中度HbE-β-地中海贫血）则不需要输血、因特定情况（如妊娠、手术或急性感染）偶尔输血、或频繁输血但仅限于特定时期（例如，为支持儿童期生长突增或处理临床并发症）。β-地中海贫血患者的非输血依赖性和输血依赖性分类现已被临床研究资格和国际管理指南普遍采用。 确诊如果基于体格检查、个人和家族史以及红细胞指标（平均红细胞体积低、平均红细胞血红蛋白含量低、红细胞分布宽度正常）怀疑β-地中海贫血，可通过血红蛋白电泳或高效液相色谱法确诊。可能需要进行DNA分析以确诊HbE并识别特定的β-地中海贫血基因型。 流行病学与全球分布关于β-地中海贫血的流行病学数据有限。根据十多年前的数据，β-地中海贫血携带者约占世界人口的1.5%，每年约有40,000名患病婴儿出生，其中约一半被归类为输血依赖型。超过90%的β-地中海贫血患者生活在从非洲延伸到南欧和中东，再到东南亚的地理“地带”，其中HbE-β-地中海贫血最为常见。某些地理区域和合作登记处的个体数据最近已被综述。在一些国家，如塞浦路斯、希腊和意大利，成功的筛查（婚前和产前）和预防计划减少了患病人数。在其他地区，此类计划常因当地公共卫生议程的限制或限制实施的文化和宗教信仰而受阻。 欧洲和北美患者数量的增加以及卫生服务使用的增加日益明显。这不仅反映了历史上人口迁徙逐渐引入携带者，也反映了近期来自冲突地区的难民流动，以及儿童收养率的增加。总体而言，地中海贫血的全球负担正在增加，因为许多移民未纳入筛查计划，且患病患者并不总能获得充分的医疗服务。 临床意义要理解与β-地中海贫血相关的并发症，不仅要熟悉其潜在的病理生理学，还必须考虑传统疗法如脾切除术、输血和铁螯合治疗如何影响病理生理学（图2）。这些疗法已融入患者的临床特征中，其使用与否决定了在疾病全过程中可能观察到哪些并发症。 图2：展示了β-地中海贫血的病理生理学及治疗干预的影响。核心是β-珠蛋白链合成减少导致的α/β链失衡。这引发两条主要路径：1) 无效红细胞生成：导致贫血、骨髓扩张（骨骼改变、疼痛、畸形、髓外造血）、铁过载（通过铁调素抑制）、肺动脉高压、血栓形成；2) 外周溶血：导致贫血、脾肿大（随后可能脾切除）、血栓形成。图表进一步显示了常规治疗（输血、铁螯合、脾切除）如何影响这些并发症路径。 无效红细胞生成和外周溶血导致慢性贫血状态，可引起生长和发育迟缓、疲劳等典型贫血相关症状、腿部溃疡，并可促进青少年和年轻成人器官衰竭。贫血对心理健康的独立影响也有报道。 无效红细胞生成导致骨髓扩张及相关的骨骼改变、疼痛和畸形，这是β-地中海贫血典型特征（如颅面部隆起）的原因。代偿性髓外造血灶也被激活，包括脾脏和肝脏（肝脾肿大）以及身体其他组织，在这些地方它们可以生长成髓外造血假瘤；如果出现在椎旁管或胸部等区域，这些假瘤可引起严重压迫，可能需要紧急处理。 β-地中海贫血中的外周溶血导致红细胞表面表达促血栓形成标志物，导致高凝状态，而血小板活化、微粒和其他凝血异常进一步加剧了这种状态。临床上，这些障碍可表现为静脉和动脉血栓形成、肺动脉高压和脑血管事件（包括无症状性脑梗死），并随年龄增长而增加。 尽管对这些并发症发生率和患病率的估计来自小型单中心研究，但很明显，非输血依赖性β-地中海贫血患者比输血依赖性β-地中海贫血患者（或正在接受输血的非输血依赖性β-地中海贫血患者）更常见这些并发症，因为输血疗法可以改善贫血和无效红细胞生成。然而，在输血依赖性β-地中海贫血患者中，如果输血延迟或未达最佳标准，尤其是有严重贫血的患者，仍可能观察到这些并发症。一项涉及非输血依赖性β-地中海贫血患者的研究显示，当血红蛋白水平低于10 g/dL时，贫血严重程度（血红蛋白每分升每降低1 g）与并发症风险相关；在血红蛋白水平较高（见于三分之一患者）时，未发现并发症。虽然脾切除术可能提高血红蛋白水平，但它逆转了脾脏清除病理性红细胞的清道夫作用，这就是为什么接受脾切除术的患者发病率（尤其是血管疾病）会增加。 铁过载仍然是β-地中海贫血中最相关的临床问题之一。铁负荷传统上通过分析血清铁蛋白水平来测量，但磁共振成像（MRI）的发展使得能够量化靶器官中的铁浓度，以便个体化管理。MRI技术目前用于测量心肌铁浓度（通过T2加权MRI）和肝脏铁浓度（通过T2或T2加权MRI；T2和T2表示弛豫时间）；肝脏铁浓度也是全身铁水平的替代指标。T2加权和T2加权图像之间的差异取决于扫描仪如何形成回波。T2用于梯度回波测量，而T2则用于射频脉冲形成的回波（自旋回波）测量。T2和T2以毫秒报告（或其倒数R2和R2*以赫兹报告），并可以使用针对活检标本测量的铁浓度验证的校准曲线转换为每克干重铁的毫克数。这些技术在国际上可重复，但需要专门的专业知识和校准才能正确应用和解读。 在输血依赖性β-地中海贫血患者中，输血性铁摄入使血清转铁蛋白的容量饱和，导致非转铁蛋白结合铁的出现，这些铁容易在身体组织中（通常是肝脏，其次是心脏和内分泌器官）积聚，造成重要器官损害。重复测量显示血清铁蛋白水平高于2500 ng/mL与心脏病和死亡风险增加相关，而低于1000 ng/mL与生存期延长相关。肝脏铁浓度高于7 mg/g与肝病风险增加相关，高于15 mg/g与心脏病风险增加相关。T2*加权MRI测量的心肌铁低于20毫秒与心律失常相关，低于10毫秒与心力衰竭或死亡相关。自1967年引入铁螯合治疗以来，输血依赖性β-地中海贫血患者因心脏铁过载死亡的风险已下降，并在2000年代初随着口服螯合剂和先进成像技术的引入进一步降低。例如，在塞浦路斯，2000年至2018年期间30岁生存率比1980年至1999年期间提高了8%。英国和希腊的登记处也报告了类似的趋势。相比之下，在一些资源有限国家，尤其是在接受不充分输血和铁螯合治疗的患者中，生存率仍然较低，不到一半患者能活到40岁。 传统上认为，对于非输血依赖性β-地中海贫血患者，在没有输血的情况下不会发生铁过载，但研究表明，此类患者中无效红细胞生成与原发性铁过载之间存在双向关系。无效红细胞生成和缺氧导致肝脏激素铁调素产生减少，进而导致肠道铁吸收增加以及其从网状内皮系统巨噬细胞中释放。红系调节激素（一种由红系前体细胞因促红细胞生成素受体-Janus激酶2-信号转导和转录激活因子5（EPOR-JAK2-STAT5）通路激活而分泌的激素）是这一过程的主要红系调节因子，使其成为药物开发的有趣靶点。参与缺氧诱导的铁调素抑制的另一个因子是血小板衍生生长因子BB（PDGF-BB）。生长分化因子15（GDF15）和扭曲原肠胚形成蛋白1（TWSG1）也曾被提议作为铁调素的潜在红系调节因子，但它们的作用随后受到挑战。铁调素抑制的最终结果——缓慢但持续的铁积累，优先储存于肝脏（心脏明显缺乏铁储存）——已得到研究证实，这些研究显示非输血依赖性β-地中海贫血患者有临床意义的肝脏铁浓度，但其血清铁蛋白水平低于具有相同肝脏铁浓度的输血依赖性β-地中海贫血患者。观察性研究已证实，在非输血依赖性β-地中海贫血患者中，铁过载（肝脏铁浓度 > 5 mg/g 且血清铁蛋白水平 > 800 ng/mL）与多种并发症相关，包括肝纤维化和肝癌、蛋白尿和肾功能衰竭以及内分泌和骨病。血管疾病也可能由铁诱导的内皮损伤引起，这进一步促进了高凝状态。 年龄增长仍然是β-地中海贫血相关并发症最重要的危险因素之一。上述许多临床并发症，如血管和肝脏疾病，是在数年内逐渐发展的。除肝癌外，在老年β-地中海贫血患者中也有血液系统和其他实体瘤的报道，并归因于骨髓的慢性应激和铁过载。此外，随着这些患者生存率的提高，也可能出现其他并发症，如心脏病、糖尿病、肾病以及与非地中海贫血人群风险因素相关的癌症。年龄增长也暴露出与婚姻、工作和社会融合相关的诸多社会和心理挑战。此外，β-地中海贫血患者的生活质量可能因疾病负担和需要长期治疗而严重受损，增加医疗需求的精神疾病并不少见。 图3：总结了β-地中海贫血的治疗选择。 A部分：输血依赖性β-地中海贫血（TDT）患者的治疗选择图。核心是定期输血联合铁螯合治疗（去铁胺[DFO]、去铁酮[DFP]、地拉罗司[DFX]）。根据血清铁蛋白和MRI（肝脏铁浓度[LIC]、心肌铁浓度）监测指导螯合剂选择和剂量调整。对于特定情况（如过敏、依从性差、心脏铁过载），显示了不同螯合剂之间的转换或联合策略（例如DFO+DFP用于心脏铁过载）。造血干细胞移植（HSCT）和基因疗法（LentiGlobin BB305）作为潜在治愈性治疗列出。罗特西普作为减少输血负担的药物列出。B部分：非输血依赖性β-地中海贫血（NTDT）患者的治疗选择图。决策基于血红蛋白（Hb）水平和并发症风险。对于Hb ≥ 10 g/dL且无并发症的患者，建议观察。对于Hb < 10 g/dL和/或存在并发症（如髓外造血、腿部溃疡、肺动脉高压、血栓形成、铁过载）的患者，列出了多种选择：脾切除术（适应症有限，因风险增加）、输血、羟基脲、铁螯合治疗（地拉罗司为主）、罗特西普（正在研究中），以及针对特定并发症的相应治疗（例如抗凝、肺动脉高压靶向药、腿部溃疡护理）。也提到了针对铁调节异常和无效红细胞生成的新药研发。 管理β-地中海贫血的现有治疗选择总结见文内图表（图3），针对特定并发症的监测和管理方法见表格。β-地中海贫血的国际和地方管理指南广泛可用，但主要基于专家意见；很少有建议是基于随机临床试验的结果。除下文讨论的治疗方案外，所有患者都应接受适当的维生素和其他必要的补充剂以维持健康和造血支持，并应考虑心理社会支持。特殊情况下（包括妊娠）的管理考虑因素已在其他地方综述。 输血与铁螯合对输血依赖型患者进行定期输血，以达到输血前血红蛋白目标水平9至10.5 g/dL（心脏病患者为11至12 g/dL）。尽管输血实践存在地区差异，但献血者血液筛查和制备技术的进步已降低了大多数国家中同种异体免疫和血源性感染的发生率。 输血依赖型患者应使用血清铁蛋白测量以及肝脏和心肌MRI监测铁过载，并在输注10单位浓缩红细胞后不久或当血清铁蛋白水平达到1000 ng/mL或更高时开始铁螯合治疗。目前有三种铁螯合剂（单独或联合使用）可用于管理铁过载：皮下注射的去铁胺和口服药物去铁酮与地拉罗司（分散片和薄膜衣片）。去铁胺和地拉罗司被批准用于2岁以上患者的治疗，而去铁酮被批准作为6岁以上患者的二线治疗，尽管最近一项随机试验显示了其在年轻患者中的有效性和安全性。所有三种螯合剂的样本数据显示，它们作为单药治疗或联合治疗（去铁胺和去铁酮）能够减少全身、肝脏和心肌铁过载，但口服螯合剂之间的头对头比较有限。铁过载减少的程度根据器官和药物而异，可能需要高剂量才能逆转心脏铁沉积。口服螯合剂在治疗依从性方面比去铁胺具有公认的优势，与分散片剂型相比，新型地拉罗司薄膜衣片与患者报告的结局改善相关。否则，铁螯合剂的选择应基于当地指南、临床判断和患者的个体铁过载情况。成功治疗取决于根据持续铁摄入量调整剂量、监测、关注依从性问题以及管理不良事件。对于已存在心脏功能障碍的患者，持续肠外去铁胺仍然是首选，并且也有去铁胺联合去铁酮获益的数据。非输血依赖性β-地中海贫血且血红蛋白水平低于10 g/dL的患者并发症风险增加。由于继发性铁过载的风险，不建议对该人群定期输血；针对此类患者的研究数据显示，在地拉罗司治疗后，血清铁蛋白和肝脏铁浓度分别显著降低。尽管有去铁胺和去铁酮的研究数据，但地拉罗司是唯一基于随机2期试验数据（显示在2年治疗期间血清铁蛋白和肝脏铁浓度显著降低）专门获批用于此人群的铁螯合剂。 罗特西普治疗罗特西普（ACE-536）是最近（在美国和欧洲）获批用于治疗成人输血依赖性β-地中海贫血的药物。它是一种重组融合蛋白，包含人激活素受体IIB型的修饰胞外结构域，与人IgG1的Fc结构域融合。这些结构域共同结合选择性转化生长因子β超家族配体，阻断SMAD2/3信号传导，并促进红系成熟。基于2期研究的鼓舞性数据，最近一项涉及成人输血依赖性β-地中海贫血的3期双盲试验（BELIEVE）显示，随机分配接受每3周一次皮下注射罗特西普（剂量1.00至1.25 mg/kg体重，224例患者）或安慰剂（112例患者）的患者中，罗特西普在固定的12周期间将输血负担降低了至少33%（罗特西普组21.4% vs. 安慰剂组4.5%）。同时观察到血清铁蛋白水平平行下降，肝脏或心肌铁浓度无临床意义的变化。与安慰剂相比，罗特西普更常见的不良事件包括一过性骨痛、关节痛、头晕、高血压和高尿酸血症。罗特西普治疗患者的血栓发生率更高。虽然这些血栓事件主要发生在已知有风险因素的患者中，但建议监测患者血栓事件的体征和症状。罗特西普正逐渐被纳入输血依赖性β-地中海贫血的地方管理方案中。关于长期使用和儿童使用的数据尚待获取。 造血干细胞移植据报道，对于具有有利风险特征和匹配同胞供者的输血依赖性β-地中海贫血儿童，造血干细胞移植（HSCT）的无病生存率超过90%。移植方案的改进和移植相关并发症的管理也使得可以使用匹配无关供者、单倍体相合亲缘供者和脐带血作为干细胞来源。结果率因地区而异，这些方法应仅在具有专业知识的中心考虑。 基因治疗基因治疗基于通过从β-地中海贫血患者体内分离造血干细胞，并用病毒载体转导以引入能够进行基因表达的外源性β样珠蛋白转基因，从而纠正β-珠蛋白链缺陷性产生的概念。首个此类基因疗法，betibeglogene autotemcel（LentiGlobin BB305），已在欧洲获得有条件上市许可，用于12岁及以上、具有非β0/β0基因型、适合移植但没有匹配同胞供者的输血依赖性β-地中海贫血患者。该批准基于两项1-2期研究的数据，涉及22名患者，他们接受了用LentiGlobin BB305载体（编码带有T87Q氨基酸替换的HbA，这是一种抗镰变的血红蛋白变体）体外转导的细胞回输。22名患者中有15名在基因治疗后停止了输血（13名非β0/β0基因型患者中的12名和9名β0/β0基因型患者中的3名），其余患者接受的年度红细胞输注量和输血次数均少于基因治疗前。治疗相关不良事件与自体造血干细胞移植的典型事件相似。 两项正在进行中的涉及β0/β0或非β0/β0输血依赖性β-地中海贫血儿童和成人的3期试验的最终数据尚待公布。其他一些载体和基因治疗方法也已进行评估。在一项涉及具有β0或严重β+突变的输血依赖性β-地中海贫血患者的1-2期试验中，骨内输注经表达β-珠蛋白的（GLOBE）慢病毒载体转导的造血干细胞，导致三名成人输血需求减少，四名接受评估的儿童中有三名完全摆脱了输血。 正在进行的临床开发除了基因治疗，最近还开发了直接纠正基因突变或破坏基因组中特定DNA序列（基因组编辑）的方法。两种工程化核酸酶——锌指核酸酶（ZFNs）和与Cas9核酸酶连接的成簇规律间隔短回文重复序列（CRISPR-Cas9）正在输血依赖性患者中进行评估。自体CD34+细胞被动员、收集并进行编辑，以破坏BCL11A的红系特异性增强子区域，增加HbF产生。产品在清髓性预处理后输注给患者。两项正在进行的临床试验正在评估接受CTX001（CRISPR-Cas9）或ST-400（ZFNs）产品治疗的输血依赖性β-地中海贫血患者的输血需求。 罗特西普也正在一项涉及成人非输血依赖性β-地中海贫血的进行中试验（BEYOND）中评估其对血红蛋白水平的影响。其他几种药物也正在该患者群体中评估类似的效应。无论这些药物是直接靶向铁调节异常（VIT-2763和TMPRSS6-LRx）还是无效红细胞生成（米他匹伐 [AG-348]），其预期效果都是减轻贫血和预防原发性铁过载，因为这两种并发症之间存在双向关系。可能需要这些药物的联合应用，或者它们中的一个或多个与铁螯合治疗的联合应用，才能完全控制或逆转非输血依赖性β-地中海贫血的潜在疾病过程。 参考文献：Taher AT, Musallam KM, Cappellini MD. β-Thalassemias. N Engl J Med. 2021;384(8):727-743. doi:10.1056/NEJMra2021838 版权声明：本文系Leuk独立撰稿，享有原创版权，欢迎个人转发分享，其他任何媒体、网站如需转载或引用本网页版权所有内容，须获得授权。本文仅供医学专业人士参考，不作为诊疗依据，未经著作人许可，不可出版发行。 （欢迎分享，点赞+关注！）

