Droxidopa

这份报告全面概述了多系统萎缩（MSA），这是一种致命的神经退行性疾病，其特点是α-突触核蛋白在少突胶质细胞中异常聚集。报告详细阐述了MSA的临床表现，包括帕金森型（MSA-P）和小脑型（MSA-C）的异质性，并强调了自主神经功能衰竭作为核心特征。 深入探讨了分子发病机制，提出α-突触核蛋白具有类似朊病毒的行为，以及不同“毒株”如何导致MSA与帕金森病的差异。此外，报告还涵盖了神经炎症和遗传易感性在疾病进展中的作用，并介绍了2022年国际运动障碍学会（MDS）的新诊断标准、先进的影像学和生物标志物，特别提到了用于早期诊断和鉴别的α-突触核蛋白种子扩增试验和皮肤活检。 最后，报告展望了治疗前沿，重点介绍了靶向α-突触核蛋白的疾病修正疗法（DMTs），并强调了全球协作在克服研究挑战和寻找有效治疗方案方面的重要性。 第一部分：重新定义多系统萎缩：临床谱系与病理学标志 多系统萎缩（Multiple System Atrophy, MSA）是一种致命的、快速进展的成人发病神经退行性疾病，其临床表现的异质性和病理过程的独特性使其成为神经科学领域最具挑战性的疾病之一。本报告旨在全面、深入地剖析MSA的全球研究现状，从基础的分子病理机制到前沿的诊断技术和治疗策略，系统性地梳理该领域的关键进展、核心挑战与未来方向。1.1 历史背景与现代定义 MSA的现代概念是在对一组临床上看似不同但病理上相关的综合征进行长期观察和研究后逐渐形成的。在20世纪下半叶，神经病学界描述了三种独立的临床实体：以严重自主神经功能衰竭为特征的夏伊-德雷格尔综合征；以帕金森样症状为主的纹状体黑质变性；以及以小脑性共济失调为主的散发性橄榄脑桥小脑萎缩。尽管它们的临床侧重点不同，但研究人员逐渐注意到这些疾病在病程、对治疗的反应以及最终的病理学发现上存在重叠。   1969年，Graham和Oppenheimer首次提出“多系统萎缩”这一术语，旨在统一这些具有共同病理基础的疾病 。这一概念的提出是一个里程碑，它标志着研究重点从临床现象学转向了对共同细胞和分子机制的探索。随后的研究，特别是在20世纪末发现了α-突触核蛋白在这些疾病中的核心作用后，进一步巩固了MSA作为一个独立疾病实体的地位 。   根据目前的共识，MSA被定义为一种散发性、进行性的成人发病（通常>30岁）神经退行性疾病，其临床核心表现为自主神经功能衰竭、帕金森综合征和小脑性共济失调的不同组合 。该病的发病年龄通常在50至60岁之间 。MSA是一种罕见病，其患病率估计为每10万人中2至5例，年发病率约为每10万人中0.6至0.7例 。然而，由于早期诊断困难且常被误诊为帕金森病，其实际患病率可能被低估 。  1.2 临床二元分型：帕金森型（MSA-P）与小脑型（MSA-C） MSA的临床异质性主要通过其两大核心运动亚型来体现，这种分型基于患者在诊断时最主要的运动障碍 。   帕金森型（MSA-P）：这是在西方人群中最常见的亚型，约占所有病例的70%至80% 。其症状与帕金森病高度相似，包括运动迟缓（bradykinesia）、肌肉僵直、姿势不稳和震颤 。然而，与典型的帕金森病不同，MSA-P患者的震颤通常不典型，可能表现为静止性和动作性震颤的混合，且常伴有肌阵挛成分 。最关键的鉴别特征之一是MSA-P对左旋多巴——帕金森病治疗的基石药物——的反应通常很差或仅有短暂的轻微改善 。这种治疗反应的差异反映了两者在神经病理学基础上的根本不同。   小脑型（MSA-C）：该亚型在东亚人群中更为普遍，例如在日本，约三分之二的MSA患者表现为MSA-C 。其临床表现主要由小脑功能障碍主导，导致步态共济失调（通常表现为宽基底步态）、肢体协调障碍、言语含糊不清（构音障碍）以及眼球运动异常，如眼震。   MSA-P和MSA-C在不同种族人群中的患病率存在显著差异，这一现象为疾病的病因学研究提供了重要线索。MSA-P在西方人群中的主导地位与MSA-C在亚洲人群中的高发，强烈暗示了遗传背景与未知的环境因素之间可能存在复杂的相互作用，共同决定了神经退行性病变优先影响的脑区。虽然MSA绝大多数为散发性疾病，但这种明显的种族/地理偏向性表明，某些在特定人群中更为常见的遗传多态性，可能使个体在暴露于某种致病触发因素时，更容易出现纹状体黑质系统（导致MSA-P）或橄榄脑桥小脑系统（导致MSA-C）的脆弱性。这一观察结果对于未来的遗传学研究具有深远意义，提示全基因组关联研究应按种族进行分层分析，以期发现与特定亚型相关的风险基因位点。1.3 普遍存在的常数：自主神经功能衰竭 无论运动亚型如何，自主神经功能衰竭都是MSA的核心和定义性特征，通常在疾病早期出现，是区分MSA与其他帕金森综合征的关键 。自主神经系统的广泛受累反映了疾病的多系统性。   其主要临床表现包括： 直立性低血压：指从卧位或坐位转为站立位时血压显著下降，导致头晕、视物模糊甚至晕厥 。这是MSA患者致残和跌倒风险的主要原因之一。   泌尿生殖系统功能障碍：包括尿急、尿频、尿失禁或尿潴留。在男性患者中，勃起功能障碍是一个非常普遍且常常是首发症状之一 。   其他自主神经症状：还包括排汗减少导致的热不耐受、顽固性便秘以及因体温调节障碍导致的手脚冰冷 。此外，睡眠障碍也十分常见，尤其是快速眼动睡眠行为障碍和夜间喉鸣，后者可导致呼吸暂停和猝死 。   1.4 毁灭性的自然病程与预后 MSA的病程以其快速和无情的进展为特征，明显快于帕金森病 。从症状出现到死亡的中位生存期约为7至10年，但个体差异很大 。   疾病的致残性里程碑迅速到来。许多患者在症状出现的几年内就需要助行器等辅助设备，大约60%的患者在发病5年后需要依赖轮椅，而在6至8年内，至少半数患者可能卧床不起 。   死亡原因通常与呼吸系统并发症有关，如因吞咽困难导致的吸入性肺炎，或因喉鸣和中枢性睡眠呼吸暂停导致的睡眠中猝死 。感染和肺栓塞也是常见的终末期事件 。  1.5 病理学金标准：胶质细胞胞浆内包涵体 MSA的确诊依赖于死后脑组织病理学检查。其病理学标志是在少突胶质细胞的胞浆内发现大量嗜酸性包涵体，即胶质细胞胞浆内包涵体，也称为Papp-Lantos小体 。   免疫组织化学研究证实，这些包涵体的主要蛋白成分是异常聚集的、呈丝状结构的α-突触核蛋白 。这一关键发现将MSA与帕金森病及路易体痴呆共同归类为α-突触核蛋白病。   然而，MSA在α-突触核蛋白病中独树一帜，因为其病理改变主要累及少突胶质细胞，即中枢神经系统中负责生产和维护髓鞘的细胞。相比之下，帕金森病和路易体痴呆的病理特征是α-突触核蛋白主要在神经元内聚集形成路易体。因此，MSA被认为是一种原发性少突胶质细胞病。学界普遍认为，少突胶质细胞的功能障碍和死亡是MSA神经退行性过程的始动环节，而神经元的变性死亡至少部分是继发于这种胶质细胞的病变 。  第二部分：MSA的分子发病机制：一种α-突触核蛋白朊病毒病 对MSA分子机制的理解在过去二十年中取得了革命性进展，其核心在于将α-突触核蛋白的角色从一个简单的病理标志物重新定位为疾病的中心致病因子。越来越多的证据表明，病理性的α-突触核蛋白表现出类似于朊病毒的行为，通过构象的自我复制和传播驱动疾病的发生发展。2.1 α-突触核蛋白：从正常功能到病理性聚集 α-突触核蛋白是一种由140个氨基酸组成的蛋白，在生理状态下主要定位于神经元的突触前末梢，参与突触囊泡的运输和释放过程，对正常的神经递质传递至关重要 。   在包括MSA、PD和DLB在内的α-突触核蛋白病中，这种通常呈可溶性单体状态的蛋白发生错误折叠，并聚集成不溶性的β-折叠片层状纤维 。这些纤维是构成GCIs（在MSA中）和路易体（在PD和DLB中）的核心成分，其在神经系统内的积累被认为是导致神经元和胶质细胞功能障碍及死亡的关键原因 。  2.2 朊病毒假说：播种、增殖与传播 “朊病毒样”（prion-like）假说为解释α-突触核蛋白病的渐进性提供了强有力的理论框架。该假说认为，错误折叠的α-突触核蛋白聚集体可以作为“种子”，通过模板导向的构象转变机制，诱导细胞内正常的可溶性α-突触核蛋白单体也转变为病理性的错误折叠构象 。   这些新形成的“种子”可以进一步聚集，并通过细胞间机制（如胞吐、胞吞、隧道纳米管等）从一个细胞传播到另一个细胞，从而在解剖学上相互连接的神经网络中扩散病理改变 。这一过程解释了为何这些疾病通常始于特定的脑区，然后随着时间的推移逐渐蔓延至更广泛的神经系统。   支持MSA是一种朊病毒病的最有力证据之一来自于动物实验。研究表明，将从MSA患者脑组织中提取的α-突触核蛋白聚集物注射到表达人源α-突触核蛋白的转基因小鼠脑内，可以诱导小鼠出现进行性的神经系统疾病和广泛的α-突触核蛋白病理沉积 。这一发现满足了“朊病毒”操作性定义中的一个关键标准，即病理蛋白的可传播性。然而，需要强调的是，这并不意味着MSA像经典的朊病毒病（如克雅氏病）一样具有人际传染性。在正常情况下，MSA的人际传播被认为是极不可能发生的 。目前，学界对于应将α-突触核蛋白称为“朊病毒”、“朊病毒样蛋白”还是“朊病毒样物”仍在进行深入的讨论 。  2.3 “毒株”理论：对临床多样性的分子解释 α-突触核蛋白病领域一个长期悬而未决的核心问题是：同一种蛋白（α-突触核蛋白）如何导致临床和病理表现截然不同的疾病，如MSA和PD？借鉴于经典朊病毒生物学的“毒株”理论为此提供了迄今为止最令人信服的解释 。   该理论提出，α-突触核蛋白可以错误折叠成多种不同的、在结构上稳定的三维构象，即“毒株”。每种“毒株”都具有独特的生物学特性，包括不同的聚集动力学、细胞毒性、细胞趋向性（即优先感染特定类型的细胞）以及在脑内的传播模式 。   近年来，低温电子显微镜技术的突破性进展为这一理论提供了直接的结构生物学证据。研究人员成功解析了从MSA和PD患者脑组织中提取的α-突触核蛋白纤维的高分辨率结构，揭示了它们之间惊人的差异。源自MSA的α-突触核蛋白纤维由两条不对称的原纤维以独特的螺旋方式缠绕而成；相比之下，源自PD的纤维则由单条原纤维构成 。   这种结构上的差异不仅仅是学术上的发现，它很可能构成了MSA与PD在临床和病理上表现迥异的根本分子基础，并能直接解释MSA为何具有更强的侵袭性。首先，临床观察证实MSA的病程进展比PD更快，患者生存期更短，致残程度更严重 。其次，病理学上的核心区别在于，MSA的标志是少突胶质细胞内的GCIs，而PD的标志是神经元内的路易体 。再次，动物实验数据表明，源自MSA的α-突触核蛋白“种子”在诱导聚集和导致神经退行性病变方面的效力远高于源自PD的“种子”。最后，cryo-EM揭示的MSA纤维独特的双原纤维结构，相比PD的单原纤维结构更为复杂和稳定 。   将这些线索整合起来，可以构建一个统一的理论模型：MSA α-突触核蛋白“毒株”所特有的双原纤维结构，可能赋予了其更高的结构稳定性或更高效的模板复制表面。这种在“播种”和增殖效率上的优势，可以直接转化为病理改变在脑内更快的传播速度，从而导致更具侵袭性的临床病程。此外，这种特定的三维构象可能对少突胶质细胞具有独特的趋向性或亲和力，解释了为何MSA主要表现为一种胶质细胞病。因此，“毒株”假说提供了一个优雅的理论，将致病蛋白的分子结构、细胞病理学特征以及毁灭性的临床现实直接联系起来。这对未来的治疗策略开发具有深远影响，它强烈暗示，有效的疾病修正疗法可能需要针对特定“毒株”进行设计，即需要开发出能够特异性识别和清除MSA型α-突触核蛋白聚集体的药物。第三部分：疾病的调节因素：神经炎症与遗传易感性 在α-突触核蛋白核心病理的周围，存在着一个复杂的生物学环境，它深刻影响着疾病的发生和发展。其中，大脑的免疫反应——神经炎症，以及个体的遗传背景，是两个最为关键的调节因素。3.1 神经炎症：损伤的恶性循环 神经炎症是MSA脑组织中的一个显著病理特征，其标志是小胶质细胞和星形胶质细胞的激活 。这并非一个被动的继发性反应，而是主动参与并加速疾病进展的关键环节。   从功能失常或死亡的细胞中释放到细胞外的α-突触核蛋白聚集体，可以作为一种“危险信号”，直接激活作为大脑常驻免疫细胞的小胶质细胞和作为支持细胞的星形胶质细胞。这种激活过程很可能通过细胞表面的模式识别受体，如Toll样受体介导 。   一旦被激活，这些胶质细胞会释放大量的促炎性细胞因子（如肿瘤坏死因子-α，白细胞介素-1β）、趋化因子和活性氧。这不仅对周围的神经元和少突胶质细胞产生直接的毒性作用，还会创造一个持续的、慢性的炎症微环境。   MSA的发病机制可以被理解为一个破坏性的正反馈循环，其中原发的少突胶质细胞病变启动了继发的、自我驱动的神经炎症反应，而后者又反过来加速和放大了整个神经退行性过程。这个过程的逻辑链条如下： 始动事件：疾病始于α-突触核蛋白在少突胶质细胞内聚集形成GCIs，这确立了MSA作为一种原发性少突胶质细胞病的本质 。   释放危险信号：承受压力或濒临死亡的少突胶质细胞将聚集的α-突触核蛋白释放到细胞外空间。 免疫激活：这些细胞外聚集体作为损伤相关分子模式，被大脑的免疫细胞——小胶质细胞和星形胶质细胞——识别并激活 。   炎症级联反应：被激活的胶质细胞释放出大量的促炎介质，形成一个具有神经毒性的炎症微环境 。   反馈与放大：这个炎症环境不仅仅是一个后果，更是一个加速器。由炎症引起的氧化应激和细胞因子信号会损害邻近神经元和少突胶质细胞的蛋白质稳态系统，即细胞内蛋白质的质量控制机制，使它们更容易发生α-突触核蛋白的错误折叠和聚集 。这会产生更多的病理性“种子”，这些“种子”随后被释放，又激活更多的胶质细胞。由此，一个恶性循环得以建立：GCI形成 → α-突触核蛋白释放 → 胶质细胞激活 → 神经炎症 → α-突触核蛋白聚集和传播加剧。这个模型不仅解释了MSA病理改变的快速和广泛性，也提示有效的治疗策略可能需要同时靶向α-突触核蛋白和神经炎症这两个环节。   3.2 遗传易感性：一幅复杂且不完整的图景 绝大多数MSA病例被认为是散发性的，即没有明确的家族遗传史，也未能发现导致绝大多数病例的单一孟德尔遗传致病基因 。   尽管如此，罕见的家族性MSA病例确实存在，并且越来越多的研究表明，遗传因素在决定个体患病风险方面扮演着重要角色 。目前的研究主要集中在识别那些可能增加MSA易感性的遗传风险因子（即多态性）。   COQ2 基因：该基因编码辅酶Q10合成通路中的一种关键酶。辅酶Q10在线粒体能量代谢和抗氧化防御中发挥着至关重要的作用。研究发现，COQ2基因的某些变异与MSA风险相关，尤其是在日本及其他东亚人群中 。其中，V393A变异是一个在东亚人群中被反复验证的显著风险因子 。然而，这种关联在欧洲和北美人群的队列研究中未能得到一致的重复，这凸显了MSA遗传结构存在的种族特异性 。   SNCA 基因：该基因编码α-突触核蛋白。虽然SNCA基因的点突变或拷贝数变异是导致家族性帕金森病的原因，但至今未发现类似的致病性突变与MSA相关。然而，一些位于SNCA基因座的常见遗传多态性被发现与高加索（白种）人群中散发性MSA的风险增加有关，但这种关联在亚洲人群中并未观察到 。   GBA 及其他基因：GBA基因的变异是帕金森病最强的遗传风险因子之一，但其在MSA中的作用仍存在争议，各项研究结果不一 。其他一些与神经退行性疾病相关的基因，如  : LRRK2和C9orf72，在MSA中的研究也大多得出了阴性或不确定的结论 。   综上所述，MSA的遗传学图谱呈现出一种复杂疾病的典型特征：它并非由单一基因主导的孟德尔遗传病，而更可能是一个由多个低外显率的遗传变异与环境因素相互作用共同决定的多基因病。COQ2在亚洲人群和SNCA在欧洲人群中的风险关联所表现出的强烈种族特异性，进一步强调了进行大规模、跨种族遗传学研究的必要性，只有这样才能全面绘制出MSA的遗传风险图谱，并揭示其发病的深层生物学机制。第四部分：诊断革命：从临床标准到分子生物标志物 MSA的诊断正在经历一场范式转变，从过去依赖于临床表现、排他性诊断和概率评估，转向一种基于生物学的、能够实现阳性识别的诊断模式。这一转变至关重要，因为它直接关系到能否将正确的患者纳入针对性的临床试验中，从而加速新疗法的开发。4.1 2022年国际运动障碍学会（MDS）诊断标准 认识到以往的诊断标准（如2008年第二版共识标准）对于疾病早期阶段的敏感性不足，国际运动障碍学会（MDS）于2022年发布了全新的MSA诊断标准 。新标准的主要目标是提高早期诊断的准确性，从而为疾病修正疗法的开发和临床试验的开展提供坚实的基础 。   新标准的关键创新之处在于： 四个确定性级别：新标准将诊断确定性分为四个等级：神经病理学确诊MSA、临床确诊MSA、临床很可能MSA，以及一个全新的类别——可能的前驱期MSA。   前驱期MSA的引入：这一创新类别旨在识别处于疾病最早阶段的个体，甚至在典型的运动综合征完全显现之前。其诊断标准要求存在经多导睡眠图证实的REM睡眠行为障碍，并伴有神经源性直立性低血压或特定的泌尿生殖系统功能衰竭 。这是迈向未来预防性临床试验的关键一步。 强化MRI的作用：特定的脑部MRI表现（如壳核萎缩、“热十字征”）从过去的支持性特征，提升为达到最高临床确定性级别（“临床确诊MSA”）的必要条件之一 。这标志着影像学在MSA诊断流程中的地位得到了显著提升。   为了更清晰地展示这一演变，下表对2008年和2022年的诊断标准进行了比较。 表1：2008年第二版共识与2022年MDS诊断标准对比 特征 2008年第二版共识标准 2022年MDS诊断标准诊断确定性级别 可能的MSA (Possible MSA) 很可能的MSA (Probable MSA) 可能的前驱期MSA (Possible prodromal MSA) 临床很可能MSA (Clinically probable MSA) 临床确诊MSA (Clinically established MSA) 神经病理学确诊MSA (Neuropathologically established MSA)核心临床特征 自主神经功能衰竭是“很可能的MSA”的必要条件。 “临床很可能MSA”可由帕金森综合征和小脑功能障碍组合诊断，不强制要求自主神经功能衰竭。支持性特征（警示征） 作为支持诊断的附加项。 在“临床确诊MSA”中，至少需要两项支持性特征，地位提升。MRI标志物 作为支持诊断的附加项。 在“临床确诊MSA”中，至少需要一项MRI标志物，成为必要条件。前驱期诊断 无此概念。 首次引入“可能的前驱期MSA”类别，旨在识别高危个体。排除标准 相对笼统。 更加具体和细化，例如明确排除了对左旋多巴的显著持续反应、不明原因的嗅觉丧失等。 4.2 先进神经影像学：病理过程的可视化 虽然常规的脑部MRI可能仅显示非特异性的脑萎缩，但先进的影像技术能够提供更具特异性的诊断线索 。   结构MRI：能够揭示MSA特征性的脑区萎缩，包括壳核、脑桥和中小脑脚的萎缩。在T2加权像上观察到的脑桥“热十字征”（hot cross bun sign）——一种十字形高信号——对MSA具有很高的特异性，但并非所有患者都会出现 。   弥散张量成像（DTI）：该技术能够探测脑白质微观结构的完整性。在MSA中，DTI可以在出现明显脑萎缩之前就检测到壳核和中小脑脚等区域的弥散性增加，反映了神经纤维束的早期损伤 。   正电子发射断层扫描（PET）：PET可以用于评估多巴胺能系统的功能状态，显示纹状体多巴胺转运体（DAT）的丢失，这与帕金森病相似。更重要的是，利用特异性示踪剂（如靶向小胶质细胞激活的示踪剂），PET能够实现神经炎症的可视化，这可能有助于将MSA与帕金森病区分开来，因为MSA通常伴有更显著的神经炎症反应 。  4.3 生化生物标志物：分子诊断时代的曙光 能够直接检测α-突触核蛋白核心病理的生物标志物是近年来MSA诊断领域最重大的突破。 α-突触核蛋白种子扩增试验（SAAs）：这类超高灵敏度的检测技术，包括实时震动诱导转化（RT-QuIC）和蛋白质错误折叠循环扩增（PMCA），能够在脑脊液（CSF）等生物体液中检测到极其微量的错误折叠α-突触核蛋白“种子” 。   皮肤活检检测磷酸化α-突触核蛋白（P-SYN）：通过对患者进行简单的皮肤活检，可以检测到病理性的、磷酸化的α-突触核蛋白在外周自主神经纤维中的沉积 。   未来精准诊断MSA的路径，将不再依赖于单一的“金标准”测试，而是一种整合策略，它将2022年MDS标准所提炼的临床怀疑与一整套特异性分子生物标志物相结合，形成一种“钳形攻势”，以极高的确定性锁定诊断。这一策略的逻辑构建如下：首先，临床医生面临的挑战是，早期MSA是帕金森病的“完美模仿者”，导致极高的误诊率，这不仅影响患者的预后判断，也严重干扰了临床试验的纯度 。为了打破这一僵局，诊断策略的第一步，即“钳形攻势”的一臂，是利用2022年MDS标准，特别是其“前驱期MSA”的定义，来系统性地识别出那些具有高概率患有α-突触核蛋白病的高风险个体 。这一步完成了临床层面的初步筛选。   接下来，分子生物标志物构成了“钳形攻势”的另一臂，提供生物学层面的确证。然而，对这些标志物的解读需要精细的策略。现有的研究表明，脑脊液的RT-QuIC试验在帕金森病患者中具有极高的阳性率，但在MSA患者中通常是阴性的 。这一看似矛盾的结果，实际上使其成为一个强大的工具：在一个临床表现模棱两可的病例中，阳性的RT-QuIC结果强烈指向帕金森病，而阴性结果则极大地增加了对MSA的怀疑。在此基础上，进行第二步分子检测——皮肤活检。研究证实，与帕金森病患者相比，MSA患者皮肤神经纤维中的磷酸化α-突触核蛋白沉积负荷更重，分布也更为广泛 。因此，在一个RT-QuIC阴性的高风险个体中，如果皮肤活检显示出广泛、高密度的磷酸化α-突触核蛋白沉积，那么就可以以超过90%的敏感性和特异性做出MSA的诊断 。这种以临床标准为导向，继以脑脊液和皮肤活检进行两步式分子鉴定的“钳形攻势”，将从根本上改变MSA的诊断范式，为未来的精准医疗和高效临床试验铺平道路。  第五部分：治疗前沿：靶向MSA核心病理 MSA的治疗领域正处于一个充满希望但又极具挑战的十字路口。一方面，对症治疗在改善患者生活质量方面取得了一定进展；另一方面，针对疾病根本原因的修正疗法（DMTs）的研发正以前所未有的速度和精准度向前推进。5.1 对症治疗：改善生活质量 目前，尚无能够治愈或阻止MSA进展的疗法，所有治疗均以缓解症状、维持功能为目标 。   帕金森综合征：左旋多巴可能对少数患者的运动症状有轻微且短暂的改善，但总体反应率低且效果不持久 。   直立性低血压：管理措施包括非药物干预（如增加水盐摄入、穿戴弹力袜、分段睡眠）和药物治疗，常用药物有米多君、屈昔多巴和氟氢可的松。一种新型的去甲肾上腺素再摄取抑制剂Ampreloxetine正在进行针对该症状的后期临床试验，显示出良好的前景 。   其他症状：针对泌尿功能障碍的药物或泌尿科干预、针对平衡障碍的物理治疗、以及针对构音和吞咽障碍的言语和吞咽康复训练，都是综合管理中不可或缺的部分 。  5.2 疾病修正疗法（DMTs）的探索 在过去，许多DMT的临床试验都以失败告终，其原因往往在于药物靶点不够精准，或是干预时机过晚，患者的神经系统已遭受不可逆的损伤 。   当前的药物研发管线呈现出高度的理性化和靶向性，绝大多数在研疗法都直接或间接地聚焦于α-突触核蛋白这一核心致病分子 。下表总结了目前处于临床开发阶段的最有希望的几种DMT。   表2：MSA临床试验管线中的关键疾病修正疗法 治疗策略 作用机制 药物名称（代码） 申办方/公司 当前开发阶段减少α-突触核蛋白生成 反义寡核苷酸（ASO） ION464 Ionis / Biogen I/IIa期（HORIZON研究）增强α-突触核蛋白清除 单克隆抗体 Amlenetug (Lu AF82422) Lundbeck III期（MASCOT研究）增强α-突触核蛋白清除 单克隆抗体 TAK-341 Takeda 临床开发中抑制α-突触核蛋白聚集 铁离子螯合/再分布 ATH434 Alterity Therapeutics II期完成，获FDA快速通道认定抑制α-突触核蛋白聚集 聚集抑制剂 Emrusolmin (TEV-'286) Teva / MODAG 临床开发中增强α-突触核蛋白清除 主动免疫（疫苗） UB-312 Vaxxinity 临床开发中 5.3 关键在研治疗策略详解 减少α-突触核蛋白的产生（基因沉默疗法）： 反义寡核苷酸（ASOs）：这是一种人工合成的短链核酸分子，被设计用来特异性地与编码α-突触核蛋白的信使RNA（mRNA）结合。这种结合会触发细胞内的降解机制，从而从源头上减少α-突触核蛋白的合成 。   ION464（Ionis/Biogen）：作为该领域的代表，ION464通过鞘内注射给药，目前正在进行一项I/IIa期临床试验。初步数据显示该药物具有良好的安全性和耐受性 。   增强α-突触核蛋白的清除（免疫疗法）： 被动免疫（单克隆抗体）：该策略通过静脉输注在体外工程化生产的特异性抗体。这些抗体能够进入中枢神经系统，结合细胞外的α-突触核蛋白聚集体，并标记它们，以便被小胶质细胞等免疫细胞识别和清除 。   Amlenetug (Lu AF82422, Lundbeck)：一种靶向α-突触核蛋白的单克隆抗体，在II期临床试验中显示出积极信号，目前已进入关键性的III期试验（MASCOT研究），并获得了美国FDA的快速通道认定，表明其巨大的治疗潜力 。   TAK-341 (Takeda)：是另一款进入临床开发阶段的单克隆抗体 。   主动免疫（疫苗）：与被动免疫不同，主动免疫旨在通过注射经过设计的抗原（如UB-312），刺激患者自身的免疫系统产生能够识别并清除病理性α-突触核蛋白的抗体 。   