IL-17C

关注并星标CPHI制药在线 JAK-STAT通路与银屑病的发生、发展密切相关，作为银屑病治疗的补充疗法和替代药物， 当代中医药的应用研究证明了其治疗银屑病的有效性。研究发现，中药单体、中药有效成分、中药复方和针灸对银屑病治疗中 JAK-STAT 通路均有明显调节作用。 1、中药单体、有效成分通过 JAK-STAT 通路调控治疗银屑病 多种中药单体或有效成分可通过调节JAK-STAT通路参与银屑病的发生发展，主要为苷类、生物碱类，它们通过调节JAK-STAT 通路而纠正银屑病免疫失调，减轻炎症反应，进而控制病情。 厚朴酚为木脂素类化合物，提取自厚朴，具有抗炎、抗菌、抗过敏等作用。研究发现，厚朴酚能抑制咪喹莫特诱导银屑病小鼠血清IL-17、IL-23水平，从而降低TNF-α、JAK/STAT ( JAK2/STAT3) 、NF-κB 等蛋白表达，进而对小鼠银屑病皮损具有良好的改善作用。 麻黄具有抗炎、抗菌、抗过敏等作用，可应用于多种临床疾病的治疗。麻黄的主要成分为盐酸麻黄 碱、盐酸伪麻黄 碱、盐酸甲基麻黄 碱等生物碱。应用麻黄单味药物的水煎剂灌胃咪喹莫特诱导的银屑病小鼠模型，发现麻黄可以改善银屑病皮损组织病理下的角化过度和炎性浸润，降低银屑病病理评分系统（Baker）和银屑病皮损面积及严重程度指数（PASI）的分值，其机制与降低血清中 IL-6 的含量，抑制皮损中 IL-6、IL-17A、IL-17C mRNA 的表达，降低皮损中 STAT3、p-STAT3蛋白含量相关。 雷公藤多苷提取自雷公藤，具有抗炎、免疫抑制、调节免疫等作用。研究报道，雷公藤多苷可降低银屑病小鼠血清 TNF-α、IL-17、IL-23 水平及银屑病皮损组织 JAK1、STAT3 蛋白表达，抑制 JAKs-STAT 信号通路的活化，进而改善皮损炎症。 人参皂苷是人参中提取的天然化合物，具有抗炎、调节免疫作用。研究发现，人参皂苷可降低咪喹莫特诱导银屑病小鼠血清 p-JAK1、p-JAK2、p-STAT3 表达，降低炎症因子IL-23、IL-17水平，抑制JAK1/2STAT3活化。 氧化苦参碱是提取自苦参、山豆根等的活性生物碱，具有抗病毒、抗炎、免疫调节等作用。研究表明，氧化苦参碱可通过降低炎症因子TNF-α、IFN-γ、IL-6、IL-8 水平，升高SOCS1 表达来抑制JAK1、STAT3 表达，阻碍JAK/STAT 信号通路激活，进而抑制KC 增殖，调节T淋巴细胞活化、平衡，从而达到治疗银屑病的目的。 丹皮酚是牡丹皮、徐长卿的主要有效成分，具有抗炎、抗肿瘤、代谢调节、镇痛等作用。丹皮酚可降低咪喹莫特诱导的银屑病小鼠皮损 microRNA-155、STAT3、IL-17、IL-23、IFN-γ 水平，升高SOCS1 表达，从而干预 JAK/STAT 及其下游 IL-2、IL-4、IL-6、IFN-γ 等细胞因子来发挥免疫效应。 紫草素为萘醌类化合物，提取自紫草，具有抗菌、抗炎等作用。紫草素能够通过STAT3 信号通路抑制IFN-γ 诱导的IL-17过度分泌，并阻断 JAK2/STAT3信号通路，抑制银屑病小鼠模型皮损部位VEGF 表达，也可抑制树突状细胞分泌细胞因子 IL-23，抑制Th17特异性免疫应答，从而发挥治疗银屑病的作用。 此外，研究发现商陆皂苷甲能有效降低银屑病模型小鼠外周血 IL-17、IL-22、IL-6、TNF-α 水平。白芍总苷可降低银屑病患者外周血IL-17、IL-22、IL-23 水平。土大黄提取物能调节咪喹莫特诱导银屑病小鼠模型IL-23/IL-17轴。洋金花提取物可抑制银屑病小鼠 IL-17、TNF-α、NF-κB 等细胞因子水平，从而降低 IL-23、IL-8、IL-6 水平，还可升高 IL-10 水平。落新妇苷能抑制咪喹莫特诱导的银屑病小鼠的Th17细胞分化，减少IL-17 释放， 削弱Th17 细胞的JAK/STAT3 信号转导。 2、中药复方通过JAK-STAT 通路调控治疗银屑病 清热利湿饮、加味凉血消风散、蜈蚣败毒饮等可通过 JAK-STAT 通路参与银屑病的发生、发展，其功效主要包括清热、利湿、凉血、解毒、祛风、止痒等。 清热利湿饮为中医经方龙胆泻肝汤的变方，由龙胆草、黄芩、柴胡、牡丹皮、当归、金银花、土茯苓、泽泻、栀子、生地黄、车前子、甘草等组成，研究表明，该中药方剂可以从动物学和细胞学2个角度抑制IL-6的表达及其介导的JAK1/STAT3信号通路的激活，并可以影响下游IL-17A 的分泌水平，改善动物模型中银屑病样的炎症反应。此外，研究发现该方剂对于IL-22、JAK1、TYK2、p-STAT3、STAT3等参与该通路中诱导、调控、磷酸化、信号终端的多个因子均具有干预作用。 消银解毒颗粒由水牛角、生地黄、牡丹皮、赤芍、忍冬藤、大青叶、紫草、甘草等组成，作用于体外经植物血凝素（PHA）和 IL-6 共同诱导的人T淋巴细胞瘤细胞（Jurkat），结果发现，经IL-6刺激后Jurkat细胞的增殖能力显著提升，以10 μg·L-1质量浓度时的增殖作用最为明显，中药方剂及其拆方均能够显著影响 JAK1、STAT3、gp130共3个指标的基因及蛋白表达量，该实验较为精确的描绘出 IL-6/JAK1/STAT3 信号通路从诱导刺激、到受体结合、再到信号激活的整体过程，也体现出中医药凉血解毒法作用的核心机制。 凉血消银颗粒剂由紫草、赤芍、白花蛇舌草、丹参、槐花、生地、白茅根、水牛角、鸡血藤、丹皮、熟地黄组成，具有清热凉血、活血化瘀的功效。研究表明，凉血消银颗粒剂可以降低银屑病模型小鼠血清TNF-α、IL-1、IL-6、IL-23水平，升高SOCS1表达，从而缓解银屑病症状。 加味凉血消风散由水牛角、生地黄、牡丹皮、连翘、僵蚕、地骨皮、紫荆皮、冬桑叶、白花蛇舌草、玄参、女贞子、旱莲草、炙甘草等组成，研究证实，该方剂可以通过下调 JAK3/STAT3信号通路，下调抑凋亡基因，上调促凋亡基因，从而诱导细胞凋亡来达到缓解银屑病的目的。中药复方制剂加味凉血消风散在 JAK/STAT 信号通路的 3 个家族亚型中均发挥调节作用，包括IL-21介导的 JAK3/STAT3 环节、IL-22及IFN-γ 分别介导的 JAK/STAT 环节，该方剂的配伍体现中医学在血分症疾治疗中的“入血就恐耗血动血，直须凉血散血”的辨证理念和“治风先治血，血行风自灭”的治疗先机，以凉血为核心，用养阴之妙法，散血热，祛风盛，以其治疗急性进展期银屑病，将中医理论围绕 JAK/STAT 信号通路家族进行了系统融合，也为同类方剂的微观机制系列研究提供了较好的借鉴和思路。 楮芍凉血汤由楮桃叶、白芍、连翘、黄连、金银花、黄芩、生地黄、威灵仙、白花蛇舌草、细辛等组成，对血热证银屑病患者进行了机制研究，结果显示其可以通过调控 JAK3/STAT3 信号通路，改善银屑病的 PASI 分值及灼热、瘙痒、心烦等一系列血热症状。 养血解毒汤由土茯苓、生地黄、板蓝根、丹参、当归、麦冬、玄参、鸡血藤、草河车、车前子组成，对银屑病模型鼠皮损组织中 JAK3、p-JAK3、STAT3、p-STAT3的表达及 Th17 相关因子 IL-17A、IL-17C、IL-22、维甲酸受体相关孤儿受体 γ（t RORγt）进行对照研究，发现以凉血养血活血、祛湿解毒的名家验方可以抑制 STAT3 的磷酸化，减少Th17 细胞相关因子的分泌，由此改善模型的银屑病样皮损。 丹参白疕消丸由丹参、乌梢蛇、全蝎、土鳖虫、大黄、蝉蜕、徐长卿、山楂、板蓝根、红花、防风、苦参、黄柏、蜈蚣、甘草等组成，其主要功效为养血活血。在干预银屑病鼠模型中发现其药物提取液能够分别降低外周血中IL-23、IL-17、IL-22、IL-6的浓度及皮损中上述因子的mRNA 表达水平，并下调皮损中STAT3的蛋白表达量，进一步提取鉴定发现，该方剂的有效成分为丹酚酸B、丹参酮Ⅱ A、盐酸小檗碱、升麻素苷、苦参碱、甘草酸铵等。 蜈蚣败毒饮由蜈蚣、紫草、土茯苓、鬼箭羽、乌梢蛇、甘草等组成，对银屑病小鼠模型血清、皮损组织中SOCS1、JAK2、STAT3，及其上游微小核糖核酸-155（microRNA-155）和下游Treg 细胞主导通路 IL-2-叉头框蛋白 P3（FoxP3）-IL-10/转化生长因子-β（TGF-β）进行研究，发现该方剂可以调控以 microRNA-155 介导的 SOCS1-JAK2/STAT3 信号通路从而影响 Treg 细胞功能，改善银屑病模型的皮损指数评分。 3、中医外治法通过JAK-STAT 通路调控治疗银屑病 体内外实验结果表明，针灸、艾灸、火针、热敏灸可通过JAK-STAT 通路参与银屑病的发生、发展，其主要具有抗炎、调节免疫的作用。 艾灸能够刺激人体的免疫系统，其温热功效能影响免疫细胞、免疫因子， 改善免疫功能。研究发现，艾灸可以降低咪喹莫特诱导的银屑病模型小鼠血清 IL-17A水平，抑制皮损组织 TNF-α、IL-1β、IL-6 mＲNA 表达，提示艾灸可降低炎性因子水平，抑制炎性反应，调节免疫功能，进而促进银屑病皮损的改善。 火针具有激发经气、扶正祛瘀、通经活络的作用。研究发现，火针可降低咪喹莫特诱导的银屑病模型小鼠皮损组织 IL-17、IL-22、TNF-α mRNA 表达，抑制 pSTAT3 表达，进而抑制 STAT3通路活化，减轻炎性细胞浸润，改善银屑病皮损。 此外，研究发现，热敏灸可降低咪喹莫特诱导的银屑病模型大鼠外关穴筋膜 JAK3、p-JAK3、STAT3、p-STAT3 蛋白表达。针灸可改善寻常型银屑病患者皮损 PASI 评分， 降低血清IL-6、TNF-α水平。 参考资料 [1]胡怡,武思仙,刘栋,等.中医药调控JAK-STAT通路治疗银屑病的研究进展[J].中成药,2024,46(02):531-536. [2]吴咚咚,曹珣,安月鹏.中医药调控JAK/STAT经典信号通路辨治银屑病的研究进展[J].中国实验方剂学杂志,2023,29(01):258-269. 作者简介：小米虫，药品质量研究工作者，长期致力于药品质量研究及药品分析方法验证工作，现就职于国内某大型药物研发公司，从事药品检验分析及分析方法验证。 END 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