Fourth-Quarter Worldwide Sales Were $16.4 Billion (5% Growth; 4% Growth ex-FX) Fourth-Quarter GAAP EPS Was $1.19; Non-GAAP EPS Was $2.04; GAAP and Non-GAAP EPS Include a Charge of $0.05 per Share for the Acquisition of MK-8690 Sole Global Rights Full-Year Worldwide Sales Were $65.0 Billion (1% Growth; 2% Growth ex-FX) KEYTRUDA/KEYTRUDA QLEX Sales Were $31.7 Billion (7% Growth Both Nominally and ex-FX); Includes KEYTRUDA QLEX Sales of $40 Million WINREVAIR Sales Were $1.4 Billion CAPVAXIVE Sales Were $759 Million GARDASIL/GARDASIL 9 Sales Were $5.2 Billion (39% Decline Both Nominally and ex-FX) Animal Health Sales Were $6.4 Billion (8% Growth; 9% Growth ex-FX) KEYTRUDA/KEYTRUDA QLEX Sales Were $31.7 Billion (7% Growth Both Nominally and ex-FX); Includes KEYTRUDA QLEX Sales of $40 Million WINREVAIR Sales Were $1.4 Billion CAPVAXIVE Sales Were $759 Million GARDASIL/GARDASIL 9 Sales Were $5.2 Billion (39% Decline Both Nominally and ex-FX) Animal Health Sales Were $6.4 Billion (8% Growth; 9% Growth ex-FX) Full-Year 2025 GAAP EPS Was $7.28; Non-GAAP EPS Was $8.98; GAAP and Non-GAAP EPS Include Charges of $0.20 per Share Related to Certain Business Development Transactions Announced Positive Late-Stage Trial Results From 18 Phase 3 Trials in 2025 Augmented Pipeline and Portfolio Through Acquisitions of Verona Pharma and Cidara Therapeutics and License Agreement With Hengrui Pharma In the Fourth Quarter Received FDA Commissioner’s National Priority Vouchers for Enlicitide and Sacituzumab Tirumotecan (Sac-TMT), Providing an Opportunity To Expedite Potential FDA Review Timelines for These Phase 3 Candidates Presented Positive Results From Phase 3 CORALreef Lipids and HeFH Trials Demonstrating Enlicitide Significantly Reduced LDL-C in Adults Reached Agreement With U.S. Government To Expand Access to Medicines and Lower Costs for Americans Received FDA Commissioner’s National Priority Vouchers for Enlicitide and Sacituzumab Tirumotecan (Sac-TMT), Providing an Opportunity To Expedite Potential FDA Review Timelines for These Phase 3 Candidates Presented Positive Results From Phase 3 CORALreef Lipids and HeFH Trials Demonstrating Enlicitide Significantly Reduced LDL-C in Adults Reached Agreement With U.S. Government To Expand Access to Medicines and Lower Costs for Americans Full-Year 2026 Financial Outlook Anticipates Worldwide Sales To Be Between $65.5 Billion and $67.0 Billion Expects Non-GAAP EPS To Be Between $5.00 and $5.15; Outlook Reflects a One-Time Charge of Approximately $3.65 per Share for the Acquisition of Cidara Anticipates Worldwide Sales To Be Between $65.5 Billion and $67.0 Billion Expects Non-GAAP EPS To Be Between $5.00 and $5.15; Outlook Reflects a One-Time Charge of Approximately $3.65 per Share for the Acquisition of Cidara RAHWAY, N.J.--(BUSINESS WIRE)--Merck & Co., Inc., Rahway, N.J., USA (NYSE: MRK), known as MSD outside the United States and Canada, today announced financial results for the fourth quarter and full year of 2025. "In 2025, we continued to advance leading-edge science to deliver transformative medicines and vaccines that are improving health outcomes for patients around the world,” said Robert M. Davis, chairman and chief executive officer. "Our business benefited from demand for our innovative portfolio, including for KEYTRUDA, increasing contributions from new launches in cardiometabolic and respiratory as well as vaccines, and strong performance of Animal Health. The transformation of our portfolio, bolstered by the acquisitions of Verona Pharma and Cidara Therapeutics, is well underway, and momentum is building as we continue to execute on our strategy. Our progress positions us to continue delivering on our purpose for patients and creating durable value for shareholders.” Financial Summary $ in millions, except EPS amounts Fourth Quarter Year Ended 2025 2024 Change Change Ex-Exchange Dec. 31, 2025 Dec. 31, 2024 Change Change Ex-Exchange Sales $16,400 $15,624 5% 4% $65,011 $64,168 1% 2% GAAP net income1 2,963 3,743 -21% -20% 18,254 17,117 7% 9% Non-GAAP net income that excludes certain items1,2* 5,088 4,372 16% 17% 22,513 19,444 16% 18% GAAP EPS 1.19 1.48 -20% -18% 7.28 6.74 8% 10% Non-GAAP EPS that excludes certain items2* 2.04 1.72 19% 19% 8.98 7.65 17% 19% *Refer to table on page 9. Generally Accepted Accounting Principles (GAAP) earnings per share (EPS) assuming dilution was $1.19 for the fourth quarter and $7.28 for the full year of 2025. Non-GAAP EPS was $2.04 for the fourth quarter and $8.98 for the full year of 2025. GAAP and non-GAAP EPS in the fourth quarter of 2025 include a charge of $0.05 per share related to an agreement with Dr. Falk Pharma GmbH (Falk) pursuant to which the Company secured the sole global rights to MK-8690. GAAP and non-GAAP EPS in the fourth quarter of 2024 include a charge of $0.23 per share related to the execution of licensing agreements with LaNova Medicines Ltd. (acquired by Sino Pharmaceutical Limited) and Hansoh Pharma. GAAP and non-GAAP EPS for the full years of 2025 and 2024 include charges of $0.20 and $1.28 per share, respectively, related to certain licensing agreements and asset acquisitions. Non-GAAP EPS excludes acquisition- and divestiture-related costs, costs related to restructuring programs, and income and losses from investments in equity securities. Non-GAAP EPS in 2025 also excludes a net tax benefit, which reflects a net benefit related to favorable audit reserve adjustments. Non-GAAP EPS in the fourth quarter and full year of 2024 also exclude a benefit due to a reduction in reserves for unrecognized income tax benefits resulting from the expiration of the statute of limitations for assessments related to certain federal tax return years. Fourth-Quarter Sales Performance The following table reflects sales of the Company’s top products and significant performance drivers. Fourth Quarter $ in millions 2025 2024 Change Change Ex-Exchange Commentary Total Sales $16,400 $15,624 5% 4% Pharmaceutical 14,843 14,042 6% 4% Increase primarily