Etanercept

前 言自身免疫疾病已经成为仅次于肿瘤领域的第二大疾病领域，中国的自免市场也在逐渐扩大，预估到2030年将达到199亿美元（约1433亿元），千亿市场亟待瓜分。上一期我们梳理了MNC在自免领域的重磅药物及布局，国内很多药企也意识到这一巨大市场，纷纷加入布局，如恒瑞医药、荃信生物、百奥泰、三生国健、康诺亚生物、智翔生物、康方生物和君实生物等。一 本文概览国内八大药企在自免领域布局情况恒瑞医药是一家综合性创新型企业，在自免领域众多的管线有靶向IL-17A的夫那奇珠单抗、URAT1的SHR4640、MASP-2的SHR-2010、IL-4Rα的SHR-1819和TSLP的SHR-1905等。荃信生物是一家专注于自身免疫及过敏性疾病生物疗法的生物医药企业，其乌司奴单抗生物类似药QX001S（HDM3001）上市申请已获受理，核心产品IL-17A单抗QX002N和IL-4Rα单抗QX005N分别处于临床3期和2期。百奥泰自免管线丰富，不仅有已获批上市的生物类似药格乐立和施瑞立，还布局了靶向IL-5、OX40、CD20和IL-17等药物。三生国健有TNF-a抑制剂益赛普、CD25单抗健尼哌和HER2单抗赛普汀3个上市产品，其中益赛普给三生国健带来大部分收入，但是专利已于2021年到期，后续自免管线有TNF-a药物301s、IL-17A药物608和IL-5药物610等。康诺亚深耕于自身免疫及肿瘤疾病领域，成立自今，已经有超过30款药物处于研发阶段，进度最快的核心产品是IL-4Rα单抗CM310，近期被CDE拟纳入优先审评。智翔金泰主攻自身免疫性、感染性和肿瘤三大类疾病，拥有涵盖这三大治疗领域共计十余款在研产品，其中针对中重度斑块状银屑病适应症的单抗药物赛立奇单抗是国产首个提交新药上市申请的IL-17类药物。康方生物已有 19 个产品在全球开展临床研究，其中IL12/IL23单抗依若奇单抗用于治疗中重度斑块状银屑病的适应症的上市申请已获受理。君实生物自免领域主要管线有上市产品阿达木单抗生物类似物君迈康、临床3期在研的IL-17A单抗JS005和临床1期在研的B淋巴细胞刺激因子（BLyS）单抗UBP1213sc。二 支付认知能力有限，国内自免市场逐渐加码自身免疫疾病是以局部或全身性异常炎症免疫反应为特征的炎症免疫性疾病，已经成为仅次于肿瘤领域的第二大疾病领域，2022年自身免疫及过敏性药物的全球市场规模为1,875亿美元，中国的自身免疫及过敏性药物的全球市场规模为90亿美元，由于支付和认知能力有限，自免药物在中国渗透率仍然较低。不过，随着治疗手段的升级，疗效更好的生物制剂逐渐将被医生和患者所接受。中国自身免疫疾病药物市场有望快速增长，由2018年的20亿美元增长至2022年的29亿美元，复合年增长率为9.8%，估计2030年将达到199亿美元，2022年至2030年的复合年增长率为27%，估计生物药在中国自身免疫疾病药物市场中的份额将由2022年的41.9%增加至2030年的69.3%[1]。图1. 2018年至2030年（估计）中国自身免疫疾病药物市场（图片来源于弗若斯特沙利文报告）三 多款药物申请上市自免市场趋于完善嗅到巨大的市场潜力，国内药企纷纷加入布局，市场上也有国产自免药物在售，如亚维药业的恩博克、百奥泰的格乐立和施瑞立、天济药业的欣比克、荣昌生物的泰爱以及三生国健的益赛普等，临床在研的更是数不胜数，如临床3期的夫那奇珠单抗、艾玛昔替尼、杰克替尼、301s和赛立奇单抗等（图2）。 图2. 部分上市和临床在研的国产自免药物四 国内自免领域千亿市场亟待瓜分，八大药企纷纷布局4.1 恒瑞医药：夫那奇珠单抗申请上市恒瑞医药是一家综合性创新型企业，业务布局较广，涉及肿瘤、自免疫、代谢疾病、心血管、感染、呼吸系统、血液病和眼科领域等。