作者｜小麦 目前自免是仅次于肿瘤的第二大市场领域，2022年全球自免药物市场规模约达1323亿美元，据弗若斯特沙利文预测，到2030年，全球自免药物市场规模有望达到1760亿美元，2022~2030年复合年增长率为3.6%。 国内在自免领域远远落后于国外，但近几年国内自免药物发展迅速，今年迪哲医药的JAK抑制剂戈利昔替尼、康诺亚生物的IL-4Rα抗体药物司普奇拜单抗、恒瑞医药的靶向IL-17A生物制剂夫那奇珠单抗和智翔金泰的靶向IL-17A生物制剂赛立奇单抗等相继获批上市，有望打破进口药的垄断地位，给患者提供更多的选择。   01   JAK靶向制剂 JAK激酶属于细胞内非受体酪氨酸激酶家族，包括JAK1、JAK2、JAK3、TYK2四个成员，介导细胞因子产生的信号，并通过JAK-STAT信号通路传递下去，参与了免疫、细胞分裂、细胞死亡和肿瘤形成等过程。该通路异常可能导致各种疾病，如皮肤病、癌症和影响免疫系统的疾病等（图1）[1]。 图1. JAK家族介导信号通路 全球已有十多款JAK抑制剂获批上市，包括第一代的托法替布、芦可替尼、巴瑞替尼、培非替尼和迪高替尼；第二代的菲达替尼、乌帕替尼、非戈替尼、阿布昔替尼和帕瑞替尼以及第三代的氘可来昔替尼等，这些抑制剂大多用于关节炎、特应性皮炎等自免疾病（图2）。 图2. 获批和部分在研的JAK抑制剂 为了提高竞争力，很多药企开始探索JAK抑制剂的新用途，如辉瑞的利特昔替尼、礼来巴瑞替尼和Concert Pharmaceuticals/Sun Pharmaceuticals的氘代芦可替尼获批斑秃新适应症，迪哲医药的戈利昔替尼获批用于治疗既往至少接受过一线系统性治疗的复发或难治的外周T细胞淋巴瘤（r/r PTCL）成人患者，成为全球首个且唯一获批用于治疗PTCL的JAK1抑制剂。 除此之外，还有很多临床在研的JAK抑制剂，如泽璟制药的杰克替尼、恒瑞医药的艾玛昔替尼、辉瑞/Priovant Therapeutics的brepocitinib和再极医药的MAX-40070等，其中杰克替尼和艾玛昔替尼都处于申报上市阶段。   02   IL-4靶向制剂 白细胞介素4（IL-4）主要是由T细胞、自然T细胞、肥大细胞和嗜酸性粒细胞产生的一种糖基化的I型细胞因子。 IL-4和IL-13是2型免疫反应中的关键细胞因子，作用于1型 IL-4Rα/γ和/或2型IL-4Rα/IL-13Rα复合物引发其信号传导作用，从而激活JAK-STAT信号通路（图3）。 图3. IL-4和IL-13介导的信号通路 目前为止全球范围内有5款靶向IL-4R药物获批上市，分别是甲磺司特、度普利尤单抗、吡美莫司、Actimmune以及司普奇拜单抗，其中度普利尤单抗是全球首款获批的IL-4R单抗药物，司普奇拜单抗是国内首个、全球范围第二个申报并获批上市的IL-4Rα抗体药物。 图4. 获批和部分在研的靶向IL-4的药物 度普利尤单抗是赛诺菲的当家花旦，在自免领域尤其是特应性皮炎适应症上取得巨大成功，撑起特药板块半边天，2023年销售额达到107.15亿欧元（115.7亿美元）。 今年7月和9月，度普利尤单抗相继在欧盟、美国和中国获批慢性阻塞性肺病（COPD）新适应症，扩大其适应人群。 除此之外，临床上还有很多在研的IL-4/IL-4R抑制剂，如康乃德的CBP-201、康方生物的AK120以及智翔医药的GR-1802等。   03   IL-17靶向制剂 白细胞介素17（IL-17）是由CD4+ T细胞分泌，能够诱导上皮细胞、内皮细胞、成纤维细胞合成分泌IL-6、IL-8、G-CSF、PGE2，促进ICAM-1的表达的促炎因子。 IL-17有 IL-17A、IL-17B、IL-17C、IL-17D、IL-17E（也被称为IL-25）和IL-17F 6个家族成员。白介素IL-17受体（IL-17R）有IL-17RA、IL-17RB、IL-17RC、IL-17RD、IL-17RE 5个家族成员（图5）[2]。 图5. IL-17介导的信号通路 全球范围内共上市7款靶向IL-17A/IL-17RA药物，分别是司库奇尤单抗、依奇珠单抗、尼塔奇单抗、比吉利珠单抗、布罗利尤单抗、夫那奇珠单抗和赛立奇单抗（图6）。 图6. 获批和部分在研的靶向IL-17药物 目前，司库奇尤单抗和依奇珠单抗是全球最畅销的两款IL-17靶向生物制剂， 司库奇尤单抗是由诺华研发的首款获批上市的靶向IL-17A单抗，用于治疗银屑病、银屑病关节炎和强直性脊柱炎等自免疾病，2022年销售额达47.88亿美元，2023年销售额达49.8亿美元。 依奇珠单抗是由礼来研发的靶向IL-17A单抗，是第一个在银屑病关节炎（PsA）头对头研究中疗效优于阿达木单抗的IL-17A拮抗剂，2022年销售额达到24.82亿美元，2023年销售额达到27.6亿美元。 今年8月份，恒瑞医药的夫那奇珠单抗和智翔金泰的赛立奇单抗获批上市，用于治疗适合接受系统治疗或光疗的中重度斑块状银屑病成人患者，成为国产首批获批的本土自主研发重组抗IL-17A人源化单克隆抗体，将打破同类进口药物的长期垄断局面，为银屑病患者提供新的治疗选择。 除此之外，还有很多临床在研的靶向IL-17的生物制剂，包括荃信生物的QX-002N，康方生物的AK-111和君实生物的JS005等。   04   IL-6靶向制剂 白介素-6（IL-6）是趋化因子家族的一种细胞因子，主要由单核巨噬细胞、 Th2细胞、血管内皮细胞、成纤维细胞产生。 IL-6的受体蛋白，由特异性的IL-6结合受体蛋白（IL-6R），和被称为信号转导蛋白的gp130所组成。按照信号传导方式的差异，IL-6参与的信号途径，可以分为经典信号通路（classical signaling）和转信号通路（Trans-signaling）。 在经典信号通路中，IL-6与其膜结合受体mIL-6R、可溶性受体sIL-6R结合后，招募gp130（一种跨膜蛋白，细胞因子受体）结合形成IL-6-IL-6R-gp130六聚体，触发下游JAK-STAT、RAS-RAF等信号通路转导和基因表达。在转信号通路中，IL-6-sIL-6R复合物与gp130结合，启动细胞内信号转导，促进细胞增殖、分化、氧化应激和免疫调节（图7）[3]。 图7. IL-6信号转导和IL-6受体系统的模式 IL-6信号通路异常与很多疾病的发病机制有关，包括类风湿性关节炎（RA）、系统性幼年特发性关节炎(sJIA)、Castleman病、巨细胞动脉炎（GCA）、大动脉炎和细胞因子释放综合征（CRS）等。 目前全球有4款药物获批上市，包括靶向IL-6R的托珠单抗、Sarilumab、和萨特利珠单抗以及靶向IL-6的司妥昔单抗，其中托珠单抗由于上市时间早应用广泛，销售额遥遥领先，受益于用于新冠治疗的获批，曾在2021年达到销售峰值39.6亿美元。 图8. 部分靶向IL-6的药物 除此之外，临床上还有很多在研的IL-6或IL-6R拮抗剂药物，为了提高竞争性，很多药企进行差异化布局，开发新的适应症，包括优时比的olokizumab、诺和诺德的ziltivekimab和罗氏的RG6179等（图6）。 Olokizumab最初由优时比公司研发，是一款靶向IL-6的人源化单抗。后来在2013年转让给了俄罗斯药企R-Pharm，目前正在进行RA领域的上市申请。 Ziltivekimab最初是由Corvidia Therapeutics研发的IL-6单抗药物，后于2020年6月，诺和诺德以21亿美元收购Corvidia Therapeutics，接管了其主要候选药物ziltivekimab的开发工作。 Ziltivekimab旨在阻断IL-6通路来降低全身炎症，从而降低动脉粥样硬化性心血管疾病（ASCVD）和慢性肾脏病（CKD）患者的主要心血管不良事件风险，具有延长的半衰期，可以通过每月一次皮下注射给药。 RG6179是由罗氏研发的IgG2类IL-6单抗，可阻断经典和转信号传导，用于糖尿病性黄斑水肿、自身炎症性疾病、黄斑水肿和葡萄膜性黄斑水肿。   小结   自免是一个很大的疾病领域，有很多疾病靶点，目前全球自身免疫病药物市场中，TNF-α和IL-12/IL-23两个自免领域老靶点抑制剂销售额仍位居前列，而JAK、IL-4R、IL-17A、IL-6、IL-5、URAT1、TSLP、MASP-2、TYK2等靶点，则吸引较多创新药企布局，本文主要介绍JAK、IL-4R、IL-17A和IL-6四个热门自免靶点及其研发进展。 参考文献 1.Aikaterini Tsiogka et.al, The JAK/STAT Pathway and Its Selective Inhibition in the Treatment of Atopic Dermatitis: A Systematic Review, J. Clin. Med. 2022, 11, 4431 2.Mandy J. McGeachy, Daniel J. Cua, and Sarah L. Gaffen, The IL-17 Family of Cytokines in Health and Disease, Immunity 50, April 16, 2019 3.Masashi Narazaki and Tadamitsu Kishimoto, The Two-Faced Cytokine IL-6 in Host Defense and Diseases, Int. J. Mol. Sci. 2018, 19, 3528. BiG近期会议 10月26日，第三届生物计算大会保留栏目-第二届吐槽大会即将再度来袭！将围绕投融资、行业心态、年轻人，及AI等热门话题展开策划，通过移幕换景，大咖带新秀，一同探讨AI+Biomed的融合之道！ ▼ 10月31日，BiG联合Citeline，将于10月底，举办自免小规模私董研讨会，聚焦：TCE vs. CAR-T，自身免疫开发策略，线上同步直播，敬请期待！ ▼ 共建Biomedical创新生态圈！ 如何加入BiG会员？