driven by growth in oncology as well as cardiometabolic and respiratory, partially offset by a decline in vaccines. KEYTRUDA/ KEYTRUDA QLEX 8,372 7,836 7% 5% Growth driven by strong global uptake in earlier-stage indications, including triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), renal cell carcinoma, cervical and head and neck cancers, as well as continued global demand in metastatic indications, including urothelial, gastric and endometrial cancers. Sales growth was partially offset by timing of purchases in the U.S. Sales of KEYTRUDA QLEX were $35 million. GARDASIL/ GARDASIL 9 1,031 1,550 -34% -35% Decline primarily due to lower demand in China, as well as lower sales in Japan following the national catch-up immunization program, partially offset by higher sales in the U.S. and timing in certain international markets. PROQUAD, M-M-R II and VARIVAX 619 594 4% 3% Increase primarily reflects higher sales of PROQUAD, which largely resulted from both the replenishment of doses borrowed from the U.S. Centers for Disease Control and Prevention Pediatric Vaccine Stockpile and from higher demand in Europe, partially offset by lower demand for M-M-R II in certain international markets and lower demand for VARIVAX in the U.S. JANUVIA/JANUMET 501 487 3% 3% Growth driven by higher net pricing in the U.S., partially offset by lower demand in China as well as in most other international markets due to generic competition. BRIDION 499 449 11% 11% Growth primarily due to higher demand and net pricing in the U.S., partially offset by lower demand in several international markets due to ongoing generic competition. WINREVAIR 467 200 133% 133% Growth primarily reflects continued uptake in the U.S. and early launch uptake in certain international markets, partially offset by lower net pricing in the U.S. largely due to Medicare Part D redesign. Lynparza* 389 365 7% 4% Growth primarily due to higher demand in several international markets. CAPVAXIVE 279 50 N/M N/M Growth largely due to continued uptake in the U.S. PREVYMIS 275 215 28% 26% Increase primarily due to higher demand in the U.S. as well as in most international markets, reflecting in part the launch of new indications. Lenvima* 272 255 7% 6% Increase due to higher sales in the U.S., primarily reflecting higher demand, partially offset by lower pricing. WELIREG 220 160 37% 37% Growth primarily due to higher demand in the U.S. and continued launch uptake in several international markets, partially offset by lower net pricing in the U.S. OHTUVAYRE 178 - - - Represents sales following the Company's Oct. 7, 2025 acquisition of Verona Pharma plc (Verona Pharma). Animal Health 1,505 1,397 8% 6% Growth primarily due to higher demand of livestock products. Livestock 987 889 11% 9% Growth primarily driven by higher demand across all species, as well as improved supply and new product launches. Companion Animal 518 508 2% 0% Growth from new product launches was partially offset by lower demand for other products in portfolio, reflecting a reduction in veterinary visits. Sales of BRAVECTO line of products were $222 million and $209 million in current and prior-year quarters, respectively, which represents an increase of 6%, or 5% excluding impact of foreign exchange. Other Revenues** 52 185 -71% -15% Decline primarily due to unfavorable impact of revenue-hedging activities and lower revenue from third-party manufacturing arrangements. *Alliance revenue for this product represents the Company’s share of profits, which are product sales net of cost of sales and commercialization costs. **Other revenues are comprised primarily of revenues from third-party manufacturing arrangements and miscellaneous corporate revenues, including revenue-hedging activities. N/M - Not meaningful. Full-Year Sales Performance The following table reflects sales of the Company’s top products and significant performance drivers. Year Ended $ in millions Dec. 31, 2025 Dec. 31, 2024 Change Change Ex-Exchange Total Sales $65,011 $64,168 1% 2% Pharmaceutical 58,142 57,400 1% 1% KEYTRUDA/KEYTRUDA QLEX 31,680 29,482 7% 7% GARDASIL/GARDASIL 9 5,233 8,583 -39% -39% JANUVIA/JANUMET 2,544 2,268 12% 13% PROQUAD, M-M-R II and VARIVAX 2,451 2,485 -1% -2% BRIDION 1,841 1,764 4% 4% Lynparza* 1,450 1,311 11% 10% WINREVAIR 1,443 419 N/M N/M Lenvima* 1,053 1,010 4% 4% PREVYMIS 978 785 25% 23% VAXNEUVANCE 825 808 2% 1% CAPVAXIVE 759 97 N/M N/M WELIREG 716 509 41% 41% ROTATEQ 673 711 -5% -5% Reblozyl* 525 371 41% 41% LAGEVRIO 380 964 -61% -61% Simponi** - 543 -100% -100% Animal Health 6,354 5,877 8% 9% Livestock 3,896 3,462 13% 14% Companion Animal 2,458 2,415 2% 2% Other Revenues*** 515 891 -42% -6% *Alliance revenue for Lynparza and Lenvima represent the Company’s share of profits, which are product sales net of cost of sales and commercialization costs. Alliance revenue for Reblozyl represents royalties. **Marketing rights in former territories of the Company reverted to Johnson & Johnson on Oct. 1, 2024. ***Other revenues are comprised primarily of revenues from third-party manufacturing arrangements and miscellaneous corporate revenues, including revenue-hedging activities. N/M - Not meaningful. In addition, Koselugo alliance revenue was $436 million for the full year of 2025 compared with $170 million for the full year of 2024. The increase was due to an amendment to the collaboration agreement with AstraZeneca in 2025, which discontinued the provisions whereby the Company shared revenue and costs with AstraZeneca, and revised the payment structure, resulting in the Company’s recognition of a $150 million upfront payment and $175 million of regulatory milestones. Full-year 2025 Pharmaceutical sales were $58.1 billion, representing growth of 1% both nominally and excluding the impact of foreign exchange. Sales growth was primarily driven by higher sales in oncology, particularly KEYTRUDA and WELIREG, as well as increased alliance revenue from Koselugo (resulting from the amendment to the collaboration agreement noted above), Reblozyl and Lynparza. Also contributing to sales growth were higher sales in the cardiometabolic and respiratory franchise largely attributable to the ongoing launch of WINREVAIR, as well as the inclusion of OHTUVAYRE sales resulting from the acquisition of Verona Pharma, which closed on Oct. 7, 2025. Growth in the diabetes franchise, largely attributable to