OATP1B3

点击上方的 行舟Drug ▲ 添加关注基于生理学的药动学/生物药剂学模型在中药药动学研究中的应用进展来源《中草药》 2023年10月 第54卷 第20期作者田锁燕，贾国香，胡静雯，卢倩，苏布达，杨珅珅，李遇伯天津中医药大学中药学院摘要中药具有多成分、多靶点、代谢复杂、临床应用广泛的特点。中药药动学（pharmacokinetics，PK）是中药研究中的重大科学问题之一，在阐释中医中药的科学性、推进中药国际化、现代化中具有重要意义。基于生理学的药动学（physiologically based pharmacokinetics，PBPK）模型与基于生理学的生物药剂学（physiologically based biopharmaceutics，PBBM）模型针对中药及其复方，采用“自下而上”的方法预测药物的体外特性与体内血浆或不同组织中药物及其代谢物的药动学过程，为阐明中药药效物质基础、揭示中药有效性与安全性的科学内涵、中药新药研发与剂型改进等方面提供重要的参考信息。介绍PBPK/PBBM模型在中药药动学研究中的优势和应用，以期为中药现代化研究和临床合理用药等方面提供参考。关键词中药药动学；生理学的药动学；生物药剂学；药物相互作用；风险评估；剂型优化与开发_正文_近些年来，中药在埃博拉病毒、疟疾和新冠肺炎等众多疑难杂症的治疗中发挥了良好的作用，也正是因为中医药悠久的历史，使得中药在世界许多地区被广泛应用于临床治疗和药品保健等领域[1-3]。由于中药的化学成分多样、生物功能复杂、药效物质基础不明确[4]，众多研究者开展了广泛而深入的中药药动学研究，为中药中各成分的体内代谢过程研究做出了重要贡献。中药药动学是运用数学函数和定量描述方法，研究中药有效成分及组成，单方或复方在体内吸收、分布、代谢及排泄（absorption，distribution，metabolism，and excretion，ADME）过程及时-效和时-量关系[5]。其研究对阐明中药药效物质基础、中药代谢途径及其代谢产物的化学结构和中药药理作用机制等具有重要意义，为中药质量监测评估、新药开发以及给药途径提供科学参考[6-8]。然而，中药药动学的研究仍然存在许多需要解决的问题：（1）符合中药自身特征的技术方法和评价体系较少；（2）中药复方的药动学研究有待加强，有些中药的药动学研究还停留在动物实验层面，不能直接应用于人体[9]，亦或是由于实验数据太少，导致中药在体内的药物代谢参数不准确[10]；（3）基于药物代谢酶和转运体的中药体内过程调控机制和中西药相互作用机制有待深入研究；（4）中药PK-PD结合模型研究需要构建新思路和新方法；（5）中药健康风险评估需要重视。目前，美国食品药品监督管理局（food and drug administration，FDA）和欧洲药品管理局（European medicines agency，EMA）分别颁布了多项关于生理学的药动学(physiologically based pharmacokinetics，PBPK)平台规范及其研究的报告规范的指南，有助于提高PBPK研究质量[11-13]。PBPK模型的建立从临床实验数据出发，通过将药物信息和生理信息结合起来，对药物浓度-时间曲线进行先验模拟。对于中药的开发和研究，PBPK模型可以弥补传统研究方法的不足，在不同年龄阶段外推、种属间外推、体外到体内外推以及基于动物数据预测人体药动学等研究方向中具有独特优势，对创新药物的临床研究，降低研发成本具有重要的意义。1PBPK/生理学的生物药剂学(physiologically based biopharmaceutics，PBBM)模型概述及PBPK研究进展1.1 PBPK模型概述基于PBPK模型是一种整合了生理、生化和解剖等方面的知识，模拟机体循环系统血液流向，从整体的角度出发将机体各器官/组织相互联结，并遵循质量守衡原理建立的数学建模技术[14-15]。1937年，Theorell首次提出使用多隔室模型模拟药动学的想法，并在模型中纳入生理参数，至此，PBPK模型逐步发展起来[16]。与传统房室模型（表1）不同的是，PBPK模型是将每个相应的组织器官单独作为一个房室看待，房室间借助血液循环连接，将各个房室内药物复杂的ADME过程简单化，求得质量平衡微分方程，将数据导入专业的PBPK软件进行计算并验证，能真实反映出某一组织/器官内药物浓度的经时变化，以此呈现出药物在体内的分布情况[17-18]，同时允许估计最大血浆浓度、吸收动力学、分布动力学和药物消除。1.2 PBBM模型概述基于PBBM在药品质量监管领域的应用正在不断发展。PBBM和基于生理学的吸收模型（physiologically based absorption modeling，PBAM）原理相同，也称为PBPK吸收模型，涵盖生物药剂学的所有领域，在本文中以PBBM统称。PBBM是在GastroPlus™（Simulations Plus，Inc）中开发的一种有前途的工具，整合了吸收建模、生物预测溶出度测试和PBPK建模，用于预测体内吸收和指导制剂开发[19]。因此，可以使用最小的PBPK或全身PBPK模型，在PBBM中模拟系统药物处置过程，对不同制剂进行全面的生理药动学/药理学研究，量化PK和PD图谱。PBBM模型被用于多个研究领域，包括（1）溶出方法/检测标准；（2）粒径分布设置；（3）IVIVR；（4）风险评估；（5）特殊人群口服吸收；（6）生物药剂学分类系统（biopharmaceutics classification system，BCS）的分类依据；（7）胃pH的影响；（8）生物等效性评价等。FDA相关会议报告决定，一般性PBPK指南适用于PBBM模型[20]。1.3 PBPK模型研究概况PBPK结合体外至体内外推（In vitro-In vivo extrapolation，IVIVE）技术，预测药物的药动学特征和药物间相互作用（drug-drug interaction，DDI）的程度等[21-22]，已变得越来越普遍。众多研究者意识到其为人类发展所带来的无限价值，利用PBPK模型在包括但不限于以下几个方面。1.3.1 特殊人群安全用药问题外推得到儿童、妊娠妇女及病理状态下（如肝、肾功能不全）药物在体内的过程和给药方案[23-26]，如Guo等[27]开发并验证了成年患者奥马利珠单抗的PBPK模型，外推到儿童患者，成功预测到患有中度至重度过敏性哮喘的2~6岁儿童的临床用药剂量。1.3.2 药物多成分相互作用研究通过考察对代谢酶和转运体的竞争性抑制，研究药物-药物相互作用（DDI）[28-30]，Lien等[31]建立PBPK模型，研究特格拉赞与CYP3A4抑制剂和诱导剂的DDI。1.3.3 仿制药和药物新制剂研发研究者可通过修改不同化合物或制剂的相应参数来获得不同药物制剂体内ADME过程[32-35]，研发临床疗效佳、生物利用度高的仿制药和药物新剂型。1.3.4 环境风险物健康风险评估已有研究[36-39]成功利用PBPK模型预测到环境中污染物的健康风险值，为人类健康和环境治理提供了参考。上述研究证明PBPK是药物体内过程研究中的一大亮点，同时为新药研发和临床患者合理安全用药研究奠定了基础。随着计算机行业的快速发展，国内外许多公司开发出不同的机制性吸收软件，包括开放软件（acslX、SAAM II、ADAPT5和Berkeley Madonna等）和用户界面友好的常用专业软件（GastroPlusTM、Simcyp®-Simulator、PK-Sim®），3个专业软件分别囊括了基础模块、PBPK模块、ACAT、ADAM模块以及儿科模块[40-41]，为PBPK/PBBM建模和模拟做出了巨大贡献，很大程度上减少了科研成本、动物实验及临床实验受试者人数。文章内容由凡默谷小编查阅文献选取，排版与编辑为原创。如转载，请尊重劳动成果，注明【来源：凡默谷公众号】。2PBPK/PBBM模型在中药药动学中的应用目前，随着中药现代化的不断推进，PBPK模型利用其自身优势克服了传统房室模型的不足，在中药体内ADME与风险评估、中药-药物相互作用、中药在特殊人群的给药方案调整、中药整体CMM BCS分类属性研究等领域发挥了极为重要的作用（图1）。例如，吴桐[42]利用PBPK模型不仅预测到雷公藤甲素（triptolide，TP）存在体内肝毒性风险和药物相互作用反应，同时观测到中度肝损伤患者体内TP血浆暴露量明显升高。图1 PBPK 建模过程及其在中药PK 中的应用Fig. 1 PBPK modeling process and its application in TCM PK2.1 中药健康风险评估近些年，随着有关中药不良反应的报道逐渐增多，人们对中药的安全使用意识逐渐提高。但是，由于中药成分复杂多样并且有些毒性成分也能发挥临床治疗效果，因此，我国中药风险效益评估仍在初步研究阶段，尚未形成完整的理论体系[43-44]。根据美国与欧盟颁布的一系列以非动物实验作为评价药物安全性指标的政策[45]，得出PBPK模型可以预测中药成分在器官组织中的暴露量，提高中药安全性评价和限量标准的科学性和准确性[46]。药物性肝损伤（drug-inducedliver injury，DILI）是临床实践中观察到的最常见不良反应之一[47]，重症DILI表现为急性肝功能衰竭甚至死亡[48]。PBPK模型可以预测肝脏组织浓度，并与体外测定的氧化应激、线粒体损伤、胆汁酸淤积和先天免疫反应的激活等肝损伤机制整合（图2），模拟中药所致肝损伤[49-52]。Li等[53]利用PBPK建模预测口服苦参碱、氧化苦参碱、雷公藤甲素和大黄素4种中药活性成分的最大安全剂量。模拟结果与后续的临床试验结果相近。Liu等[54]采用体外毒性和计算机反向剂量测定的综合方法，研究16种蒽醌及其衍生物的潜在人体肝脏毒性。PBPK模拟证实了患者服用香豆素及其代谢物不足以引起肝毒性的发生[55]。综上，利用PBPK模型进行正向或反向剂量测定有助于人类对中药的风险评估，避免肝毒性等不良事件的发生。2.2 中药活性成分与药物相互作用研究中药及其复方制剂具有复杂多样的活性成分，极易影响部分中药或化学药的药动学行为，从而发生相互作用[56]。研究发现，中药复杂成分可以改变体内细胞色素P450酶和转运蛋白的活性[57]，间接影响CYP酶和P-gp底物药或抑制剂的代谢和清除[58]，从而无法达到临床预期治疗效果甚至引发不良反应。目前，各监管机构对（drug-drug interaction，DDI）体外和临床研究的相关指南不断完善与更新。国家药监局审评中心（center for drug evaluation，CDE）于2021年发布适用于化学药品、中药、天然药物等最新版《药物相互作用研究技术指导原则》，此方案指导了经真实的临床试验或人体数据验证过的PBPK模型对不同机制引起的药物相互作用进行评价，同时支持剂量选择和外推，将有助于减少药物开发过程中的不确定性，提高研发效率[59]。PBPK模型严谨科学的预测能力为其在中药配伍及中药-药物相互作用的机制和结果研究中发挥了极其重要的作用，通过模拟获得中药对代谢酶和转运体的诱导或抑制作用，定量预测相互作用的程度，将为中药的临床剂量预测和调整以及安全使用拓宽前景。2.2.1 预测中药与CYP450酶介导的药物相互作用中药与药物代谢酶相互作用大多呈现抑制作用，易引起药物不良反应。采用PBPK建模评估方法简化了中草药产品的安全性评估，并最终促进了临床肿瘤药物的安全使用。Jeffry等[60]建立并验证了贯叶金丝桃素的PBPK模型，预测圣约翰草与CYP底物药物相互作用的程度。模拟结果表明，圣约翰草提取物显著降低了经口给药后咪达唑仑的全身暴露量，而对服用伊马替尼患者的全身暴露量未产生影响。之后，他们以相同的思路建立黄连碱和小檗碱的PBPK模型，预测白茅根提取物与伊马替尼和博舒替尼在CYP3A酶存在时相互作用的程度。建议临床上调整博舒替尼的剂量，以保证药物疗效和安全性[61]。Tanveer等[62]使用PBPK模型评估不同CYP2C9基因型中水飞蓟宾A和氯沙坦相互作用的可能性和程度。预测结果可知，在CYP2C9*1/*2基因型个体中，水飞蓟宾与氯沙坦联合给药导致中度药动学相互作用。He等[63]开发并验证了五味子醇A和五味子醇B的PBPK模型，以预测CYP3A5表达者或非表达者中五味子醇A和五味子醇B联合给药后他克莫司暴露量的变化。结果表明，多次口服五味子醇B会导致CYP3A5表达者和非表达者他克莫司的体内暴露分别增加26%和57%，相互作用较强。2.2.2 预测中药与转运蛋白介导的药物相互作用中药活性成分会对转运蛋白的功能和表达产生影响，当与化学药物联用或与中药配伍时，有的能增强或降低原有药效，有的能抑制或消除毒副作用，有的则能产生或增强毒副反应[64]。例如，Liu等[65]采用SPIP模型探讨浙贝母和附子的不相容机制。结果显示，浙贝母对P-gp的功能和表达均有抑制作用，而附子中的苯甲酰新乌头原碱是P-gp的底物。紫杉醇是P-gp底物药，也是OATP1B1和OATP1B3的体外底物，而酮康唑与维拉帕米是P-gp抑制剂。Mailys等[66]通过建立紫杉醇静脉给药PBPK模型，预测癌症患者合用紫杉醇与酮康唑或维拉帕米发生HDI的程度以及导致中性粒细胞减少的发生率。预测结果可知，紫杉醇与酮康唑或维拉帕米合并使用的情况下，预计39%和26%的人群将发生重度中性粒细胞减少症，2种抑制剂均可导致紫杉醇的AUC比值增加。如果使用酮康唑或其他强抑制剂，建议在给药紫杉醇后至少12h给药，以降低毒性风险。2.3 中药活性成分在特殊人群中的药动学研究特殊人群的机体功能和其他生理机能会影响药物在体内的过程，代谢酶与转运体的功能和表达与健康成年人存在差异，更容易产生相互作用和肝损伤等不良反应，所以其临床治疗方案的选择需尤为谨慎。CDE于2023年发布了《生理药动学模型在儿科人群药物研发中应用的技术指导原则》，其中明确提到PBPK模型通过对人体PK的预测，可为临床试验设计提供依据，如剂量选择、药物组织分布和儿科剂型开发等[67]。因此，在研究药物在特殊人群体内吸收机制时，PBPK模型提供了一个虚拟的模拟平台，通过纳入与年龄、疾病相关的生理参数，模拟健康人与特殊人群体内药物暴露量，为其剂量药动学预测和精确治疗提供更加严谨的参考信息[68]。