BALLERUP, Denmark--( BUSINESS WIRE )-- NOT FOR UK USE – NOT INTENDED FOR UK MEDIA LEO Pharma A/S, a global leader in medical dermatology, will present new clinical and real-world data from across its portfolio of products at the upcoming 33 rd European Academy of Dermatology and Venereology (EADV) Congress. The event will be held from the 25 th to the 28 th of September in Amsterdam, Netherlands, where LEO Pharma will present 5 coveted late-breaking presentations in addition to 23 scientific posters for a range of skin conditions, forming the largest collection of data LEO Pharma has ever shared at the EADV congress. 1-28 “ It is extraordinary to witness the breadth and variety of LEO Pharma’s scientific contribution at this year’s EADV Congress. It is a record-breaking presence for us – and we cannot wait to share this ground-breaking data with the medical dermatology community ,” said Christophe Bourdon, CEO of LEO Pharma. The first late-breaking presentation for Anzupgo ® (delgocitinib) cream will provide data from the 24-week DELTA FORCE trial that compared the efficacy and safety of topical delgocitinib cream with oral alitretinoin capsules in adults with severe CHE. 1 An additional late-breaking oral presentation will provide data from the matching-adjusted indirect comparison (MAIC) of the efficacy of delgocitinib and dupilumab in the treatment of moderate to severe atopic hand eczema. 25 The third delgocitinib cream late-breaking presentation will provide information on biomarker and efficacy data from the randomized vehicle-controlled clinical trial with delgocitinib cream in patients with frontal fibrosing alopecia. 26 A late-breaking presentation will also be presented for Adtralza/Adbry, highlighting the interim real-world effectiveness results of tralokinumab in adult patients with head and neck atopic dermatitis after up to 9 months of treatment in the TRACE real world evidence (RWE) study. 27 Finally, a late-breaking presentation for temtokibart will also be presented, comparing clinical and molecular responses in the targeting of IL-22RA1 with temtokibart vs dupilumab in patients with moderate to severe atopic dermatitis. 28 " The 2024 EADV Congress marks a pivotal moment for LEO Pharma as we unveil a wealth of new data," said Kreesten Meldgaard Madsen, Chief Development Officer, LEO Pharma. " Our presentations at EADV showcase our most comprehensive research portfolio to date, underscoring our unwavering commitment to developing innovative dermatological therapies and helping to bring new hope to patients grappling with challenging skin conditions." The company’s full roster at the 2024 EADV Congress, encompassing new research, encore abstracts, and 3 symposiums, 1-28 includes: Anzupgo ® (delgocitinib) cream DELTA FORCE trial: A 24-week head-to-head phase 3 trial comparing the efficacy and safety of topical delgocitinib cream with oral alitretinoin capsules in adults with severe chronic hand eczema Author: Ana Maria Giménez-Arnau Presentation ID: D1T01.1F LB presentation: Wednesday, 25 Sep, 15:30 - 15:45 Location: Auditorium Matching-adjusted indirect comparison of the efficacy of delgocitinib and dupilumab in the treatment of moderate to severe atopic hand eczema Author: David Cohen Presentation ID: D3T01.4B LB presentation: Friday, 27 Sep, 16:15 - 16:30 Location: Auditorium Randomized vehicle-controlled clinical trial with the topical JAK inhibitor delgocitinib in patients with frontal fibrosing alopecia demonstrates biomarker and clinical efficacy Author: Maryanne Makredes Senna Presentation ID: D3T01.4F LB presentation: Friday, 27 Sep, 17:15 - 17:30 Location: Auditorium Treatment response of delgocitinib cream according to Chronic Hand Eczema (CHE) subtypes in adults with moderate to severe CHE: results from the Phase 3 DELTA 1, DELTA 2, and DELTA 3 trials Author: Robert Bissonnette Presentation ID: FC07.04 Oral presentation: Friday, 27 Sep, 14:45 - 14:55 Location: G104-G105 Topical pan-JAK inhibition with delgocitinib restores the molecular signature of lesional skin in patients with Chronic Hand Eczema Author: Sonja Molin Poster ID: P0572 ePoster presentation Health-related quality of life in people with Chronic Hand Eczema - Findings from the multi-national CHECK study Author: Anthony Bewley Poster ID: P3443 ePoster presentation Clinical trial exit interviews in patients with moderate to severe Chronic Hand Eczema: perspectives on disease burden and its impact on quality of life from participants in the phase 3 DELTA 1 trial Author: Padma Mohandas Poster ID: P0532 ePoster presentation Patient characteristics and comorbidities in moderate-to-severe CHE: Results from the RWEAL study Author: Maria Concetta Fargnoli Poster ID: P2559 ePoster presentation The multifactorial and heterogenous nature of Chronic Hand Eczema in clinical practice: Results from the RWEAL study Author: Maria Concetta Fargnoli Poster ID: P0608 ePoster presentation Delgocitinib cream reduces itch and pain in adults with moderate to severe Chronic Hand Eczema: pooled analyses of the Phase 3 DELTA 1 and 2 trials Author: Andrea Bauer Poster ID: P0564 ePoster presentation Efficacy and safety of delgocitinib cream in adults with moderate to severe Chronic Hand Eczema: pooled results of the Phase 3 DELTA 1 and 2 trials Author: Marie Louise Schuttelaar Poster ID: P0569 ePoster presentation Systemic exposure and safety profile of delgocitinib cream in adults with moderate to severe Chronic Hand Eczema in the Phase 3 DELTA 2 trial Author: Melinda Gooderham Poster ID: P0581 ePoster presentation Long-term safety and efficacy of delgocitinib cream for up to 36 weeks in adults with Chronic Hand Eczema: results of the Phase 3 open-label extension DELTA 3 trial Author: Sonja Molin Poster ID: P0565 ePoster presentation Association and impact of Chronic Hand Eczema on occupational and household/leisure activities– results from the multinational CHECK study Author: Marie Noelle Crepy Poster ID: P1076 ePoster presentation Prevalence of Chronic Hand Eczema in adults: A cross-sectional multi-national study of over 60,000 respondents in the general population Author: Christian Apfelbacher Poster ID: P1901 ePoster presentation Treatment patterns in moderate to severe Chronic Hand Eczema - Results from the multinational RWEAL medical chart review Author: Ana Maria Giménez-Arnau Poster ID: P3568 ePoster presentation Self-reported disease severity and treatment of Chronic Hand Eczema from the CHECK study - A multinational study in six countries Author: Sonja Molin Poster ID: P3526 ePoster presentation Adtralza ® (tralokinumab)/Adbry ® (tralokinumab-ldrm) Real-world effectiveness of tralokinumab in adults with atopic dermatitis: Interim data on improvements in patients with head and neck atopic dermatitis after up to 9 months of treatment in the TRACE study Author: April Armstrong Presentation ID: D3T01.3C LB presentation: Friday, 27 Sep, 14:45 - 15:00 Location: Auditorium Real-world effectiveness of tralokinumab in adults with atopic dermatitis: Interim data on improvements in physician-assessed disease severity after up to 9 months of follow-up in the TRACE study Author: Elena Pezzolo Poster ID: P0689 ePoster presentation Real-world effectiveness of tralokinumab in adults with atopic dermatitis: Interim data on improvements in patient-reported outcomes after up to 9 months of follow-up in the TRACE study Author: Antonio Costanzo Poster ID: P0690 ePoster presentation Long-term safety and efficacy of tralokinumab in patients 65 years or older with moderate-to-severe atopic dermatitis Author: Andrew Blauvelt Poster ID: P0479 ePoster presentation Improvement of the head and neck regions with continuous