抑制α-突触核蛋白的聚集： 这类疗法通常是小分子药物，旨在通过多种机制干扰α-突触核蛋白从单体到纤维的聚集过程，或稳定其正常的、非致病的构象。 ATH434 (Alterity Therapeutics)：一种口服药物，其作用机制独特，旨在重新分布脑内异常积累的铁离子。铁离子被认为是促进α-突触核蛋白聚集和氧化应激的关键因素。该药物在II期试验中取得了积极结果，同样获得了FDA的快速通道认定 。   Emrusolmin (TEV-'286, Teva/MODAG)：是另一款正在进行临床研究的口服聚集抑制剂 。   5.4 MSA临床试验面临的挑战 尽管前景光明，但MSA的DMT临床试验之路依然充满挑战。 疾病罕见性：作为一种罕见病，招募足够数量的合格患者进行大规模临床试验本身就是一个巨大的挑战 。   病程快速：MSA的快速进展特性意味着治疗的窗口期非常狭窄。此外，这也给在典型的试验周期内（如1-2年）准确测量药物对延缓疾病进展的效果带来了统计学上的困难 。   临床异质性：MSA-P和MSA-C亚型在临床表现和可能的病理进展速度上存在差异，这可能需要在试验设计中对患者进行分层分析，增加了试验的复杂性。 缺乏成熟的进展生物标志物：目前尚无公认的、能够可靠追踪MSA疾病进展的生物标志物。这使得客观评估一种试验性药物是否真正减缓了疾病的生物学进程变得异常困难。血浆或脑脊液中的神经丝轻链被认为是一个有潜力的候选标志物，但仍需进一步的验证 。   药物递送：如何有效地将治疗药物，特别是像抗体和ASOs这样的大分子药物，递送通过血脑屏障进入大脑，是一个长期存在的技术瓶颈。目前的解决方案，如鞘内注射，虽然可行，但具有侵入性，并可能伴随风险 。   第六部分：全球协作努力与未来方向 对抗像MSA这样的罕见、复杂且毁灭性的疾病，任何单一的研究机构或国家都无法独立完成。只有通过全球范围内的协作，整合学术界、政府、产业界和患者群体的力量，才能加速研究进程，最终找到有效的治疗方法。6.1 领先的学术与政府研究中心 在全球MSA研究网络中，一些学术和政府机构扮演着核心枢纽的角色。 纽约大学朗格尼健康中心（NYU Langone Health）：该中心是世界顶级的MSA临床研究和患者护理中心之一。他们领导着一个全面的转化医学研究项目，其中包括迄今为止规模最大的MSA自然病程研究，协调全球超过20个研究中心共同参与 。他们的工作对于理解疾病的演变、开发新的评估工具以及为临床试验做好准备至关重要。   美国国家神经疾病和卒中研究所（NINDS）：作为美国国立卫生研究院（NIH）的一部分，NINDS是MSA研究领域的主要资助机构。它支持从基础的生物标志物开发到大规模临床试验的广泛研究组合。NINDS还提供关键的研究基础设施，如BioSEND生物样本库（用于存储和分发研究用的血液、脑脊液等样本），并积极参与像“加速药物合作计划-帕金森病”（AMP PD）这样的公私合作项目，旨在加速包括MSA在内的α-突触核蛋白病的生物标志物发现 。   北美前驱期α-突触核蛋白病联盟（NAPS）：这是一个由NIH支持的重要项目，其目标是建立一个包含处于疾病最早前驱期（如仅有RBD症状）的个体队列。通过收集这些个体的临床、影像学和生物样本数据，NAPS旨在开发能够预测疾病发生的生物标志物，并创建一个“试验就绪”的注册库，以便未来能够迅速开展针对高危人群的预防性临床试验 。  6.2 患者倡导组织与全球联盟的力量 在罕见病领域，患者倡导组织是推动研究、提供支持和提升社会认知不可或缺的力量。 Mission MSA（前身为The MSA Coalition）：作为美国领先的MSA慈善组织，Mission MSA在多个层面发挥着关键作用。它通过设立研究基金项目直接资助创新性研究，为患者和家属提供全面的教育和支持资源，并建立了覆盖全美的“卓越中心”（Centers of Excellence）网络，旨在标准化和提升MSA的临床护理水平 。   MSA联合研究联盟（MSA United Research Consortium）：这是一个由全球多个MSA慈善团体组成的国际联盟，包括美国的Defeat MSA Alliance、加拿大、爱尔兰等国的组织。它们联合起来，共同资助研究、开展医学教育，并为全球MSA社群发声，形成了强大的协同效应 。 MSA信托基金（The MSA Trust, UK）：作为英国及欧洲地区的主要力量，MSA信托基金长期致力于支持MSA研究。其研究策略明确聚焦于寻找病因、改善临床护理和开发新疗法，对该地区的研究生态产生了深远影响 。  6.3 加速研究的关键基础设施 有效的全球协作依赖于坚实的基础设施。 患者注册登记系统：由纽约大学朗格尼健康中心维护的**全球MSA患者注册系统（GLoMSAR）**是一个典范。该系统连接了全球超过1000名患者与研究人员，极大地简化和加速了临床试验的患者招募过程，这是罕见病研究中最主要的瓶颈之一 。   卓越中心（CoE）网络：由Mission MSA倡导建立的CoE网络，旨在通过认证一批具备多学科诊疗能力、积极参与研究并致力于社区教育的顶级医疗中心，来为MSA患者树立一个“金标准”的护理模式。这些中心不仅提升了患者的护理质量，也成为了临床研究和新疗法推广的重要基地 。  6.4 未来方向与未解之谜 尽管取得了显著进展，MSA研究领域仍面临着一系列根本性的问题，这些问题的解决将指引未来的研究方向。 探寻始动触发因素：究竟是什么导致了α-突触核蛋白最初在少突胶质细胞中开始错误折叠？这是一个随机事件，还是由某种环境毒素、感染因子或复杂的基因-环境相互作用所触发？这是MSA病因学研究的“圣杯”。 验证疾病进展生物标志物：迫切需要验证能够可靠追踪疾病进展的生物标志物（如血液NfL、特定的影像学指标）。这将使临床试验的设计更高效，周期更短，成本更低，从而吸引更多的药物研发投入。 开发针对“毒株”的特异性疗法：如果MSA的α-突触核蛋白“毒株”确实在结构和生物学特性上与PD的“毒株”截然不同，那么基于PD病理开发的疗法是否对MSA有效就成了一个巨大的疑问。未来的研究需要开发能够特异性识别MSA“毒株”的诊断工具和治疗药物。 探索联合治疗策略：考虑到MSA病理过程的复杂性，未来的有效治疗很可能是一种多靶点的“组合拳”，即同时使用能够减少α-突触核蛋白产生的药物（如ASOs）、增强其清除的药物（如免疫疗法）以及抑制下游神经炎症反应的药物。 迈向预防性临床试验：研究的终极目标是在“前驱期MSA”阶段进行干预，即在大量神经元和少突胶质细胞死亡之前阻止疾病的发生。2022年MDS新诊断标准的提出和高灵敏度生物标志物的出现，正使这一曾经遥不可及的梦想，一步步接近现实。 总之，多系统萎缩的研究正处在一个前所未有的转型期。分子生物学的深刻见解正在转化为精准的诊断工具和靶向性治疗策略。尽管前路依然漫长且充满挑战，但全球研究界、临床医生、患者及其家属前所未有的紧密合作，为最终战胜这一毁灭性疾病带来了切实的希望。 报告中使用的来源： 往期推荐 抗帕词典-呼吸训练 腰椎引流术在颅底手术中的应用：作用、风险、证据及临床建议 神外急诊头颅CT-“3B”阅片法 来源：https://mp.weixin.qq.com/s/e9blWCyltzx49cfOjrKf-A 仅用于学术分享，若侵权请留言，即时删侵！

VALBY, Denmark., Nov. 11, 2025 /PRNewswire/ -- Key highlights Lundbeck's total revenue grew by +14% CER[1] (+13% DKK) to DKK 18,537 million in the first nine months of 2025. Growth in the U.S. and Europe was the driver of this strong performance. United States: DKK 9,955 million (+22% CER; +19% DKK) Europe: DKK 4,318 million (+13% CER; +13% DKK) International Operations: DKK 3,880 million (+0% CER; -4% DKK) The revenue of Lundbeck's strategic brands increased by +20% CER (+18% DKK), reaching DKK 14,260 million, representing 77% of total revenue Rexulti®: DKK 4,695 million (+26% CER; +23% DKK) Brintellix®/Trintellix®: DKK 3,453 million (-1% CER; -3% DKK) Vyepti®: DKK 3,254 million (+57% CER; +54% DKK) Abilify LAI franchise[2]: DKK 2,858 million (+11% CER; +9% DKK) EBITDA increased to DKK 6,207 million, growing +39% CER (+38% DKK) and adjusted EBITDA[3] reached DKK 6,272 million, growing +22% CER (+21% DKK), driven by continuous strong momentum across strategic brands fueled by the strong performance of Vyepti® and Rexulti®. Lundbeck's disciplined capital reallocation framework allows for both investing for the future and delivering on the near-term targets, supported by a healthy cost mindset and continuous optimization of capital deployment toward the highest-return opportunities. EBITDA growth was mainly impacted by an impairment loss from one of the MAGLi projects recognized in the third quarter of 2024. Financial guidance 2025 raised On 11 November 2025, Lundbeck announced an increase in its full-year revenue and adjusted EBITDA guidance at CER. Revenue is now expected to grow by 13% to 14% at CER, up from the previous forecast of 11% to 13%, compared to the prior year's revenue excluding hedging effects. Adjusted EBITDA growth is now projected at 22% to 25% at CER, previously 16% to 21%, also excluding hedging effects. Further details can be found in section 2.8 Outlook. Lundbeck's President and CEO, Charl van Zyl said: "In the third quarter, Lundbeck continued its strong financial performance, driven by higher-than-expected growth for Vyepti ® and Rexulti ® in the U.S. The performance is a result of targeted investments enabled through our capital reallocation program. This leads us to upgrade our guidance. During the quarter, we also announced a new commercial operating model, under which 27 markets are transitioning to a partnership model. This approach frees up additional capital for reinvestment in growth opportunities, including our transformed pipeline and key commercial focus markets." Recent events On 27 October 2025, Lundbeck announced a strategic collaboration with OpenAI to transform how the company innovates and operates across its entire value chain – from molecule to patient. Through the deployment of ChatGPT Enterprise to its global workforce, Lundbeck empowers employees with AI capabilities designed to accelerate discovery, enhance decision-making, and drive unprecedented efficiency. The collaboration marks a bold step toward redefining innovation in brain health. On 20 October 2025, Lundbeck and Contera Pharma announced a strategic research collaboration aiming to accelerate the discovery and development of innovative oligonucleotide-based medicines for patients living with serious neurological conditions, where significant unmet medical needs remain. Together, the companies will explore novel RNA-targeting treatment approaches designed to deliver transformative benefits for patients worldwide. On 13 October 2025, Lundbeck announced that its investigational drug bexicaserin, for the treatment of seizures associated with Developmental and Epileptic Encephalopathies (DEEs), has been granted Breakthrough Therapy Designation (BTD) by China's Center for Drug Evaluation (CDE). The BTD procedure is designed to accelerate the development and review of innovative medicines for serious or life-threatening diseases with no adequate treatment options, or where early evidence shows substantial advantages over existing therapies. On 2 October 2025, Lundbeck announced that pipeline developments regarding amlenetug, a novel investigational molecule for the potential treatment of Multiple System Atrophy (MSA), were presented at the 2025 International Congress of Parkinson's Disease and Movement Disorders® in Honolulu, Hawaii (5-9 October). At the congress, Lundbeck shared Insights into the design of the phase III MASCOT trial and its use of innovative Bayesian progression modeling methods. On 20 September 2025, Lundbeck and Otsuka America Pharmaceutical, Inc., (Otsuka) announced that Otsuka has received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) regarding the supplemental New Drug Application (sNDA) for use of Rexulti® (brexpiprazole) in combination with sertraline as a treatment of adults with post-traumatic stress disorder (PTSD). The CRL states that the FDA has completed their review but cannot approve the application in the current form, as the application does not provide substantial evidence of effectiveness to support the approval. On 11 September 2025, Lundbeck announced a step forward in its commitment to advancing brain health by enhancing its leadership in migraine with a comprehensive collection of datasets presented at the 2025 International Headache Congress, which took place in São Paulo (10-13 September). Among data presented, Lundbeck announced the full results of the 12-week, open-label extension of the RESOLUTION trial investigating eptinezumab for the prevention of migraine in patients with chronic migraine and associated medication overuse headache (MOH) who also received standardized patient education. On 9 September 2025, Lundbeck announced a change to its commercial operating model, aimed at focusing resources and capital on the highest-growth opportunities while ensuring continued patient access to our medicines. As a next step in the continued execution of its Focused Innovator strategy, Lundbeck will transition its operations to a partnership model in 27 markets in Europe and International Operations through new partnerships with Swixx Group, Zuellig Pharma, and NewBridge Pharmaceuticals. The phased transition to the partnership model is expected to be completed by December 2025 in all countries. On 25 August 2025, Lundbeck announced that new data regarding bexicaserin, a novel treatment under investigation for seizures associated with Developmental and Epileptic Encephalopathies (DEEs), were presented at the 36th International Epilepsy Congress (IEC) in Lisbon, Portugal (30 August – 3 September). Strategy update – Focused Innovator Conference call Tomorrow at 13.00 CET, Lundbeck will be hosting a conference call for the financial community. You can find dial-ins and a link for webcast online at under the Investor section. Strategy update – Focused Innovator Lundbeck progresses well on the Focused Innovator Strategy laid out in the beginning of 2024. Scaling for the Next Phase of Growth Lundbeck is building a stronger foundation for scale and long-term value creation. Vyepti® and Rexulti® provide a durable engine for reinvestment into innovation. With five to six mid to late-stage pipeline assets on track by 2026, including amlenetug and bexicaserin, and efficiency gains from the new commercial operating model, Lundbeck is structurally positioned for sustained profitability and growth driven by Rexulti® and Vyepti®. Building on strong cash generation and late-stage visibility, Lundbeck is well placed to deliver on its 2027 mid-term targets and extend its leadership in neuroscience well into the next decade. Sustained growth from Strategic Brands Lundbeck continues to demonstrate strong and consistent progress on its Focused Innovator strategy, with strategic brands delivering