higher net pricing of JANUVIA in the U.S., also contributed to sales growth. Sales growth in 2025 was partially offset by lower sales in the vaccines franchise reflecting lower sales of GARDASIL/GARDASIL 9, which were offset in part by the ongoing launch of CAPVAXIVE and the U.S. launch of ENFLONSIA. Lower sales in the immunology franchise (due to the return of the marketing rights for Simponi and Remicade in former Company territories to Johnson & Johnson on Oct. 1, 2024) and lower sales in the virology franchise (largely attributable to LAGEVRIO) also offset Pharmaceutical sales growth in 2025. Full-year 2025 Animal Health sales were $6.4 billion, representing growth of 8%, or 9% excluding the impact of foreign exchange. Sales growth was primarily driven by the performance of Livestock products across all species and new product launches in Companion Animal. Sales of the BRAVECTO line of products were $1.1 billion in 2025, representing growth of 1% both nominally and excluding the impact of foreign exchange. Fourth-Quarter and Full-Year Expense and Related Information The table below presents selected expense information. $ in millions GAAP Acquisition- and Divestiture- Related Costs3 Restructuring Costs (Income) Loss From Investments in Equity Securities Non- GAAP2 Fourth Quarter 2025 Cost of sales $5,551 $1,054 $1,173 $- $3,324 Selling, general and administrative 2,898 48 2 - 2,848 Research and development 3,886 5 (111) - 3,992 Restructuring costs 213 - 213 - - Other (income) expense, net 432 - - 206 226 Fourth Quarter 2024 Cost of sales $3,828 $701 $121 $- $3,006 Selling, general and administrative 2,864 29 16 - 2,819 Research and development 4,585 12 (1) - 4,574 Restructuring costs 51 - 51 - - Other (income) expense, net 126 (31) - 152 5 $ in millions GAAP Acquisition- and Divestiture- Related Costs3 Restructuring Costs (Income) Loss From Investments in Equity Securities Non- GAAP2 Year Ended Dec. 31, 2025 Cost of sales $16,382 $2,871 $1,484 $- $12,027 Selling, general and administrative 10,733 120 3 - 10,610 Research and development 15,789 19 175 - 15,595 Restructuring costs 889 - 889 - - Other (income) expense, net 151 (3) - (306) 460 Year Ended Dec. 31, 2024 Cost of sales $15,193 $2,409 $495 $- $12,289 Selling, general and administrative 10,816 117 83 - 10,616 Research and development 17,938 72 1 - 17,865 Restructuring costs 309 - 309 - - Other (income) expense, net (24) (79) - 45 10 GAAP Expense, EPS and Related Information Gross margin was 66.2% for the fourth quarter of 2025 compared with 75.5% for the fourth quarter of 2024. Gross margin was 74.8% for the full year of 2025 compared with 76.3% for the full year of 2024. The gross margin decline in both periods was primarily due to the unfavorable impacts of higher restructuring costs (primarily related to the accelerated depreciation of manufacturing lines at two sites under the 2025 Restructuring Program), inventory write-offs and amortization of intangible assets, as well as the recognition of inventory fair value step-up related to the Verona Pharma acquisition, partially offset by the favorable impact of product mix. Selling, general and administrative (SG&A) expenses were $2.9 billion in the fourth quarter of 2025, an increase of 1% compared with the fourth quarter of 2024. The increase was primarily due to higher administrative costs, partially offset by lower promotional costs. Full-year 2025 SG&A expenses were $10.7 billion, a decrease of 1% compared with the full year of 2024. The decrease was primarily due to lower restructuring and promotional costs, partially offset by increased administrative costs. Research and development (R&D) expenses were $3.9 billion in the fourth quarter of 2025, a decrease of 15% compared with the fourth quarter of 2024. The decrease was primarily due to lower charges for business development activity and a reduction to estimated contractual termination costs associated with restructuring actions, partially offset by higher clinical development costs. R&D expenses were $15.8 billion for the full year of 2025, a decrease of 12% compared with the full year of 2024. The decrease was primarily due to lower charges for business development activity, partially offset by higher clinical development spending and higher restructuring costs. Other (income) expense, net, was $432 million of expense in the fourth quarter of 2025 compared with $126 million of expense in the fourth quarter of 2024 primarily due to higher net interest expense, higher foreign exchange losses and increased net losses from investments in equity securities. Other (income) expense, net, was $151 million of expense in the full year of 2025 compared with $24 million of income in the full year of 2024. The unfavorable year-over-year change primarily reflects $170 million of income in 2024 related to the expansion of an existing development and commercialization agreement with Daiichi Sankyo, as well as higher net interest expense and higher foreign exchange losses in 2025, partially offset by higher net income from investments in equity securities in 2025. The effective tax rate was 13.4% for the fourth quarter of 2025 and 13.3% for the full year of 2025. GAAP EPS was $1.19 for the fourth quarter of 2025 compared with $1.48 for the fourth quarter of 2024. The decrease was primarily driven by higher restructuring costs and amortization of intangible assets, partially offset by favorability from lower charges for business development transactions, as well as operational strength in the business driven in part by the benefits of the previously announced multiyear optimization initiative. GAAP EPS was $7.28 for the full year of 2025 compared with $6.74 for the full year of 2024. The increase was primarily driven by favorability from lower charges for business development transactions and operational strength in the business, partially offset by higher restructuring costs and amortization of intangible assets. Non-GAAP Expense, EPS and Related Information Non-GAAP gross margin was 79.7% for the fourth quarter of 2025 compared with 80.8% for the fourth quarter of 2024. The decrease was primarily due to higher inventory write-offs, partially offset by the favorable impact of product mix. Non-GAAP gross margin was 81.5% for the full year of 2025 compared with 80.8% for the full year of 2024. The increase was primarily due to the