恒瑞在自免领域也有众多布局，管线涉及IL-17A、URAT1、MASP-2、IL-4Rα和TSLP等靶点，用于治疗斑块状银屑病、强直性脊柱炎痛风、高尿酸血症、IgA肾病、特应性皮炎、慢性鼻窦炎伴鼻息肉和哮喘等（图3）。 图3. 恒瑞医药部分在研的自免管线IL-17主要由T辅助细胞TH17产生，可以直接或间接诱导多种细胞因子、趋化因子、炎症因子和抗微生物蛋白来识别介导自身免疫和慢性感染的靶基因。目前全球范围内共上市5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、比吉利珠单抗和布罗利尤单抗。其中司库奇尤单抗、依奇珠单抗和布罗利尤单抗已在国内获批，比吉利珠单抗也已在国内申报上市（图4）。 图4. 部分上市和临床在研IL-17类药物夫那奇珠单抗（SHR-1314）是由恒瑞研发的一种重组的人源化 IgG1单克隆抗体，可以靶向IL-17A并抑制其与IL-17受体的相互作用。此前，夫那奇珠单抗的一项为期36周评估其在中至重度斑块状银屑病患者中的多中心双盲2期研究（NCT03463187）取得积极结果。研究结果显示，在第12周，与安慰剂组相比，所有夫那奇珠单抗组的银屑病PASI 75都有所改善，40、80、160和240mg组PASI 75分别为56.8%、65.8%、81.6%和86.5%，而安慰剂组为5.4%；使用夫那奇珠单抗时，达到0或1的医师整体评估反应的患者也更高，40、80、160和240mg组分别为45.9%、47.4%、60.5%和73.0%，而安慰剂组为8.1%。未观察到意想不到的不良反应（图5）[2]。 图5. 夫那奇珠单抗的一项NCT03463187的临床结果2023年4月27日，夫那奇珠单抗注射液上市申请获NMPA受理，推测申报适应症为成人中重度慢性斑块型银屑病或成人强直性脊柱炎患者。4.2 荃信生物：QX001S、QX002N和QX005N荃信生物成立于2015年，是一家专注于自身免疫及过敏性疾病生物疗法的临床后期阶段生物医药企业，拥有完全自主研发的药物管线及成熟的商业级规模的内部生产能力。荃信生物临床在研项目有9项，核心产品为QX001S、QX002N和QX005N（图6），已获IND批准17项，申报国内外专利70余项。 图6. 荃信生物自免领域管线（信息来源于荃信生物官网）●QX001S (乌司奴单抗生物类似药)QX001S（HDM3001）注射液是荃信生物和华东医药子公司中美华东联合开发的乌司奴单抗生物类似药，2023年8月11日，QX001S的上市申请获得NMPA签发的《受理通知书》，受理号为CXSS2300065，用于治疗成年中重度斑块状银屑病。●QX002N (IL-17A单抗)QX002N是荃信生物的核心产品之一，是一种靶向IL-17A的高亲和力单克隆抗体，QX002N在临床上开展强直性脊柱炎及狼疮性肾炎适应症，其中强直性脊柱炎适应症已进入临床3期。强直性脊柱炎（AS）是一种原因不明的、以中轴关节慢性炎症性疾病,主要累及骶髂关节、脊柱、脊柱旁软组织及髋、膝、踝和肩等四肢外周关节。中国AS患者人数于2022年达到3.9百万人，AS药物市场也由2018年的13亿美元增加至2022年的18亿美元，估计于2030年将达到65亿美元。中国批准用于治疗AS的生物制剂有两类：TNF抑制剂和IL-17抑制剂。现行的临床指南中，IL-17A抑制剂联合同TNF-α抑制剂被推荐用于接受一线传统治疗后仍有高疾病活动度的AS患者的二线治疗方法。在两类生物疗法中，IL-17A抑制剂对TNF-α抑制剂不耐受或不能达到充分疾病控制的患者有明显的临床益处。QX002N在针对AS的1b期及2期临床试验中显示出良好疗效。在1b期临床试验中，每2周接受一次QX002N（160mg）的受试者第16周的ASAS20及ASAS40应答率分别为62.5%及37.5%，目前QX002N处于临床3期[3]。