revenue growth of +20% CER in the first nine months of 2025 and now representing 77% of total revenue. Lundbeck's double-digit CER growth reflects the continued transformation of its commercial model toward higher-value, innovation-driven franchises. Growth was led by Vyepti®, which continued to deliver double-digit CER growth and maintained its strong momentum across all regions. Demand remained particularly strong in the U.S., supported by total patient growth (+35%), world-class persistency (58%), and increasing dosage, overall further fueled by expanding access across Europe and International Operations. Rexulti® sustained above 20% growth for three consecutive quarters and contributed to the strong growth in the first nine months of 2025, with targeted affordability initiatives introduced earlier in 2025 now driving stronger patient access and demand in both the Major Depressive Disorder (MDD) and agitation associated with dementia due to Alzheimer's disease (AADAD) segments. This broad-based strength underscores Lundbeck's ability to combine focused commercial execution, portfolio discipline, and operating leverage in support of sustained growth. Pipeline Advancing Toward Late-Stage Inflection Lundbeck advanced its late-stage pipeline during the quarter, reinforcing its commitment to deliver differentiated innovation in brain health. In migraine, Vyepti® achieved a key regulatory milestone with FDA approval of its CHO manufacturing process and submission to the European Medicines Agency, supporting long-term supply scalability and cost efficiency. Lu AG09222 (anti-PACAP) continues to progress in phase IIb, with dose-response analyses guiding pivotal design, while a dual-active VIP-PACAP molecule has entered pre-clinical development with intended indication in cluster headache. In neuro-rare, amlenetug recruitment remains strong and remained positioned as a potential first disease-modifying therapy for Multiple System Atrophy. Bexicaserin is advancing according to plan and was granted Breakthrough Therapy Designation in China, further underscoring its global potential and the growing momentum behind Lundbeck's next wave of innovation. Capital Efficiency Powering Innovation Lundbeck delivered another strong operational and financial performance, demonstrating continued capital discipline and cost efficiency while investing in innovation and growth. The company achieved an adjusted EBITDA margin of 33.8% in the first nine months of 2025, supported by solid revenue growth and active cost allocation management. Strategic reallocation of resources within the Focused Innovator Strategy framework continues to fund late-stage R&D programs (adjusted R&D spending increasing 22% CER in the first nine months of 2025) and launch readiness activities without compromising profitability. Transition of 27 markets to a partnership-led model is progressing as planned and will enhance Lundbeck's flexibility and scalability across geographies. Reinvestment from these efficiencies, together with a stronger balance sheet and operating cash flow of more than DKK 4.5 billion year to date, provides Lundbeck with the capacity to advance its late-stage pipeline and support future launches. The company remains focused on maintaining a robust financial foundation while driving sustainable, innovation-led growth. CONTENT 1 Financial highlights. 5 2 Business performance. 6 2.1 Revenue by product 6 2.2 Revenue by geographical area. 8 2.3 Gross profit 9 2.4 EBIT and adjusted EBITDA. 10 2.5 Net profit and adjusted EPS. 11 2.6 Cash flow and balance sheet 12 2.7 Summary of key developments in the third quarter of 2025. 13 2.8 Outlook. 15 2.9 Lundbeck's development portfolio. 17 2.10 Sustainability update. 18 2.11 General corporate matters. 20 3 Condensed financial statements. 23 4 Notes. 28 Financial calendar 2025. 30 1 Change at CER (Constant Exchange Rates) does not include effects from hedging. 2 Adjusted gross profit is the gross profit excluding depreciation and amortization and other adjustments linked to sales. 3 EBITDA refers to Earnings Before Interest, Taxes, Depreciation and Amortization, including impairment losses. 4 Adjusted EBITDA is defined as EBITDA adjusted by certain items, for details see note 4.3 Adjusted EBITDA. 5 Adjusted net profit is the net profit excluding depreciation and amortization and other adjustments, net of taxes. 2 BUSINESS PERFORMANCE 2.1 REVENUE BY PRODUCT Revenue reached DKK 18,537 million representing growth of +14% CER (+13% DKK). The strong performance in strategic brands was driven by the U.S. and Europe, growing +26% CER (+23% DKK) and +18% CER (+18% DKK) , respectively. Approximately 84% of the strategic brands growth was attributable to the strong performance of Vyepti® and Rexulti® in the U.S. in the first nine months of 2025. Vyepti® and Rexulti® sales in the U.S. grew +56% CER (+53% DKK) and +26% CER (+24% DKK), respectively. The largest markets for the strategic brands was the U.S., Spain, Canada, Italy and France. Strategic brands The Focused Innovator Strategy amplifies Lundbeck's strategic brands representing the company's growth engine, driving revenue expansion, margin improvement, and sustainable long-term value creation. Rexulti ® (brexpiprazole) revenue reached DKK 4,695 million representing growth of +26% CER (+23% DKK). In the U.S., revenue benefitted from continued strong demand growth[4] in both agitation associated with dementia due to Alzheimer's disease (AADAD) and major depressive disorder (MDD). Total prescriptions (TRx) grew +23.5% year-over-year in the first nine months of 2025, reaching all-time high market share of 2.69% in August, and contributing to +21.1% growth in overall demand volume in the third quarter. In AADAD, Rexulti ® reached 4.35% market share within the Alzheimer segment and accounted for 23.4% of total U.S. Rexulti ® prescriptions in July, up from 17.8% same month of last year. In Europe and International Operations, Rexulti ® continued the strong and stable growth into the third quarter, driven by demand growth in countries such as Spain (+117%), expanding market share on the back of the 2024 launch, and Brazil (+13%), maintaining market share in a growing market, while Canada (+14%) continues the strong momentum on the back of nationwide reimbursement. The revenue distribution by region was 93%, 2% and 5% in the U.S., Europe and International Operations, respectively. The largest markets are the U.S., Brazil, Canada, Australia and Mexico. Brintellix®/Trintellix® (vortioxetine) revenue reached DKK 3,453 million representing a decline of -1% CER (-3% DKK), with strong performance in Europe. In Europe, the brand continued to gain market share across key markets, such as Italy (5.2% market share), France (4.1% market share), and Spain (6.4% market share). In International Operations, Japan maintained over 12% market share in the third quarter of 2025, resulting in +11% demand growth in the third quarter of 2025. The impact from generic competition was greater than expected in the third quarter of 2025. In Canada, this was primarily driven by earlier than expected decline in demand for the product following generic market entry, as well as by wholesalers reducing inventory levels to a greater extent than expected across the country. In addition, the brand has experienced the continued price and volume pressure from post–volume-based procurement (VBP) in China, which remained stable compared with the second quarter, along with ongoing generic erosion in Brazil. The year-over-year revenue development reflects the transfer of U.S. sales operations to Takeda, effective 1 January 2025 as well as the Medicare Part D redesign impacts. The revenue distribution by region was 28%, 43% and 29% in the U.S., Europe and International Operations, respectively. The largest markets for this product are the U.S., Spain, Canada, Italy and Japan. Vyepti ® (eptinezumab) delivered strong growth in the first nine months of 2025, with revenue reaching DKK 3,254 million, an increase of +57% CER (+54% DKK). Vyepti ® maintained its strong momentum across all regions. In the U.S., Vyepti ® accelerated sequentially in the third quarter of 2025, being the fastest-growing aCGRP in the U.S., reaching 11.2% market share during September through continued increase of new patient starts as well as growth in existing patient base through improved persistency with demand volume growing by +46.8%. The performance was driven by continued growth in treated patients, higher 300mg utilization, and improved persistency and infusion conversion rates across the Vyepti Infusion Network, reflecting stronger patient adherence. In Europe and International Operations, Vyepti ® maintained absolute growth momentum into the third quarter of 2025, building on consistently strong demand growth across key markets such as France (+96%), Spain (+73%), Germany (+62%), Canada (+68%) and Italy (+116%). aCGRP has expanded across all markets in overall market share with Vyepti ® outgrowing the market growth. The revenue distribution by region was 87%, 9% and 4% in the U.S., Europe and International Operations, respectively. The largest markets are the U.S., France, Canada, Spain and U.A.E. Abilify LAI franchise revenue reached DKK 2,858 million and grew +11% CER (+9% DKK). The franchise delivered solid growth in the first nine months of 2025. The Abilify LAI franchise in the U.S. grew in the third quarter to reach +10% CER growth in the first nine months of 2025 on the back of +9.5% growth in demand volume in the third quarter of 2025 on an expanding market share for the brands. Strong uptake in total prescriptions (TRx) for Abilify Asimtufii ® (63.1% in September), which grew market share to reach 3.9% in August as Lundbeck continue to source patients from oral aripiprazole, other oral antipsychotics, LAIs other than Abilify Maintena ® and naïve patients. The Abilify LAI franchise grew in Europe, driven by continued market share gains following the launch of Abilify Maintena ® 960mg, particularly in Spain (31% LAI market share), France (32% LAI market share) and Italy (42% LAI market share), underpinning the brand's ability to capture business from other antipsychotics. Conversion reached 22% by the end of the third quarter of 2025 in these countries. International Operations reported continued demand growth of Abilify Maintena ® in Canada (+6%). Australia is impacted by reduction in order volumes in anticipation of generic entry for Abilify Maintena ®, which is partially offset by launch of Abilify Asimtufii ®. The revenue distribution by region was 37%, 46% and 17% in the U.S., Europe and International Operations, respectively. The largest markets are the U.S., Spain, Canada, Italy and Australia. Mature brands Lundbeck's mature brands comprise established