favorable impact of product mix, partially offset by higher inventory write-offs. Non-GAAP SG&A expenses were $2.8 billion in the fourth quarter of 2025, an increase of 1% compared with the fourth quarter of 2024. The increase was primarily due to higher administrative costs, partially offset by lower promotional costs. Non-GAAP SG&A expenses were $10.6 billion for the full year of 2025, flat compared with the full year of 2024 as lower promotional costs were largely offset by higher administrative costs. Non-GAAP R&D expenses were $4.0 billion in the fourth quarter of 2025, a decrease of 13% compared with the fourth quarter of 2024. Non-GAAP R&D expenses were $15.6 billion for the full year of 2025, a decrease of 13% compared with the full year of 2024. The decrease in both periods was primarily due to lower charges for business development activity, partially offset by higher clinical development costs. Non-GAAP other (income) expense, net, was $226 million of expense in the fourth quarter of 2025 compared with $5 million of expense in the fourth quarter of 2024 primarily due to higher net interest expense and higher foreign exchange losses. Non-GAAP other (income) expense, net, was $460 million of expense in the full year of 2025 compared with $10 million of expense in the full year of 2024. The unfavorable year-over-year change primarily reflects $170 million of income in 2024 related to the expansion of an existing development and commercialization agreement with Daiichi Sankyo, as well as higher net interest expense and higher foreign exchange losses in 2025. The non-GAAP effective tax rate was 15.4% for the fourth quarter of 2025 and 14.4% for the full year of 2025. Non-GAAP EPS was $2.04 for the fourth quarter of 2025 compared with $1.72 for the fourth quarter of 2024. Non-GAAP EPS was $8.98 for the full year of 2025 compared with $7.65 for the full year of 2024. The increase in both periods was primarily driven by favorability from lower charges for business development transactions, as well as operational strength in the business driven in part by the benefits of the previously announced multiyear optimization initiative. A reconciliation of GAAP to non-GAAP net income and EPS is provided in the table that follows. Fourth Quarter Year Ended $ in millions, except EPS amounts 2025 2024 Dec. 31, 2025 Dec. 31, 2024 EPS GAAP EPS $1.19 $1.48 $7.28 $6.74 Difference 0.85 0.24 1.70 0.91 Non-GAAP EPS that excludes items listed below2 $2.04 $1.72 $8.98 $7.65 Net Income GAAP net income1 $2,963 $3,743 $18,254 $17,117 Difference 2,125 629 4,259 2,327 Non-GAAP net income that excludes items listed below1,2 $5,088 $4,372 $22,513 $19,444 Excluded Items: Acquisition- and divestiture-related costs3 $1,107 $711 $3,007 $2,519 Restructuring costs 1,277 187 2,551 888 Loss (income) from investments in equity securities 206 152 (306) 45 Decrease to net income before taxes 2,590 1,050 5,252 3,452 Estimated income tax (benefit) expense4 (465) (421) (993) (1,125) Decrease to net income $2,125 $629 $4,259 $2,327 Pipeline and Portfolio Highlights In 2025, the Company announced positive late-stage trial results from 18 Phase 3 trials and began enrolling patients in 21 new Phase 3 studies evaluating multiple indications and therapeutic areas, with approximately 80 Phase 3 studies currently underway. Throughout the fourth quarter, the Company made important progress to advance its broad, diverse pipeline, meeting significant regulatory and clinical milestones. Oncology: U.S. Food and Drug Administration (FDA) approved KEYTRUDA and KEYTRUDA QLEX, each in combination with Padcev, for the perioperative treatment of adult patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy based on Phase 3 KEYNOTE-905 trial. Approvals represent the first PD-1 inhibitor plus antibody-drug conjugate (ADC) regimens for this patient population. FDA awarded a priority review voucher under the Commissioner’s National Priority Voucher (CNPV) pilot program for sac-TMT, an investigational anti-TROP2 ADC being developed in collaboration with Kelun-Biotech. European Commission (EC) approved the subcutaneous route of administration and new pharmaceutical formulation of KEYTRUDA for use across all KEYTRUDA indications for adult patients in Europe. FDA accepted two supplemental Biologics License Applications (sBLAs) for KEYTRUDA and KEYTRUDA QLEX, each with Trodelvy, for the first-line treatment of certain patients with PD-L1+ inoperable (unresectable) locally advanced or metastatic TNBC based on Phase 3 KEYNOTE-D19/ASCENT-04 trial. FDA set Prescription Drug User Fee Act (PDUFA) dates in the second half of 2026 for these applications. Announced positive topline results from Phase 3 KEYNOTE-B15 trial in patients with MIBC who are eligible for cisplatin-based chemotherapy showing KEYTRUDA plus Padcev significantly improved event-free survival (EFS), overall survival (OS) and pathologic complete response (pCR) rates versus neoadjuvant chemotherapy and surgery when given before and after surgery. In collaboration with Moderna, Inc. (Moderna), announced median five-year follow-up data from Phase 2b KEYNOTE-942/mRNA-4157-P201 study for intismeran autogene, an investigational mRNA-based individualized neoantigen therapy, in combination with KEYTRUDA in patients with high-risk melanoma (stage III/IV) following complete resection. U.S. Food and Drug Administration (FDA) approved KEYTRUDA and KEYTRUDA QLEX, each in combination with Padcev, for the perioperative treatment of adult patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy based on Phase 3 KEYNOTE-905 trial. Approvals represent the first PD-1 inhibitor plus antibody-drug conjugate (ADC) regimens for this patient population. FDA awarded a priority review voucher under the Commissioner’s National Priority Voucher (CNPV) pilot program for sac-TMT, an investigational anti-TROP2 ADC being developed in collaboration with Kelun-Biotech. European Commission (EC) approved the subcutaneous route of administration and new pharmaceutical formulation of KEYTRUDA for use across all KEYTRUDA indications for adult patients in Europe. FDA accepted two supplemental Biologics License Applications (sBLAs) for KEYTRUDA and KEYTRUDA QLEX, each with Trodelvy, for the first-line treatment of certain patients with PD-L1+ inoperable (unresectable) locally advanced or metastatic TNBC based on Phase 3 