●QX005N (IL-4Rα单抗)荃信自主研发的QX005N注射液（重组人源化抗IL-4Rα单抗注射液）至少获得用于治疗五种适应症（即AD、PN、CRSwNP、CSU及哮喘）的IND批准，是中国IL-4Rα靶向候选药物中适应症最多药物的之一，目前该款药物有三项2期临床试验同步推进中。4.3 百奥泰：生物类似药和创新药双管齐下百奥泰生物制药股份有限公司成立于2003年，致力于开发新一代抗体药物，用于治疗肿瘤、自身免疫性疾病、心血管疾病以及其它危及人类生命或健康的重大疾病。百奥泰在自身免疫性疾病领域布局众多，涉及TNF-a、IL-6R、IL-5、OX40和CD20等靶点，包括生物类似药和创新药（图7）。 图7. 百奥泰自免领域管线（图片来源于百奥泰官网）●格乐立（阿达木单抗生物类似药）艾伯维开发的阿达木单抗（修美乐）是自身免疫疾病领域最重磅的产品，自从2012年修美乐打败利妥昔成为“药王”之后，直到2022年一直位居“药王”宝座，上市以来累积给艾伯维带来超过2000亿美元收入。格乐立（阿达木单抗注射液）是国内首个获批的阿达木单抗生物类似药，于2019年11月获得国家药监局正式批准，用于治疗类风湿关节炎、强直性脊柱炎和银屑病等自身免疫性疾病。 2021 年 3 月 23 日，国家药品监督管理局（NMPA）批准格乐立20mg/0.4 ml（预填充，皮下注射）的新规格，成为国产首个小剂量皮下注射剂型阿达木单抗。●施瑞立（托珠单抗生物类似药）托珠单抗是首款获批上市的IL-6R单抗，也是目前销售额最高的IL-6R单抗，目前全球已有多款托珠单抗生物类似药获批上市或在研（图8）。百奥泰的施瑞立是首款国产上市的托珠单抗生物类似药，于今年1月16日被NMPA批准上市，10月8日，施瑞立（英文商品名TOFIDENCE）被FDA批准上市，成为百奥泰第一个获得美国FDA上市批准的产品。 图8. 部分在研的托珠单抗生物类似药4.4 三生国健：益赛普独占鳌头，正在抢夺白介素领域三生国健成立于2002年，是中国首批专注于创新型抗体药物研究并持续积极创新，拥有研、产、销一体化成熟平台，专注于单抗、双抗、多抗及多功能重组蛋白等新技术研究。目前，公司拥有3个上市产品，包括TNF-a抑制剂益赛普、CD25单抗健尼哌和HER2单抗赛普汀，13个处于不同开发阶段的在研创新药物，其中大部分在研药物为治疗用生物制品1类，部分在研药物为中美双报。该公司在自免领域的管线有TNF-a药物301s、IL-17A药物608、IL-5药物610、IL-4R药物611、IL-1β药物613和IL-33药物621等（图9）。 图9. 三生国健自免领域管线（图片来源于三生国健官网）●益赛普（依那西普生物类似药）TNF-α失调与很多自免疾病有关，TNF-α抑制剂也被广泛应用于市场（图7），益赛普是依那西普生物类似药，占据国内市场很大份额，是中国首个上市的全人源抗体类药物，也是中国风湿病领域第一个上市的TNF-α抑制剂，2005 年获批用于治疗类风湿关节炎，2007 年获批强直性脊柱炎和银屑病（图10）。益赛普自2005年获批上市后，其销售收入即成为三生国健最主要的营收来源，助力三生国健于2020年7月22日成功登陆上交所科创板。 图10. 部分上市的TNF-a类药物但是益赛普的专利保护在2021年到期，三生国健必须找到新的收入来源来填补这份损失，随后，三生国健有另两款健尼哌和赛普汀上市，不过它们的市场表现不如最初的益赛普。该公司还在积极开发益赛普预充针产品（301S），适应症与原有的粉针剂产品无差，目前在申报阶段，301S上市后将是重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白的首个水针剂型，是对公司产品益赛普的有益补充，患者用药的便利性提升。