neuroscience treatments that provide stable cash generation and a solid earnings base, supporting continued investment in innovation and future growth opportunities. Cipralex®/Lexapro® (escitalopram) revenue reached DKK 1,573 million and remained unchanged at CER (-3% DKK). This performance is mainly impacted by the continued generic erosion, particularly in Japan, Canada and Italy, partially offset by price increases in Argentina driven by inflation. Regional revenue distribution was 68% and 32% in International Operations and Europe, respectively, with China, South Korea and Brazil as the largest markets. Revenue from Other pharmaceuticals, which comprises the remainder of Lundbeck's products, reached DKK 2,320 million representing a decline of -5% CER (-6% DKK). The decrease reflects the expected generic erosion of mature products such as Northera ®, Xenazine ® and Deanxit ®. This is offset by the strong performance of Sabril® in the U.S. The largest markets for Other pharmaceuticals are the U.S., China, France, South Korea and the UK. Lundbeck's five largest markets are the U.S., China, Spain, Italy and Canada constituting 70% of the total revenue. United States revenue reached DKK 9,955 million representing growth of +22% CER (+19% DKK) and continued the quarterly streak of more than 20% growth CER per quarter. The strategic brands reached DKK 9,228 million, increasing +26% CER (+23% DKK) and representing 93% of the revenue in this market. Vyepti® was the primary growth contributor, with growth accelerating in the third quarter, driven by a +46% increase in TRx demand underpinned by strong patient conversion supported by patient access and direct to consumer promotional activities. The growth was further fueled by increased 300mg dose usage, now representing nearly half of total U.S. units. The strong performance was reflected in the all-time-high market share of 11.2% in September, underpinning the exceptional performance as being the fastest-growing aCGRP in the U.S. On top of improved conversion and higher dosage, the growth was further supported by sustained high persistency (62%). Rexulti® delivered strong growth of +26% CER, supported by demand in both MDD and AADAD indications, where market share increased across all patient segments. TRx growth reached +23%, with AADAD accounting for over 21% of total prescriptions, up from 17% in the same period last year. The Abilify LAI franchise growth in the third quarter of 2025 was supported by continued TRx growth of +10.6%, primarily from Abilify Asimtufii®, which rose +57%. Growth in Abilify Maintena® was impacted by gross-to-net headwinds linked to the Medicare Part D redesign. Trintellix® reflects the effect of the Takeda transition, effective 1 January 2025 as well as the Medicare Part D redesign impacts. Mature brands declined overall, with continued erosion for Northera®, Onfi® and Xenazine®, offset by the strong performance of Sabril®. Europe revenue reached DKK 4,318 million representing a growth of +13% CER (+13% DKK). The strategic brands reached DKK 3,169 million, increasing +18% CER (+18% DKK) and representing 73% of revenue in this market. Solid growth in Europe in the first nine months of 2025 reflected sustained demand for Brintellix® and Vyepti®, together with the continued rollout of Abilify Maintena® 960mg across key markets. Growth was particularly strong in Spain, Italy, the UK and France, where demand momentum continued into the third quarter. Vyepti® further expanded its market share, underpinned by strong performance in France, Italy and Spain in particular. Brintellix® also continued to expand across markets, especially in Spain and Italy. The largest markets in Europe are Spain, Italy, France, Switzerland and the UK. International Operations comprises all Lundbeck's markets outside the U.S. and Europe. Revenue reached DKK 3,880 million and remained unchanged at CER (-4% DKK). The strategic brands reached DKK 1,863 million, increasing by +1% CER (-4% DKK) and representing 48% of revenue in this market. Despite strong momentum in strategic brands such as Rexulti® and Vyepti®, driven by continued uptake in revenue and market share expansion across key markets, and solid performance of the Abilify LAI franchise across countries, total revenue continued to decline in the third quarter of 2025 in International Operations, driven by generic competition for Brintellix® in Canada, Brazil and China. The biggest markets are China, Canada, Australia, Brazil and South Korea. China and Canada constitute approximately 42% of the regional revenue. Effects from hedging Lundbeck hedges a significant part of the revenue currency risk for a period of 12-18 months. Hedging had a positive impact of DKK 99 million on revenue in the first nine months of 2025 contributing to mitigate risks regarding the foreign exchange risks in our revenue, compared to a negative impact of DKK 43 million in the same period last year. Cost of sales reached DKK 3,021 million, decreasing by -3% CER (-4% DKK), mainly driven by the reversal of the Vyepti® provision for inventory obsolescence of DKK 389 million triggered by Vyepti®'s commercial performance. In addition, the decrease was also driven by lower amortization costs due to fully amortized product rights, partially offset by increased sales as well as costs related to a manufacturing contract for amlenetug. Excluding the reversal of the Vyepti® provision for inventory obsolescence, cost of sales increased +10% CER (+8% DKK). Gross profit reached DKK 15,516 million, increasing by +18% CER (+17% DKK). The gross margin was 83.7% representing an increase of 2.9 percentage points. Gross margin was mainly impacted by a combination of higher revenue, the reversal of the Vyepti® provision for inventory obsolescence and lower amortization costs, partially offset by costs related to a manufacturing contract for amlenetug. Adjusted gross profit is the gross profit excluding depreciation and amortization and other adjustments linked to sales and cost of sales. The adjusted gross margin was 87.8% representing a decrease of 0.7 percentage points primarily reflecting the effect of costs related to a manufacturing contract for amlenetug. Total operating expenses (OPEX) reached DKK 10,616 million, corresponding to an increase of +5% CER (+4% DKK). The OPEX ratio declined by 4.7 percentage points to 57.3%. The development primarily reflects the strong revenue growth and lower S&D ratio, partially offset by other operating expenses related to the commercial restructuring provision announced in September 2025 and higher R&D costs. Adjusted for the effect of impairment loss of DKK 547 million related to one of the MAGLi projects recognized in the third quarter of 2024, OPEX ratio declined by 1.4 percentage points in the first nine months of 2025. Sales and distribution costs reached DKK 5,714 million, corresponding to an increase of +2% CER (-1% DKK). The S&D ratio decreased by 4.1 percentage points to 30.8%, primarily reflecting leverage from the strong revenue growth and improved cost efficiency. Additionally, the decrease in S&D ratio reflects the redeployment of resources following the Trintellix® transition in the U.S., alongside disciplined resource allocation and capital reallocation in line with the Focused Innovator strategy. These savings have enabled continued investments in strategic brands, particularly Rexulti® and Vyepti® in the U.S., supporting sales force expansion and the global roll-out of Vyepti®. Administrative expenses reached DKK 1,077 million and was in line with the same period last year. The administrative expense ratio reached 5.8%, representing a decrease of 0.8 percentage points. Adjusting for non-recurring items in both periods, underlying costs rose by DKK 107 million, mainly due to inflation as well as continued investment in Longboard integration. Research and development costs reached DKK 3,440 million, with an R&D ratio of 18.6%, increasing +2% CER (+2% DKK). The development in the first nine months of 2025 reflects the continued commitment to innovation and was primarily driven by advancing key pipeline programs, including bexicaserin and amlenetug (anti-α-synuclein), as well as ongoing progress in anti-ACTH and anti-PACAP programs. In addition, in the third quarter of 2024, Lundbeck recognized an impairment loss of DKK 547 million on part of the carrying amount of one of the MAGLi projects following a negative data read out from a phase I project. Adjusted for the MAGLI impairment loss, R&D costs increased +22% CER (+21% DKK). Other operating expenses, net reached DKK 385 million due to the already announced commercial restructuring in September 2025. EBIT reached DKK 4,900 million, increasing by +59% CER (+58% DKK) reflecting a combination of improved gross profit driven by strong sales growth, the reversal of the Vyepti® provision for inventory obsolescence and lower amortization costs as well as lower S&D ratio. This performance was partially offset by other operating expenses regarding the commercial restructuring provision announced in September 2025 as well as costs related to a manufacturing contract for amlenetug and higher R&D costs. EBIT growth was also impacted by an impairment loss from one of the MAGLi projects recognized in the third quarter of 2024. Total amortization and depreciation reached DKK 1,307 million, representing a decrease of -6% CER (-7% DKK), mainly driven by fully amortized product rights of one product since February 2024. Amortization of product rights amounted to DKK 977 million, corresponding to a decrease of -10% CER (-11% DKK). Amortization of other intangible assets corresponded to DKK 45 million in the first nine months of 2025. Depreciation amounted to DKK 285 million, corresponding to an increase of +5% CER (+4% DKK). Adjusted EBITDA reached DKK 6,272 million representing an increase of +22% CER (+21% DKK) reflecting the sales growth driven by strong performance of strategic brands, despite continued investments in building the R&D pipeline and the commercial investments to support the growth of strategic brands. The adjusted EBITDA margin was 33.8%, representing an increase of 2.2 percentage points. Net financial (income)/expenses amounted to an expense of DKK 773 million in the first nine months of 2025, primarily driven by the higher interest costs due to new debt obtained in connection with the acquisition of Longboard as well as unfavorable foreign exchange effects of DKK 342 million mainly due to the depreciation of USD leading to the negative impact through currency revaluation. The effective tax rate for the first nine months of 2025 was 22.0% (23.0% for the first nine months of 2024). The tax rate is in line with the full-year expectation. Net profit reached DKK 3,219 