KEYNOTE-D19/ASCENT-04 trial. FDA set Prescription Drug User Fee Act (PDUFA) dates in the second half of 2026 for these applications. Announced positive topline results from Phase 3 KEYNOTE-B15 trial in patients with MIBC who are eligible for cisplatin-based chemotherapy showing KEYTRUDA plus Padcev significantly improved event-free survival (EFS), overall survival (OS) and pathologic complete response (pCR) rates versus neoadjuvant chemotherapy and surgery when given before and after surgery. In collaboration with Moderna, Inc. (Moderna), announced median five-year follow-up data from Phase 2b KEYNOTE-942/mRNA-4157-P201 study for intismeran autogene, an investigational mRNA-based individualized neoantigen therapy, in combination with KEYTRUDA in patients with high-risk melanoma (stage III/IV) following complete resection. Infectious Diseases: Announced positive topline results from the Phase 3 trial of the investigational, once-daily, oral, two-drug, single-tablet regimen of doravirine/islatravir (DOR/ISL) for the treatment of adults with HIV-1 infection who had not previously received antiretroviral treatment (treatment-naïve). Announced positive topline results from the Phase 3 trial of the investigational, once-daily, oral, two-drug, single-tablet regimen of doravirine/islatravir (DOR/ISL) for the treatment of adults with HIV-1 infection who had not previously received antiretroviral treatment (treatment-naïve). Cardiometabolic and Respiratory: Presented new data at the American Heart Association Scientific Sessions 2025, including results from the Phase 3 CORALreef Lipids and heterozygous familial hypercholesterolemia (HeFH) trials, demonstrating that enlicitide decanoate, an investigational, oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor being evaluated for the treatment of adults with hypercholesterolemia, significantly reduced low-density lipoprotein cholesterol (LDL-C) with a safety profile comparable to placebo. FDA awarded a priority review voucher under the CNPV pilot program for enlicitide decanoate. In January 2026, EC approved an expanded indication for WINREVAIR, in combination with other pulmonary arterial hypertension (PAH) therapies, for the treatment of PAH (Group 1 pulmonary hypertension) in adult patients with World Health Organization (WHO) Functional Class II, III and IV based on Phase 3 ZENITH trial. In February 2026, FDA accepted a new sBLA for WINREVAIR seeking approval to update the U.S. product label based on Phase 3 HYPERION trial. FDA set PDUFA date of September 21, 2026. Announced that Phase 2, proof-of-concept CADENCE study evaluating WINREVAIR in adults for the treatment of combined post- and precapillary pulmonary hypertension (CpcPH) due to heart failure with preserved ejection fraction (HFpEF) met its primary endpoint. Presented new data at the American Heart Association Scientific Sessions 2025, including results from the Phase 3 CORALreef Lipids and heterozygous familial hypercholesterolemia (HeFH) trials, demonstrating that enlicitide decanoate, an investigational, oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor being evaluated for the treatment of adults with hypercholesterolemia, significantly reduced low-density lipoprotein cholesterol (LDL-C) with a safety profile comparable to placebo. FDA awarded a priority review voucher under the CNPV pilot program for enlicitide decanoate. In January 2026, EC approved an expanded indication for WINREVAIR, in combination with other pulmonary arterial hypertension (PAH) therapies, for the treatment of PAH (Group 1 pulmonary hypertension) in adult patients with World Health Organization (WHO) Functional Class II, III and IV based on Phase 3 ZENITH trial. In February 2026, FDA accepted a new sBLA for WINREVAIR seeking approval to update the U.S. product label based on Phase 3 HYPERION trial. FDA set PDUFA date of September 21, 2026. Announced that Phase 2, proof-of-concept CADENCE study evaluating WINREVAIR in adults for the treatment of combined post- and precapillary pulmonary hypertension (CpcPH) due to heart failure with preserved ejection fraction (HFpEF) met its primary endpoint. Business Development: In 2026, completed acquisition of Cidara Therapeutics, Inc. (Cidara) for a total transaction value of approximately $9.2 billion. Added MK-1406 (formerly CD388), an investigational long-acting, strain-agnostic antiviral agent designed to prevent influenza infection in individuals at higher risk of complications, to the Company’s portfolio. MK-1406 is currently being evaluated in the Phase 3 ANCHOR study. Entered into strategic financing agreement with Blackstone Life Sciences to partially fund the development of sac-TMT in 2026. Entered into an agreement with Falk for certain development and commercialization rights to MK-8690, an investigational anti-CD30 ligand monoclonal antibody. In 2026, completed acquisition of Cidara Therapeutics, Inc. (Cidara) for a total transaction value of approximately $9.2 billion. Added MK-1406 (formerly CD388), an investigational long-acting, strain-agnostic antiviral agent designed to prevent influenza infection in individuals at higher risk of complications, to the Company’s portfolio. MK-1406 is currently being evaluated in the Phase 3 ANCHOR study. Entered into strategic financing agreement with Blackstone Life Sciences to partially fund the development of sac-TMT in 2026. Entered into an agreement with Falk for certain development and commercialization rights to MK-8690, an investigational anti-CD30 ligand monoclonal antibody. Notable recent news releases on the Company’s pipeline and portfolio are provided in the table that follows. Visit the News Releases section of the Company’s website to read the releases.