Li等[69]通过PK-Sim软件，建立了广金钱草总黄酮的标志性成分夏佛塔苷的人体PBPK模型，考察包括老年人（71~80岁）和慢性肾功能受损患者在内的特殊人群PK特征。预测结果显示，慢性肾脏病患者中夏佛托苷的血浆浓度比健康成年人要高得多，老年人口服TFDS后暴露量差异不大。因此，对于重度肾损害患者，建议减少临床用药剂量。陈琳[70]应用SimCypTM软件构建了欧前胡素、异欧前胡素的大鼠和人体PBPK模型，预测严重吸烟人群血浆药动学和HDI潜能，为服用含有补骨脂素中药的吸烟人群提供安全有效的用药指南。李会娟[71]基于PBPK模型联合PA-1细胞，对补骨脂的胚胎毒性进行定性定量研究。此方法为建立符合中医药特点的中药胚胎毒性筛查体系奠定基础，为妊娠期应用中药的安全性研究搭建良好的平台。2.4 中药整体CMMBCS分类属性研究中药活性成分大多为BCS-Ⅲ类或Ⅳ类药物，不能完全被人体吸收入血，导致口服生物利用度低，PBPK模型可以预测出剂量数、吸收数及溶出数等参数[72]，进而完善BCS分类属性，揭示中药肠吸收的特征与行为。中药溶解性、渗透性是PBPK建模的核心参数之一，一方面，通过体外实验获得的中药BCS数据，可更进一步校验PBPK建模的默认参数，从而更准确地对中药人体吸收进行预测[73]。另一方面，PBPK模型也可以预测出剂量数、吸收数及溶出数等关键指标参数[74]，以进一步完善中药BCS分类。Liu等[75]以葛根芩连复方中的黄芩素为研究对象，基于大鼠、比格犬和健康人的PBPK模型及CMM BCS理念，研究黄芩素BCS属性分类。结果显示黄芩素为BCS-II类，与体外溶出速率结果一致。通过PBPK模型异速增长方程预测了槲皮素、大豆苷元、芒柄花素等体内有效渗透系数和吸收分数[76]。尹秀文[77]通过GastroPlus软件建立并验证小檗碱大鼠吸收PBPK模型，预测小檗碱在大鼠体内的吸收系数和CMMBCS属性分类。以上案例充分证明PBPK模型结合体内外实验方法是研究中药CMMBCS分类及预测人体吸收的良好工具，为中药成分的体内吸收研究方面提供数据基础及科学理论参考。2.5 中药剂型优化及开发美国FDA在药品开发早期就鼓励对PBPK技术的开发，尤其对于溶出是限速步骤的产品[78]。对于成分复杂或者不便于使用常规PK等效方法进行评估的中药制剂，基于生物药剂学的PBPK建模可将药物体内吸收、临床表现、药物关键质量参数和体外评估方法等联系起来[79]，进行生物等效性预测（图3），帮助建立体外-体内联系，辅助制剂优化和新剂型开发，制定以患者为中心的临床制剂质量标准。为了研究中药单体雷公藤红素及其纳米制剂在大鼠体内的药动学行为以及肝毒性，石忠波[80]成功利用雷公藤红素及纳米制剂的大鼠全身PBPK模型，预测血浆及各组织雷公藤红素的C-t关系，获取相关药动学参数。发现雷公藤红素在肝脏中分布最多，有蓄积现象。与雷公藤红素比较，其纳米制剂腹腔注射后生物利用度提高、肝毒性降低，其他药动学行为亦有所改善。Wang等[81]用GastroPlus软件建立3种姜黄素口服制剂PBBM模型，评估姜黄素在肠道吸收动力学参数。PBBM模型预测值与大鼠体内药动学实测值基本一致，表明其模拟中药制剂体内吸收结果可靠。此外，Gao等[82]以高疏水性药物穿心莲内酯作为模型药物，用PK-Sim软件分别建立大鼠口服纯穿心莲内酯、穿心莲内酯滴丸和穿心莲内酯环糊精三元复合制剂的PBBM模型，预测3种制剂的PK参数，并通过细胞和动物实验进行验证，辅助临床成功研制出穿心莲内酯环糊精三元复合制剂。综上所述，基于生理学的建模技术已经成为促进中药复方配方设计的有力工具，相比于传统药动学模型，其能够更加准确的预测出不同制剂的体内吸收过程，为中药制剂优化和新剂型开发提供科学指南。3结语与展望近些年来改进的机制性生理模型由于综合了口服药物吸收的多重过程及影响因素，拥有更好的模拟和预测能力，与Caco-2细胞模型及在体肠灌流模型的预测结果具有良好的相关性。PBPK模型在探索中药复方配伍的科学内涵、中药-药物相互作用、体内体外相关性和指导临床合理安全用药等方面具有极大的优势，同时可为药物说明书中特殊人群用法用量的撰写提供依据，加快了中药新药的研发历程。美国FDA等权威监管机构已经意识到PBPK模型的重要性，将其列入了新药注册的审查环节[83-84]。PBBM模型由于近年来在支撑药品质量标准制定领域使用的增加，人们对这一PBPK模型分支的兴趣渐长，在生理相关性溶出方法基础上构建的PBBM模型的模式，不仅可以帮助预测中药的体内吸收情况，还可以为中药复方生物豁免提供依据。相信未来这类技术在中药标准化中的使用会越来越普及和规范化。在以上应用实例中，中西药相互作用研究占比较大。临床工作中，中西药联用现象也十分普遍，并且取得了突出成绩。然而，PBPK模型预测中西药相互作用仍面临不少挑战，一方面，由于中药成分复杂、种属差异等因素，使得模型预测结果无法得到保证，目前将PBPK建模用于代谢酶和转运体参与的体内HDI研究并不多[85-86]；另一方面，中西药相互作用研究缺乏整体的定量评价体系和因果关系，无法从根源解决联合用药带来的安全问题。相信随着科学技术的发展与新的体外和体内数据的出现，PBPK等机制性生理模型在中药-药物相互作用研究中将会得到更多的开发和使用，为临床安全用药提供科学有用的参考指南，为中西药联用的增效减毒研究开启新篇章。此外，以上方法用于中药生物药剂学分类规律的研究对解释低生物利用度、高生物学效应的中药药效物质与作用机制的研究具有指导意义，从而促进中药复方剂型优化和开发。PBPK模型作为一种机制性模型，其预测结果的准确性依赖于当前科学认知水平和数据的可靠性。目前，对人类PBPK建模的研究尚处于积累阶段，系统参数来源少、参数准确性无法保证、模型验证缺少严谨性和计算复杂等难题，使得其无法在中药研究中被广泛使用。但随着各学科间的相互渗透、相互影响和更多科研工作者不懈的努力，PBPK在中药标准化研究中的应用会越来越广泛和深入。参考文献详见《中草药》 2023年10月 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LOS ANGELES, Oct. 25, 2023 /PRNewswire/ -- The Prostate Cancer Foundation (PCF) and Bayer today announced two 2023 Bayer-PCF Darolutamide Challenge Awards totaling $2 million to support clinical investigations on darolutamide in prostate cancer. In 2019, the U.S. Food and Drug Administration approved Bayer's Nubeqa® (darolutamide), an androgen receptor inhibitor (ARI), for the treatment of adults with non-metastatic, castration-resistant prostate cancer (nmCRPC). In 2022, darolutamide was FDA-approved in combination with docetaxel chemotherapy for adults with metastatic hormone-sensitive prostate cancer (mHSPC), or metastatic prostate cancer patients receiving their first line of hormonal treatment. "We are proud and pleased to work with Bayer on these awards," said Howard R. Soule, PhD, PCF Executive Vice President and Chief Science Officer. "We congratulate the investigators and look forward with great anticipation to the results of their research." "Prostate Cancer is the most commonly diagnosed cancer in men with nearly 35,000 expected to die from this disease in the U.S. this year.2 While we have made great progress, continued research is essential," said Iain Webb, Vice President and Head of U.S. Medical Affairs, Oncology at Bayer. "Collaborating with other innovators brings new research to the forefront, which has the potential to lead to new clinical uses for treatment options. We congratulate the winners of these awards and are excited to see the results of the research." The teams awarded 2023 Bayer-PCF Darolutamide Challenge Awards are: Principal Investigators: Praful Ravi, MD, Dana-Farber Cancer Institute; David Einstein, MD, Beth Israel Deaconess Medical Center Co-Investigators: Heather Jacene, MD, Mary-Ellen Taplin, MD, Jacob Berchuck, MD, all of Dana-Farber Cancer Institute; Steve Balk, MD, Beth Israel Deaconess Medical Center Young Investigator: Daniel Fein, MD, Beth Israel Deaconess Medical Center Project Title: Darolutamide to Augment Radiotheranostic Therapy in Biochemically Recurrent Prostate Cancer (DART-BCR) Principal Investigators: Russell Szmulewitz, MD, Megan Huisingh-Scheetz, MPH, MD, University of Chicago Young Investigator: Nabiel Mir, MBBS, University of Chicago Project Title: DAROSTEP: Evaluating Step Counts as a Biomarker and its Relationship on Treatment Outcomes in Vulnerable Patients with Metastatic Hormone-Sensitive Prostate Cancer on Darolutamide and Androgen Deprivation Therapy About NUBEQA® (darolutamide)1 NUBEQA is an androgen receptor inhibitor (ARi) with a distinct chemical structure that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. On July 30, 2019, the FDA approved NUBEQA® (darolutamide) based on the ARAMIS trial, a randomized, double-blind, placebo-controlled, multi-center Phase III study, which evaluated the safety and efficacy of oral NUBEQA in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Based on results from the ARASENS trial, a randomized, Phase III, multi-center, double-blind, placebo-controlled trial, NUBEQA plus androgen deprivation therapy (ADT) and docetaxel was approved on August 5, 2022 for the treatment of adult patients with metastatic hormone-sensitive prostate cancer (mHSPC). NUBEQA is also being investigated in additional studies across various stages of prostate cancer, including in the ARANOTE Phase III