million, corresponding to a growth of 26%. Adjusted net profit and EPS Adjusted net profit is the net profit excluding depreciation and amortization and other adjustments, net of taxes. Adjusted net profit reached DKK 4,289 million, increasing +10%. The main difference from reported EBIT to adjusted net profit is the net financials development, primarily impacted by unfavorable foreign exchange and higher interest costs related to financial debts. Adjusted EPS was DKK 4.32, corresponding to an increase of +10%, in line with the adjusted net profit. Cash flows from operating activities amounted to an inflow of DKK 4,560 million compared to an inflow of DKK 4,480 million in the first nine months of 2024. This increase was primarily driven by higher EBIT and lower trade and other payables, partially offset by a higher prepaid tax in the first quarter of 2025. Lundbeck's net cash flows from investing activities were an outflow of DKK 409 million compared to an outflow of DKK 346 million in the first nine months of 2024. The investing activities mainly include capital expenditures in property, plant and equipment. Lundbeck's net cash flows from financing activities were an outflow of DKK 5,297 million compared to an outflow of DKK 808 million in the first nine months of 2024. The increase primarily reflects repayments of the Revolving Credit Facility (RCF) used for the acquisition of Longboard. Additionally, a four-year EUR 500 million bond was issued in the second quarter of 2025 to refinance the RCF mentioned above. Higher dividend payouts in March 2025 also contributed to the outflow. The net cash outflow reached DKK 1,146 million compared to an inflow of DKK 3,326 million in the first nine months of 2024. Net debt increased from a net cash position of DKK 3,982 million at the end of September 2024 to a net debt of DKK 9,085 million at the end of September 2025, primarily due to higher leverage following the acquisition of Longboard. The net debt/EBITDA ratio is 1.3x at the end of September 2025 versus 1,8x at the end of June 2025, compared to -0.8x at the end of September 2024. Interest-bearing debt was DKK 12,564 million at the end of September 2025 compared to DKK 4,340 million at the end of September 2024. On 30 September 2025, Lundbeck's total assets amounted to DKK 53,193 million compared to DKK 56,976 million at the end of 2024 mainly driven by intangible assets due to ongoing amortization and the impact from translation of foreign currencies as well as lower cash and cash equivalents reflecting repayments of the Revolving Credit Facility used for the acquisition of Longboard. On 30 September 2025, Lundbeck's total liabilities amounted to DKK 28,040 million compared to DKK 31,966 million at the end of 2024. The decrease primarily reflects repayments of the Revolving Credit Facility used for the acquisition of Longboard, partially offset by the issuance of a four-year EUR 500 million bond in the second quarter of 2025. On 30 September 2025, Lundbeck's equity amounted to DKK 25,153 million. 1 Change at CER (Constant Exchange Rates) does not include effects from hedging. 2 Adjusted gross profit is the gross profit excluding depreciation and amortization and other adjustments linked to sales. 3 EBITDA refers to Earnings Before Interest, Taxes, Depreciation and Amortization. 4 EBITDA refers to Earnings Before Interest, Taxes, Depreciation and Amortization. Adjusted EBITDA is defined as EBITDA adjusted by certain items, for details see section 4 Notes, note 3 Adjusted EBITDA. REVENUE Revenue reached DKK 6,279 million representing a growth of +14% CER (+10% DKK) in the third quarter of 2025. The increase in revenue is mainly driven by strong performance across the strategic brands reaching DKK 4,824 million, representing a growth of +18% CER (+12% DKK), equivalent to 77% of total revenue (see section 2.1) in the third quarter of 2025. The increase in revenue was partly offset by unfavorable currency effects primarily coming from USD, CAD and BRL in the third quarter of 2025. The performance is mainly driven by higher demand for Rexulti® and Vyepti® primarily in the U.S. (+26% CER and +56% CER, respectively). Moreover, Brintellix® / Trintellix® revenue decreased despite the strong performance in Europe, mainly driven by demand growth in Spain (+17% CER), Italy (+11% CER) and France (+7% CER). In Canada, the impact from generic competition was greater than expected in the third quarter of 2025, this was primarily driven by earlier than expected decline in demand for the product following generic market entry, as well as by wholesalers reducing inventory levels to a greater extent than expected across the country. The decline in the U.S. reflects the transfer of U.S. sales operations to Takeda, effective 1 January 2025 as well as the Medicare Part D redesign impacts. The Abilify LAI franchise grew in all regions, driven by strong demand growth of Abilify Maintena® 960mg in Spain, France and Germany as well as Abilify Asimtufii ® in the U.S. Mature brands decreased -1% CER (-5% DKK) due to the continued generic erosion. GROSS PROFIT Cost of sales decreased to DKK 846 million decreasing by -19% CER (-23% DKK) mainly driven by the reversal of the Vyepti® provision for inventory obsolescence of DKK 389 million. In addition, the decrease was also driven by lower amortization costs due to fully amortized product rights, partially offset by increased sales as well as costs related to a manufacturing contract for amlenetug. Excluding the reversal of Vyepti® provision for inventory obsolescence, cost of sales increased +16% CER (+13% DKK). In the third quarter of 2025, gross profit reached DKK 5,433 million increasing by +22% CER (+17% DKK). The gross margin was 86.5% representing an increase of 5.6 percentage points. Gross margin was mainly impacted by a combination of higher revenue, the reversal of the Vyepti® provision for inventory obsolescence and lower amortization costs, partially offset by costs related to a manufacturing contract for amlenetug. Adjusted gross margin was 86.3% in the third quarter of 2025 representing a decrease of 1.9 percentage point primarily reflecting the effect of costs related to a manufacturing contract for amlenetug. EBIT AND ADJUSTED EBITDA Total operating expenses (OPEX) reached DKK 3,802 million corresponding to an increase of +3% CER (+0% DKK). The OPEX ratio decreased by 6.1 percentage points primarily driven by the strong revenue growth and lower S&D ratio, partially offset by higher R&D costs. Adjusted for the effect of impairment loss of DKK 547 million related to the MAGLi projects recognized in the third quarter of 2024, OPEX ratio increased by 3.5 percentage points in the third quarter of 2025. Sales and distribution costs reached DKK 1,896 million corresponding to an increase of +3% CER (-3% DKK). The S&D ratio decreased by 3.9 percentage points in the third quarter of 2025 primarily driven by strong revenue growth and improved cost efficiency. As Lundbeck has limited variable sales and distribution costs, significant revenue growth translates into meaningful ratio improvement. Administrative expenses reached DKK 364 million increasing by +8% CER (+6% DKK) mainly impacted by inflation and continued investment in Longboard integration. The administrative expense ratio reached 5.8%, decreasing by 0.2 percentage points. Research and development costs reached DKK 1,157 million corresponding to a decrease of -22% CER (-24% DKK) with an R&D ratio of 18.4%. The development in the third quarter of 2025 reflects the continued commitment to innovation and was primarily driven by advancing key pipeline programs, including bexicaserin and amlenetug (anti-α-synuclein), as well as ongoing progress in anti-ACTH and anti-PACAP programs. In addition, in the third quarter of 2024, Lundbeck recognized an impairment loss of DKK 547 million on part of the carrying amount of one of the MAGLi projects following a negative data read out from a phase I project. Adjusted for the impairment loss of DKK 547 million prior year, R&D costs increased +21% CER (+19% DKK). Other operating expenses, net reached DKK 385 million due to the already announced commercial restructuring in September 2025. EBIT reached DKK 1,631 million increasing by +109% CER (+101% DKK) reflecting a combination of improved gross profit driven by strong sales growth, the reversal of the Vyepti® provision for inventory obsolescence and lower amortization costs as well as lower S&D ratio. This performance was partially offset by other operating expenses regarding the commercial restructuring provision announced in September 2025 and higher R&D costs. EBIT growth was also impacted by an impairment loss from one of the MAGLi projects recognized in the third quarter of 2024. Total amortization, depreciation and impairment losses reached DKK 426 million representing a decrease of -6% CER (-9% DKK) mainly driven by lower product rights amortization. Amortization of product rights amounted to DKK 317 million corresponding to a decrease of -9% CER (-12% DKK). Amortization of other intangible assets corresponded to DKK 15 million in the third quarter of 2025. Depreciation amounted to DKK 94 million, corresponding to an increase of +2% CER (+2% DKK). Adjusted EBITDA reached DKK 2,051 million representing an increase of +16% CER (+12% DKK) reflecting the strong revenue growth driven by performance of strategic brands, which offsets the continued investment in the R&D pipeline and the commercial investments to support the growth of strategic brands. The adjusted EBITDA margin was 32.7% representing an increase of 0.7 percentage points. NET PROFIT AND ADJUSTED EPS Net financial (income)/expenses reached DKK 219 million driven by unfavorable foreign exchange due to the depreciation of USD and higher interest costs related to financial debts. The effective tax rate for the third quarter of 2025 was 22.0%. Net profit reached DKK 1,101 million corresponding to an increase of +42%. Adjusted net profit reached DKK 1,429 million, representing an increase of +11%, reflecting the EBIT development including unfavorable foreign exchange and higher interest costs related to financial debts. 