* Oncology FDA Approved KEYTRUDA and KEYTRUDA QLEX, Each With Padcev, as Perioperative Treatment for Adults With Cisplatin-Ineligible MIBC; Based on Results From Phase 3 KEYNOTE-905 Trial EC Approved Subcutaneous Administration of KEYTRUDA for All Adult Indications Approved in EU; Based on Results From Phase 3 3475A-D77 Trial KEYTRUDA Plus Padcev Significantly Improved EFS, OS and pCR Rates for Cisplatin-Eligible Patients With MIBC When Given Before and After Surgery; Based on Results From Phase 3 KEYNOTE-B15 Trial The Company and Moderna Announced 5-Year Data for Intismeran Autogene in Combination With KEYTRUDA Demonstrated Sustained Improvement in the Primary Endpoint of Recurrence-Free Survival in Patients With High-Risk Stage III/IV Melanoma Following Complete Resection; Based on Follow-up Analysis From Phase 2b KEYNOTE-942/mRNA-4157-P201 Trial The Company Initiated Phase 3 KANDLELIT-007 Trial Evaluating Calderasib (MK-1084), an Investigational Oral KRAS G12C Inhibitor, in Combination With KEYTRUDA QLEX in Certain Patients With Advanced NSCLC The Company Presented Data at the American Society of Hematology Annual Meeting 2025 That Showcased Continued Advancements in Hematology Pipeline and Novel Therapeutic Approaches Vaccines and Infectious Diseases The Company Announced Positive Topline Results From Pivotal Phase 3 Trial Evaluating Investigational, Once-Daily, Oral, Two-Drug, Single-Tablet Regimen of DOR/ISL in Treatment-Naïve Adults With HIV-1 Infection Cardiometabolic and Respiratory Enlicitide Decanoate Significantly Reduced LDL-C in Phase 3 CORALreef Lipids Trial Enlicitide Decanoate Significantly Reduced LDL-C in Adults With HeFH in Phase 3 CORALreef HeFH Trial WINREVAIR Met Primary Endpoint in Phase 2, Proof-Of-Concept CADENCE Study in Adults With CpcPH Due to HFpEF Neuroscience The Company Showcased Data for Alzheimer’s Disease Candidates MK-2214 and MK-1167 at Clinical Trials on Alzheimer’s Disease 2025 Animal Health FDA Conditionally Approved EXZOLT CATTLE-CA1 for Prevention and Treatment of New World Screwworm (Cochliomyia Hominivorax) Larvae (Myiasis) *References to the Company’s name in the above news release titles have been modified for the purpose of this announcement. U.S. Government Agreement The Company reached an agreement with the U.S. government that is intended to lower medicine costs for Americans. This agreement enables the Company to continue its long-standing commitment to advancing breakthrough scientific discoveries for patients and helps ensure Americans can access the medicines they need at lower costs. The voluntary agreement addresses all four components of the President’s July letter. Under the agreement, among other things, the Company plans to provide key products through a direct-to-patient program at affordable prices for eligible patients in the U.S. In addition, the Company reached an understanding with the U.S. Department of Commerce to delay Section 232 tariffs for three years, enabling the Company to make investments in the U.S. to reshore manufacturing for American patients. The Company has committed more than $70 billion in capital and R&D spending to strengthen U.S. production and innovation. Full-Year 2026 Financial Outlook The following table summarizes the Company’s full-year financial outlook. Full Year 2026 Sales* $65.5 billion to $67.0 billion Non-GAAP Gross margin2 Approximately 82% Non-GAAP Operating expenses2** $35.9 billion to $36.9 billion Non-GAAP Other (income) expense, net2 Approximately $1.3 billion expense Non-GAAP Effective tax rate2 23.5% to 24.5% Non-GAAP EPS2*** $5.00 to $5.15 Share count (assuming dilution) Approximately 2.48 billion *The Company does not have any non-GAAP adjustments to sales. **Includes a one-time charge of approximately $9.0 billion associated with the acquisition of Cidara. Outlook does not assume any additional significant potential business development transactions. ***Includes a one-time charge of approximately $3.65 per share associated with the acquisition of Cidara. The Company has not provided a reconciliation of forward-looking non-GAAP gross margin, non-GAAP operating expenses, non-GAAP other (income) expense, net, non-GAAP effective tax rate and non-GAAP EPS to the most directly comparable GAAP measures, given it cannot predict with reasonable certainty the amounts necessary for such a reconciliation, including intangible asset impairment charges, legal settlements, and income and losses from investments in equity securities either owned directly or through ownership interests in investment funds, without unreasonable effort. These items are inherently difficult to forecast and could have a significant impact on the Company’s future GAAP results. The Company anticipates full-year 2026 sales to be between $65.5 billion and $67.0 billion, including a positive impact from foreign exchange of approximately 1% at mid-January 2026 exchange rates. The Company’s full-year non-GAAP effective income tax rate is expected to be between 23.5% and 24.5% including the impact of the non-tax deductible one-time charge for the acquisition of Cidara. The Company expects full-year 2026 non-GAAP EPS to be between $5.00 and $5.15, including a positive impact from foreign exchange of approximately $0.10 per share at mid-January 2026 exchange rates. This range includes a one-time charge of approximately $9.0 billion, or approximately $3.65 per share, as well as approximately $0.30 per share of related financing and operational costs, related to the acquisition of Cidara. In 2025, non-GAAP EPS of $8.98 was negatively impacted by one-time charges of $0.20 per share related to certain business development transactions. Consistent with past practice, the financial outlook does not assume additional significant potential business development transactions. Non-GAAP EPS excludes acquisition- and divestiture-related costs, costs related to restructuring programs, as well as income and losses from investments in equity securities. Earnings Conference Call Investors, journalists and the general public may access a live audio webcast of the call on Tuesday, Feb. 3, at 9 a.m. ET via this weblink. A replay of the webcast, along with the sales and earnings news release, supplemental financial disclosures and slides highlighting the results, will be available on the Company’s website. All participants may join the call by dialing (800) 369-3351 (U.S. and Canada Toll-Free) or (517) 308-9448 and using the access code 9818590. About Our Company At Merck & Co., Inc., Rahway, N.J., USA, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “Company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the Company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the Company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the Company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The Company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the Company’s Annual Report on Form 10-K for the year ended December 31, 2024 and the Company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov). Appendix