trial evaluating NUBEQA plus ADT versus ADT alone for mHSPC, as well as in the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) led international Phase III co-operative group DASL-HiCaP (ANZUP1801) trial evaluating NUBEQA as an adjuvant treatment for localized prostate cancer with very high risk of recurrence. Information about these trials can be found at . Developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company, NUBEQA is indicated for the treatment of adults with nmCRPC or with mHSPC in combination with docetaxel.1 Filings in other regions are underway or planned. INDICATIONS NUBEQA® (darolutamide) is an androgen receptor inhibitor indicated for the treatment of adult patients with: Non-metastatic castration-resistant prostate cancer (nmCRPC) Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel IMPORTANT SAFETY INFORMATION Warnings & Precautions Ischemic Heart Disease – In a study of patients with nmCRPC (ARAMIS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA versus 2.5% receiving placebo, including Grade 3-4 events in 1.7% vs. 0.4%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA vs. 0.2% receiving placebo. In a study of patients with mHSPC (ARASENS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA with docetaxel vs. 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% vs. 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel vs. 0% receiving placebo with docetaxel. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue NUBEQA for Grade 3-4 ischemic heart disease. Seizure – In ARAMIS, Grade 1-2 seizure occurred in 0.2% of patients receiving NUBEQA vs. 0.2% receiving placebo. Seizure occurred 261 and 456 days after initiation of NUBEQA. In ARASENS, seizure occurred in 0.6% of patients receiving NUBEQA with docetaxel, including one Grade 3 event, vs. 0.2% receiving placebo with docetaxel. Seizure occurred 38 to 340 days after initiation of NUBEQA. It is unknown whether anti-epileptic medications will prevent seizures with NUBEQA. Advise patients of the risk of developing a seizure while receiving NUBEQA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of NUBEQA in patients who develop a seizure during treatment. Embryo-Fetal Toxicity – Safety and efficacy of NUBEQA have not been established in females. NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with NUBEQA and for 1 week after the last dose. Adverse Reactions In ARAMIS, serious adverse reactions occurred in 25% of patients receiving NUBEQA vs. 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA included urinary retention, pneumonia, and hematuria. Fatal adverse reactions occurred in 3.9% of patients receiving NUBEQA vs. 3.2% of patients receiving placebo. Fatal adverse reactions in patients who received NUBEQA included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%). The most common adverse reactions (>2% with a ≥2% increase over placebo), including laboratory test abnormalities, were increased AST, decreased neutrophil count, fatigue, increased bilirubin, pain in extremity, and rash. Clinically relevant adverse reactions occurring in ≥2% of patients treated with NUBEQA included ischemic heart disease and heart failure. In ARASENS, serious adverse reactions occurred in 45% of patients receiving NUBEQA with docetaxel vs. 42% of patients receiving placebo with docetaxel. Serious adverse reactions in ≥2% of patients who received NUBEQA with docetaxel included febrile neutropenia (6%), decreased neutrophil count (2.8%), musculoskeletal pain (2.6%), and pneumonia (2.6%). Fatal adverse reactions occurred in 4% of patients receiving NUBEQA with docetaxel vs. 4% of patients receiving placebo with docetaxel. Fatal adverse reactions in patients who received NUBEQA included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%). The most common adverse reactions (≥10% with a ≥2% increase over placebo with docetaxel) were constipation, rash, decreased appetite, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (≥30%) were anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST, increased ALT, and hypocalcemia. Clinically relevant adverse reactions in <10% of patients who received NUBEQA with docetaxel included fractures, ischemic heart disease, seizures, and drug-induced liver injury. Drug Interactions Effect of Other Drugs on NUBEQA – Combined P-gp and strong or moderate CYP3A4 inducers decrease NUBEQA exposure, which may decrease NUBEQA activity. Avoid concomitant use. Combined P-gp and strong CYP3A4 inhibitors increase NUBEQA exposure, which may increase the risk of NUBEQA adverse reactions. Monitor more frequently and modify NUBEQA dose as needed. Effects of NUBEQA on Other Drugs – NUBEQA inhibits breast cancer resistance protein (BCRP) transporter. Concomitant use increases exposure (AUC) and maximal concentration of BCRP substrates, which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use where possible. If used together, monitor more frequently for adverse reactions, and consider dose reduction of the BCRP substrate. NUBEQA inhibits OATP1B1 and OATP1B3 transporters. Concomitant use may increase plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor more frequently for adverse reactions and consider dose reduction of these substrates. Review the Prescribing Information of drugs that are BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA. For important risk and use information about NUBEQA, please see the accompanying full Prescribing Information . About the Prostate Cancer Foundation The Prostate Cancer Foundation (PCF) is the world's leading philanthropic organization dedicated to funding life-saving prostate cancer research. Founded in 1993 by Mike Milken, PCF has been responsible for raising more than $1 billion in support of cutting-edge research by more than 2,200 research projects at 245 leading cancer centers in 28 countries around the world. Since PCF's inception, and through its efforts, patients around the world are living longer, suffering fewer