2.8 OUTLOOK Financial guidance 2025 On 11 November 2025, Lundbeck announced an increase in its full-year revenue and adjusted EBITDA guidance at constant exchange rates (CER). Based on the strong performance of Vyepti® and Rexulti®, revenue is now expected to grow by 13% to 14% at CER (previously 11% to 13%) compared to the prior year's revenue excluding hedging effects. The upgrade reflects higher-than-expected demand driven by additional investments in these two strategic brands. Our expectations for adjusted EBITDA growth have also been raised, primarily driven by the higher contribution from Vyepti® and Rexulti®, as well as effective execution of Lundbeck's capital reallocation program. Lundbeck now expects adjusted EBITDA growth of 22% to 25% at CER (previously 16% to 21%) in 2025. The updated guidance continues to include the expected initial impact from loss of exclusivity (LoE) on Brintellix® in Canada, while the generic entry for Abilify Maintena® in Europe now is expected in 2026. Brintellix®/Trintellix® will continue to be affected by the modified collaboration with Takeda in the U.S. as well as the generic entry in Canada in June 2025. The underlying erosion of mature brands is expected to continue, thereby expected to show a mid-single-digit revenue decline. Given the current exchange rates against the Danish krone, sales growth reported in DKK is expected to be approximately 1.5 percentage lower to CER. As a central component of our Focused Innovator strategy, Lundbeck remains committed to invest in research and development, advancing both our late-stage and early development pipeline. In 2025, we anticipate an acceleration of investments in R&D, including the integration of Longboard and the initiated phase III clinical trials of bexicaserin and amlenetug. Lundbeck anticipates increasing R&D investments up to DKK 5.0 billion in 2025, compared to DKK 3,954 million in 2024 (excluding the MAGLi impairment loss communicated in October 2024). This significant increase in R&D investments is financed by the dedicated efforts towards capital reallocation initiatives across our full value chain, as well as additional contributions from accelerated revenue growth. Lundbeck's capital reallocation program has accelerated ahead of expectations in the first nine months of 2025. Given the current exchange rates against the Danish krone, growth in adjusted EBITDA reported in DKK is expected to be around 1 percentage points lower than at CER. The 2025 guidance underscores Lundbeck's ability and focus to sustain profitability while expanding and progressing the pipeline. Effects from hedging are expected to reach a gain around DKK 300 million compared to a loss of DKK 52 million for 2024. Depreciation, amortization, and impairment losses are expected to be around 1.8 billion, compared to DKK 1,876 million in 2024. Lundbeck anticipates financial items (net) to result in a loss of approximately 750 million following the acquisition of Longboard in 2024, compared to an income of DKK 449 million in 2024. The effective tax rate for 2025 is expected to range between 21% and 24%, compared to 15.5% in 2024. This guidance assumes no significant changes in the global or regional macroeconomic and political environment that would impact Lundbeck's business, including major healthcare reforms, legislative changes, or legal outcomes. It also assumes stable currency exchange rates from current level, particularly the U.S. dollar against the Danish krone, and reflects current estimates of gross-to-net developments in U.S. sales. The guidance excludes potential effects from new significant business development transactions, significant impairments of intangible assets in 2025, and any shifts in trade policy, such as pharmaceutical tariffs or further healthcare reforms. 1 Total revenue at CER for the period divided by total revenue (IFRS) before hedging for the comparative period. 1 Adjusted EBITDA at CER for the period divided by adjusted EBITDA before hedging for the comparative period. Mid-term targets Based on organic growth, the company expects revenue to show a mid-single digit compound annual growth rate (CAGR) over the mid-term period (2023 to 2027). The company maintains its target for adjusted EBITDA-margin of more than 30% at the end of the mid-term period in 2027, to account for the impact of the Longboard acquisition, progression of the pipeline and excluding any business development activities. Lundbeck plans to ensure appropriate investments in R&D and prelaunch activities for bexicaserin and amlenetug following the successful closure of the acquisition of Longboard. Several R&D projects are expected to mature in the period, including projects such as Lu AF28996 (D1/D2 agonist). Moreover, in accordance with the Focused Innovator strategy, Lundbeck has initiated its most significant capital reallocation program in its history to sustain the company's growth with increased focus on innovation. The mid-term targets exclude potential effects from new significant business development transactions, significant impairments of intangible assets in 2025, and any shifts in trade policy, such as pharmaceutical tariffs or further healthcare reforms. Forward-looking statements Forward-looking statements are subject to risks, uncertainties, and inaccurate assumptions. This may cause actual results to differ materially from expectations. Various factors may affect future results, including interest rates and exchange rate fluctuations, delay or failure of development projects, production problems, unexpected contract breaches or terminations, governance-mandated or market-driven price decreases for products, introduction of competing products, Lundbeck's ability to successfully market both new and existing products, exposure to product liability and other lawsuits, changes in reimbursement rules and governmental laws, and unexpected growth in expenses. 2.9 LUNDBECK'S DEVELOPMENT PORTFOLIO Lundbeck is developing several new and promising medicines for the treatment of brain diseases. The pipeline developments are summarized below. 1 CGRP: Calcitonin gene-related peptide. 2 Two phase III clinical studies completed, supporting registration in Asia, including China and Japan: SUNRISE, and SUNSET trials. 3 PACAP: Pituitary adenylate cyclase activating peptide. 4 ACTH: Adrenocorticotropic hormone. Two phase Ib trials are currently ongoing in Congenital Adrenal Hyperplasia and Cushing's Disease. For technical reasons, officially categorized as a phase II trial to adhere to local requirements in some countries. 5 Acts as a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors. 6 Complete Response Letter Received 20 September 2025. 7 Post-traumatic stress disorder. 8 The DEEp clinical program consists of two-phase III trials in Dravet Syndrome (DEEpSEA) and DEEs and Lennox-Gastaut Syndrome (DEEpOCEAN). 9 Monoacylglycerol lipase inhibitor ("MAGLipase"). 10 Dopamine receptor D1 and D2. 11 Phase Ib trial ongoing in TED (Thyroid Eye Disease). Key developments in the quarter Circuitry / neuronal biology Brexpiprazole in Post-Traumatic Stress Disorder (PTSD) On 20 September 2025, a Complete Response Letter (CRL) was issued by the FDA regarding the sNDA for use of Rexulti® (brexpiprazole) in combination with sertraline as a treatment of adults with PTSD. The CRL states that the FDA has completed their review but cannot approve the application in the current form, as the application does not provide substantial evidence of effectiveness to support the approval. This follows the review of the sNDA for Rexulti (brexpiprazole) in combination with sertraline as a potential treatment for PTSD by the FDA's Psychopharmacologic Drugs Advisory Committee (PDAC) in July 2025. Following a thorough review of the data, the committee voted 1–10, concluding that the efficacy of brexpiprazole, when initiated concurrently with sertraline, has not been established for the treatment of PTSD based on the evidence presented. Lundbeck filed a supplemental new drug application (sNDA) for brexpiprazole in combination with sertraline for the treatment of adults with PTSD in June 2024. The sNDA is based on data from three randomized clinical trials evaluating the safety and efficacy of brexpiprazole in combination with sertraline in adult patients with PTSD, namely the phase II trial 061 and the two phase III trials 071 and 072. The primary endpoint for all three trials was the change from week 1 to week 10 in the Clinician-Administered PTSD Scale (CAPS-5) total score for brexpiprazole and sertraline combination therapy versus sertraline plus placebo in patients diagnosed with PTSD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The trials were randomized, double blind, and active-controlled, and trials 061 and 071 were flexible-dose trials, while trial 072 was a fixed-dose trial. In both trials 061 and 071, brexpiprazole in combination with sertraline was associated with a statistically significant reduction (p<0.05) in PTSD symptoms compared to sertraline plus placebo, as measured by the change in the CAPS-5 total score from week 1 to week 10 (primary end-point). In trial 072, while the primary endpoint was not met, reductions in PTSD symptom severity with brexpiprazole in combination with sertraline were consistent with trials 061 and 071. Across the three randomized trials, the combination of brexpiprazole and sertraline in adult patients with PTSD was generally well-tolerated, and no new safety observations were identified. Bexicaserin in Developmental and Epileptic Encephalopathies (DEEs) – Phase III In October 2025 bexicaserin was granted Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) in China for the treatment of seizures associated with DEEs, highlighting bexicaserin's potential to address significant unmet medical needs of patients and their caregivers living with DEEs in China. Bexicaserin has shown encouraging anti-seizure effects to date in preclinical and clinical studies, with its next-generation super agonist mechanism specifically targeting 5-HT2C receptors, supporting bexicaserin's potential to offer a highly differentiated and best-in-class profile, and emphasized by having U.S. FDA Break-Through Designation, while being afforded Orphan Drug designation in both Dravet Syndrome and Lennox-Gastaut Syndrome in the U.S. In 2024, Lundbeck acquired Longboard with the lead asset bexicaserin which holds blockbuster potential. A global phase III program (DEEp) has been initiated, evaluating bexicaserin for the treatment of seizures associated with Dravet Syndrome in the DEEp SEA trial, as well as seizures associated with Developmental and Epileptic Encephalopathies (DEEs), including Lennox-Gastaut Syndrome (LGS) in the DEEp Ocean trial. 2.10 SUSTAINABILITY UPDATE Lundbeck's sustainability strategy aims to ensure that we mitigate our most significant sustainability risks and adverse impacts, while acting on the opportunities to make a positive impact on the environment, for patients, and the communities where we operate. This sustainability update presents progress on key sustainability matters and metrics. ENVIRONMENTAL PERFORMANCE 1 See Annual Report 2024 for accounting policies and definitions. 