tralokinumab treatment for up to 4 years in adults with moderate-to-severe atopic dermatitis Author: Raj Chovatiya Poster ID: P0595 ePoster presentation Tralokinumab formulated as a pre-filled pen was efficacious and well-tolerated in adults and adolescents with moderate-to-severe atopic dermatitis Author: Jennifer Soung Poster ID: P0574 ePoster presentation Stability of long-term therapeutic responses to tralokinumab in adults with moderate-to-severe atopic dermatitis Author: Andrew Blauvelt Poster ID: P0596 ePoster presentation Kyntheum ® (brodalumab) Observational study to assess the real-life descriptive effectiveness in patients with moderate to severe plaque psoriasis treated with Brodalumab stratified by patients with BMI>30 and patients with BMI ≤ 30. The BROACTIVE Study. 2 years - results. Author: Juan Escalas Poster ID: P3205 ePoster presentation Long-term management outcome assessment of adult patients with moderate-to-severe plaque psoriasis treated with brodalumab in Greece: The ReSOLVE study. Author: Pantelis Panagakis Poster ID: P3102 ePoster presentation Temtokibart Targeting IL-22RA1 with temtokibart in patients with moderate to severe atopic dermatitis induces fast clinical and molecular responses, distinct from dupilumab Author: Christine Bangert Presentation ID: D2T01.3A LB presentation: Thursday, 26 Sep, 14:15 - 14:30 Location: Auditorium Individual responses to IL-22RA1 inhibition in Asian patients with moderate-to-severe atopic dermatitis in Phase 1 and 2a clinical trials Author: Diamant Thaçi Poster ID: P0691 ePoster presentation In addition to the abstracts and poster presentations, LEO Pharma will also present 3 symposiums at the meeting: A New Era in Atopic Dermatitis Speakers: Prof. Melinda Gooderham, Prof. April Armstrong and Prof. Marjolein de Bruin-Weller 17:45–19:15 CEST on Thursday the 26th of September in Room 7.1, RAI Amsterdam Plaque psoriasis and obesity — a double burden for patients? Speakers: Prof. Dr med. Khusru Asadullah and Dr Matteo Megna 11:15-12:00 CEST on Thursday the 26th of September in Amtrium 1, Hall 4, RAI Amsterdam Chronic Hand Eczema Breaking the Silent Conversation Speakers: Prof. Swen Malte John, Prof. April Armstrong, Dr Marie-Louise Schuttelaar 13:00-14:00 CEST on Friday the 27 th of September in Room 7.3, RAI Amsterdam. About Chronic Hand Eczema Chronic hand eczema (CHE) is defined as hand eczema (HE) that lasts for more than three months or relapses twice or more within a year. 29,30 CHE is one the most common skin disorder of the hands with a prevalence rate of approximately 4.7%. 31 In a substantial number of patients, HE can develop into a chronic condition. 32 CHE is a fluctuating disorder characterized by itch and pain, and patients may experience signs such as erythema, scaling, lichenification, hyperkeratosis, vesicles, edema, and fissures on hands and wrists. 33 CHE has been shown to cause psychological and functional burdens that impact patient quality of life, 34 with approximately 70% of individuals who live with severe CHE admitting to problems in performing everyday activities, and suffering disruption in their daily life due to the condition. 35 Furthermore, careers and earning potential have also been shown to be impacted by the burden of living with CHE. 36 About Atopic Dermatitis Atopic dermatitis is a chronic, inflammatory skin disease characterized by intense itch and eczematous lesions. 37 Atopic dermatitis is the result of skin barrier dysfunction and immune dysregulation, leading to chronic inflammation. 38 Type 2 cytokines, including IL-13, play an important role in the key aspects of atopic dermatitis pathophysiology. 37,38 Excessive IL-22 production is also known to contribute to the pathogenesis of AD. 39 About Psoriasis Psoriasis is a chronic, systemic inflammatory disease that primarily affects the skin in 125 million people worldwide. 40,41 Psoriasis is the result of skin barrier cell proliferation and the activation of cytokines (a family of proteins involved in immune responses) that cause inflammation. 