4.5 康诺亚：IL-4Rα单抗CM310被CDE拟纳入优先审评康诺亚生物成立于2016年，总部位于四川成都，是一家专注创新生物疗法的生物科技公司，深耕于自身免疫及肿瘤疾病领域未被满足的临床需求，在单抗、ADC、双抗领域建立起一体化自主研发平台。凭借优秀的创新管线推进能力，康诺亚生物成立自今，已经有超过30款药物处于研发阶段，进度最快的核心产品是IL-4Rα单抗CM310（图11）。 图11. 康诺亚自免领域布局（图片来源于康诺亚官网）CM310是由康诺亚开发的，国内首家获批临床的以人IL-4Rα为靶点的创新型人源化单克隆抗体，于11月10日被CDE拟纳入优先审评，适应症为治疗外用药控制不佳或不适合外用药治疗的成人中重度特应性皮炎，目前该公司正就CM310治疗成年人中重度特应性皮炎的新药申请(NDA)与国家药监局进行沟通，预期将于今年提交新药申请。目前临床上对CM310开展多项试验，适应症包括慢性鼻-鼻窦炎伴鼻息肉，中度至重度哮喘（与石药合作），儿童中度至重度特应性皮炎患者，中度至重度特应性皮炎，慢性瘙痒和季节性过敏性鼻炎等过敏性疾病（图12）。 图12. 部分CM310临床在研试验2023年7月，CM310用于治疗重度嗜酸性粒细胞型慢性鼻窦炎鼻息肉（eCRSwNP）的多中心随机、双盲、安慰剂对照2期临床试验（CROWNS-1研究）取得积极结果：与安慰剂相比，CM310减少鼻息肉大小（NPS）和缓解鼻塞（NCS）达到主要疗效终点 [4]。4.6 智翔金泰：国产首个提交新药上市申请的IL-17单抗赛立奇单抗智翔金泰成立于2015年，总部位于重庆国际生物城，是一家以抗体药物发现技术为驱动的创新型生物制药企业，主攻自身免疫性、感染性和肿瘤三大类疾病，在研产品以单克隆抗体和双特异性抗体药物为主。该公司拥有涵盖三大治疗领域共计十余款在研产品，其中针对中重度斑块状银屑病适应症的单克隆抗体药物赛立奇单抗（GR1501）已进入上市申请阶段，其他产品均处于在研状态（图13）。 图13. 智翔金泰自免领域管线（图片来源于智翔金泰官网）银屑病是影响面容的一种皮肤病，对中重度患者的身心都造成危害，据统计，2021年我国银屑病患者人数增加至667万。针对中重度斑块状银屑病，目前业内治疗方案包括酸类药物、光照疗法、生物制剂等。生物制剂是针对特定发病机制进行设计的一类大分子，具有靶向性，减少脱靶副作用等优点，在临床上得到广泛应用，包括TNF-a、IL-12/IL-23和IL-17抑制剂等。赛立奇单抗是由智翔金泰研发的一款重组全人源抗IL-17A单克隆抗体，可选择性地与IL-17A结合，抑制IL-17RA的下游信号转导，抑制IL-17A诱导的炎性反应。IL-17类生物制剂中最常用的进口药物，包括诺华制药的司库奇尤单抗和礼来的依奇珠单抗，但是它们治疗费用并不低，司库奇尤单抗单价为1188元/支，年治疗费用高达4.04万元；而依奇珠单抗的定价则高达4318元/支，年治疗费用为2.59万元。赛立奇单抗是国内企业首个提交新药上市申请的IL-17单抗，今年3月25日它的上市申请获NMPA受理，有望成为首个获批的国产IL-17单抗。4.7 康方生物：依若奇单抗的NDA获受理康方生物成立于2012年，是一家致力于研究、开发、生产及商业化全球病人可负担的创新抗体新药的生物制药公司，于2020年4月24日正式在香港联合交易所有限公司主板挂牌上市。公司目前拥有30个以上用于治疗肿瘤、自身免疫、炎症、代谢疾病等重大疾病的创新候选药物，截至目前，公司已有 19 个产品在全球开展临床研究，13项临床研究处于注册性/3期临床研究阶段。公司在自免领域中进展最快的是IL12/IL23药物依若奇单抗（图14）。 图14. 康方生物自免领域管线（图片来源于康方生物官网）●依若奇单抗（IL-12/IL-23靶标）依若奇单抗是康方生物自主研发的靶向于IL-12/IL-23的全人源单克隆抗体，它的新药上市许可申请（NDA）于今年8月份被受理，用于治疗中度至重度斑块型银屑病，是首个申报上市的以IL-12/IL-23为靶点的国产创新专利药。