complications, and enjoying better quality of all life. PCF is committed to creating a global public square for prostate cancer, in service to our mission of ending death and suffering from the disease. Learn more at pcf.org. About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. Its products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2022, the Group employed around 101,000 people and had sales of 50.7 billion euros. R&D expenses before special items amounted to 6.2 billion euros. For more information, go to . Forward-Looking Statements This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer's public reports which are available on the Bayer website at . The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments. PP-NUB-US-2810-1 10/23 PCF MEDIA CONTACT: Staci L. Vernick Prostate Cancer Foundation [email protected] [email protected] 610-812-6092 BAYER MEDIA CONTACT: Carolyn Nagle [email protected] 201-419-0337 References NUBEQA® (darolutamide) tablets [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, October 2023. American Cancer Society. Facts & Figures 2023. American Cancer Society. Atlanta, Ga. 2023. SOURCE Prostate Cancer Foundation

Bayer’s focus remains on prostate cancer care with NUBEQA® (darolutamide), supported by additional ARASENS and ARAMIS trial analyses, evaluating prostate-specific antigen (PSA) outcomes in metastatic hormone-sensitive prostate cancer (mHSPC), and health-related quality of life (HRQoL) deterioration-free survival (DetFS) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) New data from the REASSURE observational study of Xofigo® (radium Ra 223 dichloride) will explore clinical outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) Real-world data will explore Stivarga® (regorafenib) in refractory metastatic colorectal cancer (mCRC), in addition to the safety and effectiveness in unresectable hepatocellular carcinoma (uHCC) Bayer will present data from a post-hoc pooled analysis of three clinical trials evaluating Vitrakvi® (larotrectinib) in the treatment of patients with treatment-naïve non-primary central nervous system (CNS) TRK fusion cancer, alongside updated efficacy and safety data from three pooled clinical trials evaluating Vitrakvi for the treatment of patients with TRK fusion cancer Bayer will highlight the first disclosure of investigational clinical data from a first-in-human, Phase I trial of BAY 2927088, an oral tyrosine kinase inhibitor (TKI) in patients with EGFR or HER2 mutant non-small cell lung cancer (NSCLC) Presentations: 1784P, 1781P, 1816P, 616P, 994P, 667P, 668P, 1320MO WHIPPANY, N.J.--(BUSINESS WIRE)-- Bayer will present new data from across its oncology portfolio at the upcoming European Society for Medical Oncology (ESMO) Congress taking place in Madrid, Spain from October 20-24, 2023. The breadth of new data showcases Bayer’s ongoing commitment to supporting patients living with cancer. NUBEQA® (darolutamide) data includes further analyses from the Phase III ARASENS trial which evaluates prostate-specific antigen (PSA) outcomes of NUBEQA plus androgen deprivation therapy (ADT) and docetaxel, compared to ADT and docetaxel by disease volume in metastatic hormone-sensitive prostate cancer (mHSPC). In addition, Bayer will present new data on health-related quality of life (HRQoL) deterioration-free survival (DetFS) by PSA decline in the Phase III ARAMIS trial in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). NUBEQA is currently indicated in the U.S. in combination with docetaxel for the treatment of adult patients with mHSPC and for the treatment of adult patients with nmCRPC.1 Bayer will also present new data from the REASSURE observational study, evaluating the clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) who received combined treatment with Xofigo® (radium Ra 223 dichloride) and enzalutamide. Xofigo is indicated for the treatment of patients with mCRPC, symptomatic bone metastases, and no known visceral metastatic disease.2 Bayer remains committed to gastrointestinal (GI) cancer care. New real-world data featuring Stivarga® (regorafenib) explores the clinical outcomes of Stivarga-treated patients when administered prior to trifluridine/tipiracil ± bevacizumab in patients with refractory metastatic colorectal cancer (mCRC). Additionally, Bayer will highlight data from the REFINE study, evaluating the safety and effectiveness of Stivarga in patients with unresectable hepatocellular carcinoma (uHCC) and prior liver transplantation (PLT). Stivarga is indicated for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy. Stivarga is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.3 Bayer will highlight the latest efficacy and safety data of Vitrakvi® (larotrectinib), including data from a post-hoc pooled analysis of three clinical trials evaluating Vitrakvi in the treatment of patients with treatment-naïve non-primary central nervous system (CNS) TRK fusion cancer, and updated data from a pooled analysis from three clinical trials of patients with longer follow-up. Vitrakvi is approved for the treatment of adult and pediatric patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. Patients should be selected for therapy based on a FDA-approved test. This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.4 Bayer will highlight the latest data from its precision oncology pipeline, including the first disclosure of investigational clinical data from a first-in-human, Phase I trial of BAY 2927088, an oral tyrosine kinase inhibitor (TKI) in patients with non-small cell lung cancer (NSCLC). Details on presentations from Bayer for the 2023 ESMO Congress are listed below: Darolutamide Prostate-specific antigen (PSA) outcomes with darolutamide (DARO), androgen-deprivation therapy (ADT) and docetaxel (DOC) in patients (pts) with high- and low-volume metastatic hormone-sensitive prostate cancer (mHSPC) in ARASENS E-Poster: 1784P; October 22 Health-related quality of life (HRQoL) deterioration-free survival (DetFS) by prostate-specific antigen (PSA) decline in darolutamide (DARO)-treated patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) from ARAMIS E-Poster: 1781P; October 22 Radium-223 dichloride (Ra-223) Combination treatment with radium-223 (223Ra) and enzalutamide (enza) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) in the REASSURE study E-Poster: 1816P; October 22 Regorafenib Sequential treatment with regorafenib (REG) and trifluridine/tipiracil (TAS) +/- bevacizumab (Bev) in refractory metastatic colorectal cancer (mCRC) in community clinical practice in the USA E-Poster: 616P; October 22 Regorafenib (REG) in patients (pts) with unresectable hepatocellular carcinoma (uHCC) in real-world (RW) practice: Final analysis of the prospective, observational REFINE study by prior liver transplantation (PLT) E-Poster: 994P; October 23 Larotrectinib Efficacy and safety of larotrectinib (laro) as first-line treatment for patients (pts) with tropomyosin receptor kinase (TRK) fusion cancer E-Poster: 667P; October 23 Efficacy and Safety of Larotrectinib in a Pooled Analysis of Patients (Pts) with Tropomyosin Receptor Kinase (TRK) Fusion Cancer E-Poster: 668P; October 23 Precision Oncology Pipeline Early evidence of efficacy in patients (pts) with non-small cell lung cancer (NSCLC) with HER2 exon20 insertion (ex20ins) mutations treated in a Phase I study with BAY 2927088 Oral Presentation: 1320MO; October 23 About NUBEQA® (darolutamide)1 NUBEQA is an androgen receptor inhibitor (ARi) with a distinct chemical structure that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. On July 30, 2019, the FDA approved NUBEQA® (darolutamide) based on the ARAMIS trial, a randomized, double-blind, placebo-controlled, multi-center Phase III study, which evaluated the safety and efficacy of oral NUBEQA in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Based on results from the ARASENS trial, a randomized, Phase III, multi-center, double-blind, placebo-controlled trial, NUBEQA plus androgen deprivation therapy (ADT) and docetaxel was approved on August 5, 2022 for the treatment of adult patients with metastatic hormone-sensitive prostate cancer (mHSPC). NUBEQA is also being investigated in additional studies across various stages of prostate cancer, including in the ARANOTE Phase III trial evaluating NUBEQA plus ADT versus ADT alone for mHSPC, as well as in the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) led international Phase III co-operative group DASL-HiCaP (ANZUP1801) trial evaluating NUBEQA as an adjuvant treatment for localized prostate cancer with very high risk of recurrence. Information about these trials can be found at Developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company, NUBEQA is indicated for the treatment of adults with nmCRPC or with mHSPC in combination with docetaxel.1 Filings in other regions are underway or planned. INDICATIONS NUBEQA® (darolutamide) is an androgen receptor inhibitor indicated for the treatment of adult patients with: Non-metastatic castration-resistant prostate cancer (nmCRPC) Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel IMPORTANT SAFETY INFORMATION Warnings & Precautions Ischemic Heart Disease – In a study of patients with nmCRPC (ARAMIS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA versus 2.5% receiving placebo, including Grade 3-4 events in 1.7% vs. 0.4%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA vs. 0.2% receiving placebo. In a study of patients with mHSPC (ARASENS), ischemic heart disease occurred in 2.9% of patients receiving NUBEQA with docetaxel vs. 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% vs. 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel vs. 0% receiving placebo with docetaxel. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue NUBEQA for Grade 3-4 ischemic heart disease. Seizure – In ARAMIS, Grade 1-2 seizure occurred in 0.2% of patients receiving NUBEQA vs. 0.2% receiving placebo. Seizure occurred 261 and 456 days after initiation of NUBEQA. In ARASENS, seizure occurred in 0.6% of patients receiving NUBEQA with docetaxel, including one Grade 3 event, vs. 0.2% receiving placebo with docetaxel. Seizure occurred 38 to 340 days after initiation of NUBEQA. It is unknown whether anti-epileptic medications will prevent seizures with NUBEQA. Advise patients of the risk of developing a seizure while receiving NUBEQA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of NUBEQA in patients who develop a seizure during treatment. Embryo-Fetal Toxicity – Safety and efficacy of NUBEQA have not been established in females. NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with NUBEQA and for 1 week after the last dose. Adverse Reactions In ARAMIS, serious adverse reactions occurred in 25% of patients receiving NUBEQA vs. 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA included urinary retention, pneumonia, and hematuria. Fatal adverse reactions occurred in 3.9% of patients receiving NUBEQA vs. 3.2% of patients receiving placebo. Fatal adverse reactions in patients who received NUBEQA included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%). The most common adverse reactions (>2% with a ≥2% increase over placebo), including laboratory test abnormalities, were increased AST, decreased neutrophil count, fatigue, increased bilirubin, pain in extremity, and rash. Clinically relevant adverse reactions occurring in ≥2% of patients treated with NUBEQA included ischemic heart disease and heart failure. In ARASENS, serious adverse reactions occurred in 45% of patients receiving NUBEQA with docetaxel vs. 42% of patients receiving placebo with docetaxel. Serious adverse reactions in ≥2% of patients who received NUBEQA with docetaxel included febrile neutropenia (6%), decreased neutrophil count (2.8%), musculoskeletal pain (2.6%), and pneumonia (2.6%). Fatal adverse reactions occurred in 4% of patients receiving NUBEQA with