42 About 80% to 90% of patients are affected by plaque psoriasis, the most common clinical form of psoriasis. 43 The symptoms of plaque psoriasis are itchy or painful raised scaly and inflamed plaques. Plaques may appear anywhere on the body, but often appear on the scalp, knees, elbows and torso. 43 About Anzupgo ® (delgocitinib) cream Anzupgo ® (delgocitinib) cream 20 mg/g is a topical pan-Janus kinase (JAK) inhibitor for the treatment of moderate to severe CHE. It inhibits the activation of JAK-STAT signaling, which plays a key role in the pathogenesis of CHE. 44 The pathophysiology is characterized by skin barrier dysfunction, inflammation of the skin, and alterations of the skin microbiome. 45 Anzupgo is currently approved in the European Union for the treatment of moderate to severe chronic hand eczema (CHE) in adults for whom topical corticosteroids are inadequate or inappropriate. In 2014, LEO Pharma A/S and Japan Tobacco Inc. (JT) entered into a license agreement in which LEO Pharma gained exclusive rights to develop and commercialize delgocitinib cream for topical use in dermatological indications worldwide, excluding Japan, where JT retains rights. About Adtralza ® (tralokinumab) / Adbry ® (tralokinumab-ldrm) Adtralza ® (tralokinumab), which is marketed under the tradename Adbry ® in the U.S., is a high-affinity fully human monoclonal antibody developed to bind to and inhibit the interleukin IL-13 cytokine, which plays a role in the immune and inflammatory processes underlying atopic dermatitis signs and symptoms. 38,46 Adtralza ® specifically binds to the IL-13 cytokine, thereby inhibiting interaction with the IL-13 receptor α1 and α2 subunits (IL-13Rα1 and IL-13Rα2). 47 Adtralza ® is approved for the treatment of moderate to severe AD in adult and adolescent patients 12 years and older in the European Union, Canada, Great Britain, the United Arab Emirates, and South Korea. Adtralza ® is approved for use in adults with moderate to severe AD in the U.S., Switzerland, Saudi Arabia, and Japan. About Kyntheum ® (brodalumab) Kyntheum ® (brodalumab) is a recombinant fully human monoclonal immunoglobulin IgG2 antibody that binds with high affinity to human IL-17RA and blocks the biological activities of the pro-inflammatory cytokines IL-17A, IL-17F, IL-17A/F heterodimer, IL-17C and IL-17E (also known as IL-25), resulting in inhibition of the inflammation and clinical symptoms associated with psoriasis. IL-17RA is a protein expressed on the cell surface and is a required component of receptor complexes utilized by multiple IL-17 family cytokines. IL-17 family cytokine levels have been reported to be increased in psoriasis. IL-17A, IL-17F and IL-17A/F heterodimer have pleiotropic activities including the induction of pro-inflammatory mediators such as IL-6, GROα, and G-CSF from epithelial cells, endothelial cells and fibroblasts that promote tissue inflammation. IL-17C has been shown to induce similar responses as IL-17A and IL-17F in keratinocytes. Blocking IL-17RA inhibits IL-17 cytokine-induced responses resulting in normalization of inflammation in the skin. 48 Kyntheum ® is indicated in the European Union, Great Britain, the United Arab Emirates, and Brazil for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy. About temtokibart Temtokibart (LEO 138559) is an investigational monoclonal antibody that targets the IL-22RA1 receptor subunit, currently in Phase 2 development for the potential treatment of moderate to severe atopic dermatitis. 49 It blocks the IL-22RA1 subunit and thereby inhibits the effects of the IL-22 cytokine, and potentially also to some extent the effects of IL-20 and IL-24. 49 Temtokibart does not bind to the IL-22 cytokine itself. 