Generic product names are provided below. Pharmaceutical BRIDION (sugammadex) CAPVAXIVE (Pneumococcal 21-valent Conjugate Vaccine) ENFLONSIA (clesrovimab-cfor) GARDASIL (Human Papillomavirus Quadrivalent [Types 6, 11, 16 and 18] Vaccine, Recombinant) GARDASIL 9 (Human Papillomavirus 9-valent Vaccine, Recombinant) JANUMET (sitagliptin and metformin HCl) JANUVIA (sitagliptin) KEYTRUDA (pembrolizumab) KEYTRUDA QLEX (pembrolizumab and berahyaluronidase alfa-pmph) LAGEVRIO (molnupiravir) Lenvima (lenvatinib) Lynparza (olaparib) M-M-R II (Measles, Mumps and Rubella Virus Vaccine Live) OHTUVAYRE (ensifentrine) PREVYMIS (letermovir) PROQUAD (Measles, Mumps, Rubella and Varicella Virus Vaccine Live) Reblozyl (luspatercept-aamt) ROTATEQ (Rotavirus Vaccine, Live, Oral, Pentavalent) Simponi (golimumab) VARIVAX (Varicella Virus Vaccine Live) VAXNEUVANCE (Pneumococcal 15-valent Conjugate Vaccine) WELIREG (belzutifan) WINREVAIR (sotatercept-csrk) Animal Health BRAVECTO (fluralaner) ____________________ 1 Net income attributable to the Company. 2 The Company is providing certain 2025 and 2024 non-GAAP information that excludes certain items because of the nature of these items and the impact they have on the analysis of underlying business performance and trends. Management believes that providing this information enhances investors’ understanding of the Company’s results because management uses non-GAAP results to assess performance. Management uses non-GAAP measures internally for planning and forecasting purposes and to measure the performance of the Company along with other metrics. In addition, annual employee compensation, including senior management’s compensation, is derived in part using a non-GAAP pretax income metric. This information should be considered in addition to, but not as a substitute for or superior to, information prepared in accordance with GAAP. For a description of the non-GAAP adjustments, see Table 2a attached to this release. 3 Reflects expenses related to business combinations, including the amortization of intangible assets, intangible asset impairment charges, and expense or income related to changes in the estimated fair value measurement of liabilities for contingent consideration. Also includes integration, transaction and certain other costs associated with acquisitions and divestitures, as well as amortization of intangible assets related to collaborations, licensing arrangements and asset acquisitions, and recognition of fair value step-up to inventories for asset acquisitions. 4 Includes the estimated tax impacts on the reconciling items based on applying the statutory rate of the originating territory of the non-GAAP adjustments for all periods presented. Amount in the full year of 2025 also includes a $60 million net benefit, which reflects a net benefit related to favorable audit reserve adjustments. Amounts in the fourth quarter and full year of 2024 also include a $260 million benefit and a $519 million benefit, respectively, due to reductions in reserves for unrecognized income tax benefits resulting from the expiration of the statute of limitations for assessments related to certain federal tax return years. The benefit recognized in the fourth quarter of 2024 relates to the 2020 federal tax return year and the benefit for the full year of 2024 relates to both the 2020 and 2019 federal tax return years. 4Q25 4Q24 $ 16,400 $ 15,624 5% $ 65,011 $ 64,168 1% 5,551 3,828 45% 16,382 15,193 8% 2,898 2,864 1% 10,733 10,816 -1% 3,886 4,585 -15% 15,789 17,938 -12% 213 51 889 309 432 126 151 (24 ) 3,420 4,170 -18% 21,067 19,936 6% 458 425 2,804 2,803 2,962 3,745 -21% 18,263 17,133 7% (1 ) 2 9 16 $ 2,963 $ 3,743 -21% $ 18,254 $ 17,117 7% $ 1.19 $ 1.48 -20% $ 7.28 $ 6.74 8% 2,488 2,537 2,507 2,541 13.4 % 10.2 % 13.3 % 14.1 % $ 5,551 1,054 1,173 2,227 $ 3,324 2,898 48 2 50 2,848 3,886 5 (111 ) (106 ) 3,992 213 213 213 – 432 206 206 226 3,420 (1,107 ) (1,277 ) (206 ) (2,590 ) 6,010 458 (187 ) (3) (234 ) (3) (44 ) (3) (465 ) 923 2,962 (920 ) (1,043 ) (162 ) (2,125 ) 5,087 2,963 (920 ) (1,043 ) (162 ) (2,125 ) 5,088 $ 1.19 (0.37 ) (0.42 ) (0.06 ) (0.85 ) $ 2.04 13.4 % 15.4 % $ 16,382 2,871 1,484 4,355 $ 12,027 10,733 120 3 123 10,610 15,789 19 175 194 15,595 889 889 889 – 151 (3 ) (306 ) (309 ) 460 21,067 (3,007 ) (2,551 ) 306 (5,252 ) 26,319 2,804 (525 ) (3) (473 ) (3) 65 (3) (60 ) (4) (993 ) 3,797 18,263 (2,482 ) (2,078 ) 241 60 (4,259 ) 22,522 18,254 (2,482 ) (2,078 ) 241 60 (4,259 ) 22,513 $ 7.28 (0.99 ) (0.83 ) 0.10 0.02 (1.70 ) $ 8.98 13.3 % 14.4 % 2025 2024 4Q Full Year $15,529 $15,806 $17,276 $16,400 $65,011 $15,775 $16,112 $16,657 $15,624 $64,168 5 4 1 2 13,638 14,050 15,611 14,843 58,142 14,006 14,408 14,943 14,042 57,400 6 4 1 1 7,205 7,956 8,142 8,337 31,641 6,947 7,270 7,429 7,836 29,482 6 5 7 7 5 35 40 - - - - 312 370 379 389 1,450 292 317 337 365 1,311 7 4 11 10 258 265 258 272 1,053 255 249 251 255 1,010 7 6 4 4 137 162 196 220 716 85 126 139 160 509 37 37 41 41 119 107 136 164 525 71 90 100 110 371 48 48 41 41 1,327 1,126 1,749 1,031 5,233 2,249 2,478 2,306 1,550 8,583 -34 -35 -39 -39 539 609 684 619 2,451 570 617 703 594 2,485 4 3 -1 -2 230 229 226 140 825 219 189 239 161 808 -13 -16 2 1 107 129 244 279 759 47 50 97 228 121 204 119 673 216 163 193 139 711 -14 -15 -5 -5 41 38 45 42 166 61 59 68 74 263 -43 -44 -37 -37 441 461 439 499 1,841 440 455 420 449 1,764 11 11 4 4 208 228 266 275 978 174 188 208 215 785 28 26 25 23 70 74 81 87 312 56 62 64 70 252 24 23 24 24 83 96 43 25 247 73 92 96 79 340 -68 -68 -27 -27 280 336 360 467 1,443 70 149 200 419 133 133 106 123 112 129 470 98 106 102 109 415 18 18 13 13 68 80 82 83 312 70 72 72 73 287 14 9 9 6 178 178 - - - - 102 83 138 57 380 350 110 383 121 964 -53 -53 -61 -61 90 86 82 67 325 111 89 102 92 394 -27 -28 -18 -18 67 83 77 79 306 56 60 65 69 249 15 9 23 20 45 41 43 42 171 42 39 42 40 163 6 4 5 4 50 40 47 49 186 46 53 78 45 222 8 9 -16 -16 184 172 189 543 -100 -100 39 35 41 114 -100 -100 549 372 382 302 1,604 419 405 278 232 1,334 30 30 20 21 247 251 243 199 940 251 224 204 255 935 -22 -22 1 2 729 584 948 658 2,917 632 618 638 699 2,590 -6 -5 13 13 1,588 1,646 1,615 1,505 6,354 1,511 1,482 1,487 1,397 5,877 8 6 8 9 924 961 1,023 987 3,896 850 837 886 889 3,462 11 9 13 14 664 685 592 518 2,458 661 645 601 508 2,415 2 0 2 2 303 110 50 52 515 258 222 227 185 891 -71 -15 -42 -6