2 All comparative figures were updated to reflect the implementation of Corporate Sustainability Reporting Directive in 2024, e.g., inclusion of emissions from affiliates. This is reflected in the updated accounting policy. Climate Action Lundbeck is committed to protecting the environment and believes that a healthy environment is a precondition for good health and wellbeing. Lundbeck has net-zero targets to reduce its total carbon footprint across its own operations, supply chain, and distribution. In the first nine months of 2025, Scope 1 + 2 GHG emissions decreased by 11%, compared to the first nine months of 2024. Scope 1 GHG emissions decreased by 8%, compared with the same period last year, primarily reflecting the increasing share of electric and hybrid vehicles in the company's fleet. Emissions from production sites and affiliates remained broadly stable. Scope 2 GHG emissions decreased by 20%, mainly due to the acquisition of Guarantees of Origin electricity certificates for the Valbonne site and EU sales affiliates, along with the general decarbonization of electricity grids. Lundbeck remains on track to meet its climate targets for Scope 1 + 2 GHG emissions, as the planned actions in the low carbon transition plan will come into effect. Other topics In 2022, traces of PFAS (per- and polyfluoroalkyl substances) were found at Lundbeck's Lumsås production facility. The pollution stems from the use of fire-retardant foam containing the PFAS type PFOS (perfluorooctane sulfonate) until 2011, in compliance with national fire safety and environmental regulations at the time. Lundbeck switched to a supply of PFOS-free fire-retardant foam. Since the pollution was detected, Lundbeck has been engaged in a close and recurring dialogue with the Danish Environmental Protection Agency (EPA) and local authorities regarding the mapping and remediation possibilities of the pollution. Lundbeck continues this close dialogue with the authorities and affected stakeholders and is also conducting additional testing to determine more precisely the extent of the pollution. Lundbeck has received orders from the EPA requiring the installation of a pump and treat solution for subsoil water. The implementation work has been initiated, and it is estimated that the pump and treat solution will be operational in the end of 2025. SOCIAL PERFORMANCE 1 New accounting policy: Upper management includes all members of Executive Leadership Team (ELT) who report to the Board of Directors, as stated in their employment contract, which corresponds to layer 1 as defined in the Gender Balance Act. Additionally, it includes employees who report directly to a member of ELT and hold formal people management responsibilities. These individuals correspond to layer 2 in the Gender Balance Act. 2 9M 2024 data has been restated following an update to the accounting policy, which affected the classification of upper management roles. For previously published Corporate Releases in 2024, data was reported for senior management and is therefore not fully comparable to the figures reported in this release. 3 Variation in percentage points. Inclusion, Diversity and Equity Lundbeck embraces the unique perspectives and experiences of each individual enhancing our ability to address complex challenges and driving our commitment to improving brain health. Our ethos and culture foster an environment which fuels creativity, enhances decision-making, and drives innovation where every colleague is empowered to contribute, collaborate, and bring perspectives that reflect the communities we serve every day. Lundbeck recognizes the target required in accordance with the Danish Gender Balance Act to reach and maintain gender balance in upper management. In the first nine months of 2025, the underrepresented gender balance in upper management decreased to 40.7% female, compared to 42.6% in the first nine months of 2024, a decrease of 1.9 percentage points. The change primarily reflects organizational adjustments and external recruitments during the period, where a higher proportion of leadership appointments were male, leading to a slight decline in the overall share of the underrepresented gender. Lundbeck's commitment to a diverse leadership pipeline is reinforced through initiatives such as the global Enterprise Leadership Program launched in the third quarter of 2025. By combining leadership development with an unbiased recruitment approach, Lundbeck strengthens succession planning and supports progress toward gender balance targets. HEALTH AND SAFETY 1 See Annual Report 2024 for accounting policies and definitions. Health and Safety The health and safety of our workplace is a priority at Lundbeck, and we are committed to fostering a safety culture that minimizes work-related accidents. To support this, we closely monitor the frequency, number, and severity of incidents, enabling us to establish action plans and set ambitious safety objectives. In the first nine months of 2025, the Lost Time Incident Rate (LTIR) decreased to 1.9, compared to 3.1 in the first nine months of 2024. The positive development represents a -39% overall reduction in accidents resulting in absence compared to last year. The improvement reflects the effectiveness of site-specific safety initiatives, particularly in Valbonne, France where ergonomic improvements have had a significant impact. Additionally, the global prevention campaign Take Care, launched in early 2025, continues to strengthen safety awareness and promote safer work practices by focusing on a dedicated safety topic each month. Other topics In connection with the announced commercial restructuring on 9 September 2025, Lundbeck has conducted sustainability due diligence as part of the selection of the new commercial partners. Lundbeck has also carried out impact assessments and put action plans in place to mitigate potential negative impact on patients and people in the countries that are in scope of this change. 2.11 GENERAL CORPORATE MATTERS Pending legal proceedings Lundbeck is involved in several legal proceedings, including patent disputes and environmental matters, the most significant of which are described below. Some of these involve significant amounts and are subject to considerable uncertainty. Management continuously assesses the risks associated with the legal proceedings, and their likely outcome. Management is of the opinion that, apart from items recognized in the financial statements, the outcome of these legal proceedings and disputes are not probable or cannot be reliably estimated in terms of amount or timing. Further, ongoing proceedings may develop over time, and new proceedings may occur, in a way which could have a material impact on the Group's financial position and/or cash flows. In June 2013, Lundbeck received the European Commission's decision that agreements concluded with four generic competitors concerning citalopram violated competition law. The decision included fining Lundbeck EUR 93.8 million (approximately DKK 700 million). Lundbeck paid and expensed the fine in the third quarter of 2013. In March 2021, the European Court of Justice rejected Lundbeck's final appeal of the European Commission's decision. So-called "follow-on claims" for reimbursement of alleged losses, resulting from violation of competition law, often arise when decisions and fines issued by the European Commission are upheld by the European Court of Justice. The below mentioned "follow-on claims" are ongoing or threatened. Lundbeck disagrees with all claims and intends to defend itself against them. At the end of first quarter 2023, the UK health authorities served their claim form on Lundbeck and several generic companies, and Lundbeck filed its defense in the third quarter of 2023. The hearing on whether the claim is time-barred was held in the second quarter of 2024 and the Competition Appeal Tribunal has subsequently issued a decision in favor of the UK health authorities. Lundbeck was granted permission to appeal the decision to the Court of Appeal, and the Court of Appeal issued a decision in favor of the UK health authorities in the second quarter of 2025. Lundbeck has filed an application for permission to appeal the time-barring decision to the Supreme Court with the Courts of Appeal. In late October 2021, Lundbeck received a writ of summons from a German health care company claiming compensation for an alleged loss of profit plus interest payments, allegedly resulting from Lundbeck's conclusion of agreements with two of the four generic competitors, which were comprised by the EU Court of Justice ruling. Lundbeck filed its first defense in May 2022, and the parties have subsequently exchanged additional pleadings. The first instance court hearing was held in the second quarter of 2024, and Lundbeck currently expects a first instance court ruling in 2025 or 2026. The first instance court ruling may be appealed, and it make take several years before a final conclusion is reached by the German courts. In October 2024, Lundbeck received a claim form from the health authority in one of the regions (comunidades autónomas) in Spain and in November 2024 Lundbeck filed its defense. The first instance court hearing was held in the second quarter of 2025, and a first instance ruling was issued in the third quarter of 2025. The court dismissed the health authority's claim based on time-barring. The health authority has appealed the decision. Lundbeck has been informed about potential claims in several European countries, however, it is still uncertain whether the potential claims will be actively pursued. In Canada, Lundbeck is involved in two product liability class-action lawsuits relating to Cipralex®/Celexa® (one case alleging various Celexa-induced birth defects and one case against several SSRI manufacturers (incl. Lundbeck) alleging that SSRI (Celexa®/Lexapro®) induces autism birth defect), three relating to Abilify Maintena® (alleging i.a. failure to warn about compulsive behavior side effects) and one relating to Rexulti® (also alleging i.a. failure to warn about compulsive behavior side effects). Lundbeck strongly disagrees with the claims. The Celexa birth defect litigation has been discontinued in Quebec (already approved by court) and Ontario (court approval of the discontinuance in Ontario is expected in 2025). A settlement agreement has been signed by the parties in the Abilify Maintena® cases and has been approved by the courts in Quebec and Ontario. In the Rexulti® matter, a settlement agreement was signed by the parties on 13 June 2025, and court approval of the settlement is expected in the fourth quarter of 2025. Lundbeck received a Civil Investigative Demand ("CID") from the U.S. Department of Justice ("DOJ") in March 2020. The CID seeks information regarding the sales, marketing, and promotion (including the promotional speaker program) of Trintellix®. Lundbeck is cooperating with the DOJ. Otsuka and Lundbeck have received