49 LEO Pharma has obtained a worldwide exclusive license to develop and commercialize temtokibart from argenx. About LEO Pharma LEO Pharma is a global company dedicated to advancing the standard of care for the benefit of people with skin conditions, their families and society. Founded in 1908 and majority owned by the LEO Foundation, LEO Pharma has devoted decades of research and development to advance the science of dermatology, and today, the company offers a wide range of therapies for all disease severities. LEO Pharma is headquartered in Denmark with a global team of 4,200 people, serving millions of patients across the world. In 2023, the company generated net sales of DKK 11.4 billion. References Giménez-Arnau AM, Pinter A, Sondermann W et al. DELTA FORCE trial: A 24-week head-to-head phase 3 trial comparing the efficacy and safety of topical delgocitinib cream with oral alitretinoin capsules in adults with severe chronic hand eczema. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. Oral Presentation. D1T01.1F. Bisonnette R, Schliemann S, Gooderham M, et al. Treatment response of delgocitinib cream according to Chronic Hand Eczema (CHE) subtypes in adults with moderate to severe CHE: results from the Phase 3 DELTA 1, DELTA 2, and DELTA 3 trials. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. Oral Presentation. FC07.04 Giménez-Arnau AM, Bewley A, Molin S, et al. Patient characteristics and comorbidities in moderate-to-severe CHE: Results from the RWEAL study. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P2559 Fargnoli MN, Molin S, Bewley A, et al. The multifactorial and heterogenous nature of Chronic Hand Eczema in clinical practice: Results from the RWEAL study. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P0608. Worm M, Jiang L, Litman T, et al. Topical pan-JAK inhibition with delgocitinib restores the molecular signature of lesional skin in patients with Chronic Hand. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. Oral Presentation. P0572. Bewley A, Molin S, Crepy MN, et al. Health-related quality of life in people with Chronic Hand Eczema - Findings from the multi-national CHECK study. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P3443. Mohandas P, Devani AR, Baranowski K, et al. Clinical trial exit interviews in patients with moderate to severe Chronic Hand Eczema: perspectives on disease burden and its impact on quality of life from participants in the phase 3 DELTA 1 trial. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. 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Observational study to assess the real-life descriptive effectiveness in patients with moderate to severe plaque psoriasis treated with Brodalumab stratified by patients with BMI>30 and patients with BMI ≤ 30. The BROACTIVE Study. 2 years - results. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P3205. Panagakis P, Chasapi V, Kalapothakou K, et al. Long-term management outcome assessment of adult patients with moderate-to-severe plaque psoriasis treated with brodalumab in Greece: The ReSOLVE study. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P3102. Thaçi D, Bangert C, Laquer V, et al. Individual responses to IL-22RA1 inhibition in Asian patients with moderate-to-severe atopic dermatitis in Phase 1 and 2a clinical trials. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P0691. Blauvelt A, Merola J, Carrascosa JM, et al. Long-term safety and efficacy of tralokinumab in patients 65 years or older with moderate-to-severe atopic dermatitis. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P0479. Bauer A, Schuttelaar ML, Baranowski K, et al. Delgocitinib cream reduces itch and pain in adults with moderate to severe Chronic Hand Eczema: pooled analyses of the Phase 3 DELTA 1 and 2 trials. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P0564. Schuttelaar ML, Bisonnette R, Worm M, et al. Efficacy and of delgocitinib cream in adults with moderate to severe Chronic Hand Eczema: pooled results of the Phase 3 DELTA 1 and 2 trials. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P0569. Gooderham M, Thaçi D, Damgaard T, et al. Systemic exposure and safety profile of delgocitinib cream in adults with moderate to severe Chronic Hand Eczema in the Phase 3 DELTA 2 trial. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P0581. Molin S, Gooderham M, Bisonnette R, et al. Long-term safety and efficacy of delgocitinib cream for up to 36 weeks in adults with Chronic Hand Eczema: results of the Phase 3 open-label extension DELTA 3 trial. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P0565. Crepy MN, Molin S, Giménez-Arnau AM, et al. Association and impact of Chronic Hand Eczema on occupational and household/leisure activities– results from the multinational CHECK study. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P1076. Apfelbacher C, Bewley A, Molin S, et al. Prevalence of Chronic Hand Eczema in adults: A cross-sectional multi-national study of over 60,000 respondents in the general population. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P1901. Giménez-Arnau AM, Bewley A, Apfelbacher C et al. Treatment patterns in moderate to severe Chronic Hand Eczema - Results from the multinational RWEAL medical chart review. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P3568. Molin S, Fargnoli MN, Crepy MN, et al. Self-reported disease severity and treatment of Chronic Hand Eczema from the CHECK study - A multinational study in six countries. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P3526 . Chovatiya R, Wollenberg A, Ribero S, et al. Improvement of the head and neck regions with continuous tralokinumab treatment for up to 4 years in adults with moderate-to-severe atopic dermatitis. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P0595. Soung J, Laquer V, Zirwas M, et al. Tralokinumab formulated as a pre-filled pen was efficacious and well-tolerated in adults and adolescents with moderate-to-severe atopic dermatitis. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P0574. Blauvelt A, Hong HC, Peris K, et al. Stability of long-term therapeutic responses to tralokinumab in adults with moderate-to-severe atopic dermatitis. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. EPoster Presentation. P0596. Cohen D, Bewley A, Wollenberg A, et al. Matching-adjusted indirect comparison of the efficacy of delgocitinib and dupilumab in the treatment of moderate to severe atopic hand eczema. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. Oral Presentation.D3T01.4B. Senna MM, Soerensen OE, Nielsen AB et al. Randomized vehicle-controlled clinical trial with the topical JAK inhibitor delgocitinib in patients with frontal fibrosing alopecia demonstrates biomarker and clinical efficacy. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. Oral Presentation. D3T01.4F. Armstrong A, Ameen A, Bagel J et al. Real-world effectiveness of tralokinumab in adults with atopic dermatitis: Interim data on improvements in patients with head and neck atopic dermatitis after up to 9 months of treatment in the TRACE study. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. Oral Presentation. D3T01.3C Bangert C, Berdyshev E, Alkon N et al. Targeting IL-22RA1 with temtokibart in patients with moderate to severe atopic dermatitis induces fast clinical and molecular responses, distinct from dupilumab. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. Oral Presentation. D2T01.3A. Lynde C, Guenther L, Diepgen TL, et al. 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Current and emerging therapies for hand eczema. Dermatol Ther. 2019;32(3):e12840. Bieber T. Interleukin-13: targeting an underestimated cytokine in atopic dermatitis. Allergy . 2020; 75:54-62. Popovic B, Breed J, Rees DG, et al. Structural Characterisation Reveals Mechanism of IL-13-Neutralising Monoclonal Antibody Tralokinumab as Inhibition of Binding to IL-13Rα1 and IL-13Rα2. J Mol Biol. 2017;429(2):208-219. Electronic Medicines Compendium. SmPC. Kyntheum (brodalumab). 10 Jan 2023. https://www.ema.europa.eu/en/documents/product-information/kyntheum-epar-product-information_en.pdf Accessed September, 2024. Thaçi D, et al. Efficacy and safety of IL-22R inhibition in patients with moderate-to-severe atopic dermatitis: results from a phase 2a monotherapy trial. Presented at the 2023 American Academy of Dermatology Annual Meeting; March 17–21 2023; New Orleans, LA. MAT-76322 September 2024