docetaxel vs. 4% of patients receiving placebo with docetaxel. Fatal adverse reactions in patients who received NUBEQA included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%). The most common adverse reactions (≥10% with a ≥2% increase over placebo with docetaxel) were constipation, decreased appetite, rash, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (≥30%) were anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST, increased ALT, and hypocalcemia. Clinically relevant adverse reactions in <10% of patients who received NUBEQA with docetaxel included fractures, ischemic heart disease, seizures, and drug-induced liver injury. Drug Interactions Effect of Other Drugs on NUBEQA – Combined P-gp and strong or moderate CYP3A4 inducers decrease NUBEQA exposure, which may decrease NUBEQA activity. Avoid concomitant use. Combined P-gp and strong CYP3A4 inhibitors increase NUBEQA exposure, which may increase the risk of NUBEQA adverse reactions. Monitor more frequently and modify NUBEQA dose as needed. Effects of NUBEQA on Other Drugs – NUBEQA inhibits breast cancer resistance protein (BCRP) transporter. Concomitant use increases exposure (AUC) and maximal concentration of BCRP substrates, which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use where possible. If used together, monitor more frequently for adverse reactions, and consider dose reduction of the BCRP substrate. NUBEQA inhibits OATP1B1 and OATP1B3 transporters. Concomitant use may increase plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor more frequently for adverse reactions and consider dose reduction of these substrates. Review the Prescribing Information of drugs that are BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA. For important risk and use information about NUBEQA, please see the accompanying full Prescribing Information. About Xofigo® (radium Ra 223 dichloride) Injection2 Xofigo is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. Important Safety Information for Xofigo® (radium Ra 223 dichloride) Injection Warnings and Precautions: Bone Marrow Suppression: In the phase 3 ALSYMPCA trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression–notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia–has been reported in patients treated with Xofigo. Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued Increased Fractures and Mortality in Combination With Abiraterone Plus Prednisone/Prednisolone: Xofigo is not recommended for use in combination with abiraterone acetate plus prednisone/prednisolone outside of clinical trials. At the primary analysis of the Phase 3 ERA-223 study that evaluated concurrent initiation of Xofigo in combination with abiraterone acetate plus prednisone/prednisolone in 806 asymptomatic or mildly symptomatic mCRPC patients, an increased incidence of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received Xofigo in combination with abiraterone acetate plus prednisone/prednisolone compared to patients who received placebo in combination with abiraterone acetate plus prednisone/prednisolone. Safety and efficacy with the combination of Xofigo and agents other than gonadotropin-releasing hormone analogues have not been established Embryo-Fetal Toxicity: The safety and efficacy of Xofigo have not been established in females. Xofigo can cause fetal harm when administered to a pregnant female. Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise male patients to use condoms and their female partners of reproductive potential to use effective contraception during and for 6 months after completing treatment with Xofigo Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations Fluid Status: Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting, which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia Injection Site Reactions: Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo Secondary Malignant Neoplasms: Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow-up for patients on the trial Subsequent Treatment With Cytotoxic Chemotherapy: In the randomized clinical trial, 16% of patients in the Xofigo group and 18% of patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%) Please see the full Prescribing Information for Xofigo (radium Ra 223 dichloride). About Stivarga® (regorafenib)3 In April 2017, Stivarga was approved for use in patients with hepatocellular carcinoma who have been previously treated with sorafenib. In the United States, Stivarga is also indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy. It is also indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. Regorafenib is a compound developed by Bayer. In 2011, Bayer entered into an agreement with Onyx, now an Amgen subsidiary, under which Onyx receives a royalty on all global net sales of regorafenib in oncology. Indication Stivarga is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild- type, an anti-EGFR therapy. Stivarga is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. Stivarga is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. Important Safety Information for STIVARGA® (regorafenib) WARNING: HEPATOTOXICITY Severe and sometimes fatal hepatotoxicity has occurred in clinical trials. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence. Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients across all clinical trials. In most cases, liver dysfunction occurred within the first 2 months of therapy and was characterized by a hepatocellular pattern of injury. In metastatic colorectal cancer (mCRC), fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and in 0.4% of patients in the placebo arm. In gastrointestinal stromal tumor (GIST), fatal hepatic failure occurred in 0.8% of patients in the STIVARGA arm. In hepatocellular carcinoma (HCC), there was no increase in the incidence of fatal hepatic failure as compared to placebo. Liver Function Monitoring: Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the upper limit of normal (ULN) or baseline values. Temporarily hold and then reduce or permanently discontinue STIVARGA, depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis. Infections: STIVARGA caused an increased risk of infections. The overall incidence of infection (Grades 1-5) was higher (32% vs 17%) in 1142 STIVARGA-treated patients as compared to the control arm in randomized placebo-controlled trials. The incidence of grade 3 or greater infections in STIVARGA treated patients was 9%. The most common infections were urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) and pneumonia (2.6%). Fatal outcomes caused by infection occurred more often in patients treated with STIVARGA (1.0%) as compared to patients receiving placebo (0.3%); the most common fatal infections were respiratory (0.6% vs 0.2%). Withhold STIVARGA for Grade 3 or 4 infections, or worsening infection of any grade. Resume STIVARGA at the same dose following resolution of infection. Hemorrhage: STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 18.2% in 1142 patients treated with STIVARGA vs 9.5% with placebo in randomized, placebo-controlled trials. The incidence of grade 3 or greater hemorrhage in patients treated with STIVARGA was 3.0%. The incidence of fatal hemorrhagic events was 0.7%, involving the central nervous system or the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage and monitor INR levels more frequently in patients receiving warfarin. Gastrointestinal Perforation or Fistula: Gastrointestinal perforation occurred in 0.6% of 4518 patients treated with STIVARGA across all clinical trials of STIVARGA administered as a single agent; this included eight fatal events. Gastrointestinal fistula occurred in 0.8% of patients treated with STIVARGA and in 0.2% of patients in the placebo arm across randomized, placebo-controlled trials. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula. Dermatological Toxicity: In randomized, placebo-controlled trials, adverse skin reactions occurred in 71.9% of patients with STIVARGA arm and 25.5% of patients in the placebo arm including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia syndrome (PPES) and severe rash, requiring dose modification. In the randomized, placebo-controlled trials, the overall incidence of HFSR was higher in 1142 STIVARGA-treated patients (53% vs 8%) than in the placebo-treated patients. Most cases of HFSR in STIVARGA-treated patients appeared during the first cycle of treatment. The incidences of Grade 3 HFSR (16% vs <1%), Grade 3 rash (3% vs <1%), serious adverse reactions of erythema multiforme (<0.1% vs 0%), and Stevens-Johnson syndrome (<0.1% vs 0%) were higher in STIVARGA-treated patients. Across all trials, a higher incidence of HFSR was observed in Asian patients treated with STIVARGA (all grades: 72%; Grade 3:18%). Toxic epidermal necrolysis occurred in 0.02% of 4518 STIVARGA-treated patients across all clinical trials of STIVARGA administered as a single agent. Withhold STIVARGA, reduce the dose, or permanently discontinue depending on the severity and persistence of dermatologic toxicity. Hypertension: Hypertensive crisis occurred in 0.2% in STIVARGA-treated patients and in none of the patients in placebo arm across all randomized, placebo-controlled trials. STIVARGA caused an increased incidence of hypertension (30% vs 8% in mCRC, 59% vs 27% in GIST, and 31% vs 6% in HCC). The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (67% in randomized, placebo-controlled trials). Do not initiate STIVARGA until blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold STIVARGA for severe or uncontrolled hypertension. Cardiac Ischemia and Infarction: STIVARGA increased the incidence of myocardial ischemia and infarction (0.9% with STIVARGA vs 0.2% with placebo) in randomized placebo-controlled trials. Withhold STIVARGA in patients who develop new or acute cardiac ischemia or infarction and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristics finding on MRI occurred in one of 4800 STIVARGA-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, severe headache, visual disturbances, confusion, or altered mental function. Discontinue STIVARGA in patients who develop RPLS. Wound Healing Complications: Impaired wound healing complications can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, STIVARGA has the potential to adversely affect wound healing. Withhold STIVARGA for at least 2 weeks prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of STIVARGA after resolution of wound healing complications has not been established. Embryo-Fetal Toxicity: STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with STIVARGA and for 2 months after the final dose. Nursing Mothers: Because of the potential for serious adverse reactions in breastfed infants from STIVARGA, do not breastfeed during treatment with STIVARGA and for 2 weeks after the final dose. Most Frequently Observed Adverse Drug Reactions in mCRC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in mCRC, respectively, were: asthenia/fatigue (64% vs 46%), pain (59% vs 48%), decreased appetite and food intake (47% vs 28%), HFSR/PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%). Most Frequently Observed Adverse Drug Reactions in GIST (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo treated patients in GIST, respectively, were: HFSR/PPE (67% vs 12%), pain (60% vs 55%), hypertension (59% vs 27%), asthenia/fatigue (52% vs 39%), diarrhea (47% vs 9%), mucositis (40% vs 8%), dysphonia (39% vs 9%), infection (32% vs 5%), decreased appetite and food intake (31% vs 21%), and rash (30% vs 3%). Most Frequently Observed Adverse Drug Reactions in HCC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in HCC, respectively, were: pain (55% vs 44%), HFSR/PPE (51% vs 7%), asthenia/fatigue (42% vs 33%), diarrhea (41% vs 15%), hypertension (31% vs 6%), infection (31% vs 18%), decreased appetite and food intake (31% vs 15%). Please see full Prescribing Information, including Boxed Warning for Stivarga (regorafenib). About Vitrakvi® (larotrectinib)4 Vitrakvi® (larotrectinib) is indicated for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. Select patients for therapy based on an FDA-approved test. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Important Safety Information for Vitrakvi® (larotrectinib) Warnings and Precautions Central Nervous System Effects: Central nervous system (CNS) adverse reactions occurred in patients receiving VITRAKVI, including dizziness, cognitive impairment, mood disorders, and sleep disturbances. In patients who received VITRAKVI, all grades CNS effects including cognitive impairment, mood disorders, dizziness and sleep disorders were observed in 42% with Grades 3-4 in 3.9% of patients. Cognitive impairment occurred in 11% of patients. The median time to onset of cognitive impairment was 5.6 months (range: 2 days to 41 months). Cognitive impairment occurring in ≥ 1% of patients included memory impairment (3.6%), confusional state (2.9%), disturbance in attention (2.9%), delirium (2.2%), cognitive disorders (1.4%), and Grade 3 cognitive adverse reactions occurred in 2.5% of patients. Among the 30 patients with cognitive impairment, 7% required a dose modification and 20% required dose interruption. Mood disorders occurred in 14% of patients. The median time to onset of mood disorders was 3.9 months (range: 1 day to 40.5 months). Mood disorders occurring in ≥1% of patients included anxiety (5%), depression (3.9%), agitation (2.9%), and irritability (2.9%). Grade 3 mood disorders occurred in 0.4% of patients. Dizziness occurred in 27% of patients, and Grade 3 dizziness occurred in 1.1% of patients. Among the 74 patients who experienced dizziness, 5% of patients required a dose modification and 5% required dose interruption. Sleep disturbances occurred in 10% of patients. Sleep disturbances included insomnia (7%), somnolence (2.5%), and sleep disorder (0.4%). There were no Grade 3-4 sleep disturbances. Among the 28 patients who experienced sleep disturbances, 1 patient each (3.6%) required a dose modification or dose interruption. Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed. Skeletal Fractures: Among 187 adult patients who received VITRAKVI across clinical trials, fractures were reported in 7% and among 92 pediatric patients, fractures were reported in 9% (N=279; 8%). Median time to fracture was 11.6 months (range 0.9 to 45.8 months) in patients followed per fracture. Fractures of the femur, hip or acetabulum were reported in 4 patients (3 adult, 1 pediatric). Most fractures were associated with minimal or moderate trauma. Some fractures were associated with radiologic abnormalities suggestive of local tumor involvement. VITRAKVI treatment was interrupted due to fracture in 1.4% patients. Promptly evaluate patients with signs or symptoms of potential fracture (e.g., pain, changes in mobility, deformity). There are no data on the effects of VITRAKVI on healing of known fractures or risk of future fractures. Hepatotoxicity: In patients who received VITRAKVI, increased AST of any grade occurred in 52% of patients and increased ALT of any grade occurred in 45%. Grade 3-4 increased AST or ALT occurred in 3.1% and 2.5% of patients, respectively. The median time to onset of increased AST was 2.1 months (range: 1 day to 4.3 years). The median time to onset of increased ALT was 2.3 months (range: 1 day to 4.2 years). Increased AST and ALT leading to dose modifications occurred in 1.4% and 2.2% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 3 (1.1%) patients. Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed. Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. VITRAKVI resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI. Adverse Reactions The most common adverse reactions (≥20%), including laboratory abnormalities, were: increased AST (52%), increased ALT (45%), anemia (42%), musculoskeletal pain (42%), fatigue (36%), hypoalbuminemia (36%), neutropenia (36%), increased alkaline phosphatase (34%), cough (32%), leukopenia (28%), constipation (27%), diarrhea (27%), dizziness (27%), hypocalcemia (25%), nausea (25%), vomiting (25%), pyrexia (24%), lymphopenia (22%) and abdominal pain (21%). Drug Interactions Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John’s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the VITRAKVI dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs. For coadministration with moderate CYP3A4 inhibitors, monitor for adverse reactions more frequently and reduce the dosage based on severity. For coadministration with moderate CYP3A4 inducers, modify dose as recommended. Use in Specific Populations Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the final dose. Please see the full Prescribing Information for VITRAKVI® (larotrectinib). About Oncology at Bayer Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer includes six marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated. About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. Its products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2022, the Group employed around 101,000 people and had sales of 50.7 billion euros. R&D expenses before special items amounted to 6.2 billion euros. For more information, go to . © 2023 Bayer BAYER, the Bayer Cross, NUBEQA, Xofigo, Stivarga and Vitrakvi are registered trademarks of Bayer. Forward-Looking Statements This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at . The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments. References NUBEQA® (darolutamide) tablets [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, August 2022. Xofigo® (radium-223 dichloride) Injection [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, December 2019. Stivarga® (regorafenib) tablets [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, December 2020. Vitrakvi® [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; March 2021. PP-PF-ONC-US-2991-1 10/23