paragraph IV certifications from Sun Pharma, Apotex and Alvogen with respect to certain of the patents listed for Abilify Maintena® in the U.S. and commenced patent infringement proceedings against all three companies. The FDA will stay approval to Sun, Apotex and Alvogen until 30 months from receipt of the respective paragraph IV certifications or a court decision in Sun's and/or Apotex' favor. In June 2022 in the U.S., several entities, created for the purpose of receiving assignment of claims from payors providing health insurance coverage pursuant to Medicare Parts C and D and Medicaid, filed a complaint against Lundbeck and others. The complaint alleges that Lundbeck and the other defendants conspired to increase the unit price and quantity dispensed of Xenazine®. The case was dismissed with prejudice earlier in 2023 and is currently under appeal. In June 2023 in the U.S., Humana Inc., an insurer, filed a complaint against Lundbeck U.S. legal entities. The complaint alleges that Lundbeck engaged in an illegal kickback scheme to increase the sales and sale price of Lundbeck's Xenazine®. The complaint alleges that Lundbeck's activities targeted Humana Inc. and other private Medicare insurers who were forced to bear the costs of the alleged illegally subsidized drug sales. Lundbeck denies the allegations in the complaint and intends to defend itself. STATEMENT OF THE BOARD OF DIRECTORS AND THE REGISTERED EXECUTIVE LEADERSHIP TEAM The Board of Directors and the Registered Executive Leadership Team have discussed and adopted the financial report of H. Lundbeck A/S for the period 1 January to 30 September 2025. The financial report is presented in accordance with IAS 34 Interim Financial Reporting, as adopted by the EU and additional Danish disclosure requirements for interim financial reports of listed companies. We consider the accounting policies applied to be appropriate. Accordingly, the financial report gives a true and fair view of the Group's assets, liabilities and financial position as of 30 September 2025, and of the results of the Group's operations and cash flows for the period, which ended on 30 September 2025. In our opinion, the Management's Review (pages 6-21) gives a true and fair view of activity developments, the Group's general financial position and the results for the period. It also gives a fair view of the significant risks and uncertainty factors that may affect the Group relative to the disclosures in the Annual Report 2024. The financial report has not been subject to audit or reviewed by the company's independent auditors. Valby, 11 November 2025 Registered Executive Leadership Team Board of Directors 3 CONDENSED FINANCIAL STATEMENTS CONDENSED STATEMENT OF PROFIT OR LOSS STATEMENT OF COMPREHENSIVE INCOME CONDENSED STATEMENT OF FINANCIAL POSITION STATEMENT OF CHANGES IN EQUITY CONDENSED STATEMENT OF CASH FLOWS STATEMENT OF PROFIT OR LOSS – ADJUSTED EBITDA RECONCILIATION (9M AND Q3) 4 NOTES 4.1 BASIS OF PREPARATION The interim condensed consolidated financial statements for the first nine months ended 30 September 2025, have been prepared in accordance with IAS 34 Interim Financial Reporting as adopted by the EU and additional Danish disclosure requirements for interim financial reporting of listed companies. The interim condensed consolidated financial statements do not include all the information and disclosures required in the annual financial statements and should be read in conjunction with the Group's annual consolidated financial statements at 31 December 2024, published 5 February 2025. The accounting policies, judgements and significant estimates are consistent with those applied in the Annual Report 2024. Further IAS 34 disclosure requirements for interim financial reporting are included in section 2, Business Performance. For disclosures regarding revenue and segment information see section 2.1 Revenue by product and section 2.2 Revenue by geographical area and for disclosures regarding pending legal proceedings (contingent liabilities) see section 2.11 General corporate matters. As part of the acquisition of Longboard (Longboard Pharmaceuticals, Inc) on 2 December 2024, Lundbeck is finalizing the purchase price allocation assessment, which is expected to be reflected in our consolidated financial statements 2025 in line with the IFRS requirements. A number of new amendments came into effect from 1 January 2025. The Group did not have to change its accounting policies or make retrospective adjustments as a result of adopting these amended standards. 4.2 FAIR VALUE MEASUREMENT Financial assets and financial liabilities measured or disclosed at fair value 1 Measured at fair value 2 Disclosed at fair value The fair value of listed securities is based on publicly quoted prices of the invested assets. The fair value of derivatives is calculated by applying recognized measurement techniques, whereby assumptions are based on the market conditions prevailing at the balance sheet date. The fair value of contingent consideration is calculated as the discounted cash outflows (DCF method) from future milestone payments, taking probability of success into consideration. The fair value of other financial assets is calculated through the financial performance of the market inputs (i.e. interest s) and other market conditions prevailing at the balance sheet date. The carrying amount of bank and bond debt is believed to be equal to or close to fair value as the interest is variable for these instruments. 4.3 ADJUSTED EBITDA Adjusted EBITDA is the main performance indicator measuring ongoing operational profitability and is used internally and externally. To permit a better understanding of the underlying operational performance, the operating result is adjusted to exclude depreciation and amortization, impairment losses and reversals of impairment losses, as well as adjustments restricted to the following categories: (i) Integration expenses, (ii) Restructuring expenses, (iii) Gains/losses on divestment of businesses, (iv) Acquisition expenses, (v) Other adjustments. Adjusted EBITDA, adjusted gross profit, adjusted net profit and adjusted EPS are non-IFRS performance measures. FINANCIAL CALENDAR 2026 Lundbeck contacts About H. Lundbeck A/S Lundbeck is a biopharmaceutical company focused exclusively on brain health. With more than 70 years of experience in neuroscience, we are committed to improving the lives of people with neurological and psychiatric diseases. Brain disorders affect a large part of the world's population, and the effects are felt throughout society. With the rapidly improving understanding of the biology of the brain, we hold ourselves accountable for advancing brain health by curiously exploring new opportunities for treatments. As a focused innovator, we strive for our research and development programs to tackle some of the most complex neurological challenges. We develop transformative medicines targeting people for whom there are few or no treatments available, expanding into neuro-specialty and neuro-rare from our strong legacy within psychiatry and neurology. We are committed to fighting stigma and we act to improve health equity. We strive to create long term value for our shareholders by making a positive contribution to patients, their families and society as a whole. Lundbeck has approximately 5,700 employees in more than 50 countries and our products are available in more than 80 countries. For additional information, we encourage you to visit our corporate site  and connect with us via LinkedIn. Safe Harbor/Forward-Looking Statements This corporate release contains forward-looking statements that provide our expectations or forecasts of future events such as new product introductions, product approvals and financial performance. Forward looking statements include, without limitation, any statement that may predict, forecast, indicate or imply future results, performance or achievements, and may contain words like "believe", "anticipate", "expect", "estimate", "intend", "plan", "project", "will be", "will continue", "will result", "could", "may", "might", or any variations of such words or other words with similar meanings. All statements other than statements of historical facts included in this presentation, including, without limitation, those regarding our financial position, business strategy, plans and objectives of management for future operations (including development plans and objectives relating to our products), are forward looking statements. Such forward looking statements involve known and unknown risks, uncertainties and other factors which may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by such forward looking statements. Factors that may affect future results include, among others, interest rate and currency exchange rate fluctuations, delay or failure of development projects, production or distribution problems, unexpected contract breaches or terminations, government-mandated or market-driven price decreases for Lundbeck's products, introduction of competing products, Lundbeck's ability to successfully market both new and existing products, exposure to product liability and other lawsuits, changes in reimbursement rules and governmental laws and related interpretation thereof, and unexpected growth in costs and expenses. The forward-looking statements in this document and oral presentations made on behalf of Lundbeck speak only as at the date of this document. Lundbeck does not undertake any obligation to update or revise forward-looking statements in this presentation or oral presentations made on behalf of Lundbeck, nor to confirm such statements to reflect subsequent events or circumstances after the date of the presentation or in relation to actual results, unless otherwise required by applicable law or applicable stock exchange regulations. [1] Change at CER (Constant Exchange Rates) does not include effects from hedging. [2] Abilify long-acting injectable (LAI) franchise comprises following products: Abilify Maintena®, Abilify Maintena® 960 mg and Abilify Asimtufii® [3] EBITDA refers to Earnings Before Interest, Taxes, Depreciation and Amortization, including impairment losses. Adjusted EBITDA is defined as EBITDA adjusted by certain items, for details see note 4.3 Adjusted EBITDA. [4] Demand in the U.S. is based on prescription level data, thereby constituting patient demand. Demand in Europe and International Operations is based on volume sell-in to pharmacies and thereby considered a proxy for patient demand. CONTACT: H. Lundbeck A/S Ottiliavej 9, 2500 Valby, Denmark +45 3630 1311 [email protected] This information was brought to you by Cision The following files are available for download: SOURCE H. Lundbeck A/S 21% more press release views with Request a Demo