在中重度斑块型银屑病患者中，依若奇单抗针共开展了5项临床研究，其中2项关键3期临床研究分别提供了依若奇单抗在中重度斑块型银屑病患者中的16周短期和52周长期的关键有效性和安全性数据。研究结果显示，依若奇单抗治疗中重度斑块型银屑病16周及52周均疗效显著，安全性良好。依若奇单抗在改善皮损的同时有效提高了患者的生活质量[5]。4.8 君实生物：自免上市产品君迈康、临床在研的JS005和UBP1213sc君实生物于2012年12月在上海成立，是一家以创新为驱动，致力于在肿瘤免疫疗法，以及自身免疫系统疾病、慢性代谢类疾病、神经系统疾病、感染类疾病等治疗方面进行布局开发的生物制药公司。君实生物在自免领域主要管线有靶向TNF-a的君迈康、IL-17A单抗JS005和B淋巴细胞刺激因子（BLyS）单抗UBP1213sc等（图15）。 图15. 君实生物自免领域管线（信息来源于君实生物官网）君迈康是君实生物与迈威生物合作开发的阿达木单抗生物类似物，靶向TNF-a，君迈康于去年3月份获得NMPA批准上市，用于治疗类风湿关节炎、强直性脊柱炎、银屑病、克罗恩病、葡萄膜炎、多关节型幼年特发性关节炎、儿童斑块状银屑病和儿童克罗恩病，是君实生物第三款商业化产品。JS005是君实生物自主研发的特异性抗IL-17A单克隆抗体。目前，JS005针对中重度斑块状银屑病、强直性脊柱炎的2期临床研究均已完成。中重度斑块状银屑病已进入3期注册临床研究，强直性脊柱炎已启动注册临床试验沟通交流。UBP1213sc注射液是由君实生物研发的重组人源化抗B淋巴细胞刺激因子（BLyS）单抗药物，用于治疗系统性红斑狼疮（SLE）及狼疮肾炎（LN）等自身免疫性疾病。2016年11月，UBP1213的静脉注射剂型（IV）获得国家药监局的药物临床试验批件，君实生物成为国内该靶点单抗首家获得NMPA的IND批准的中国企业。后续开发了皮下注射（SC）给药途径的UBP1213sc，患者通过培训后可自行给药，提高了患者的顺应性。UBP1213sc已获NMPA批准，目前正在健康志愿者中开展1期临床研究。  写在最后  自免是一个很大的市场，前期由于价格以及意识等问题，自免药物在国内的渗透率不高，随着国人加强意识以及更好生物制剂的普及，中国的自免市场正在逐渐扩大。国内也有很多药企纷纷加入抢夺自免市场这一块蛋糕，本文总结了国内药企如恒瑞医药、荃信生物、百奥泰、三生国健、康诺亚生物、智翔生物、康方生物和君实生物在自免领域的布局和进展，以上内容供各位同行参考。References1.https://www1.hkexnews.hk/app/sehk/2023/105783/a117520/sehk23100303481_c.pdf2.Chunlei Zhang, Kexiang Yan, A multicenter, randomized, double-blinded, placebo-controlled, dose-ranging study evaluating the efficacy and safety of vunakizumab in patients with moderate-to-severe plaque psoriasis, J Am Acad Dermatol. 2022 Jul;87(1):95-102.3.https://www.qyuns.net/col49/index.html4.Yuan Zhang,a,y Bing Yan,b,c,d,y Shen Shen, et.al, Efficacy and safety of CM310 in severe eosinophilic chronic rhinosinusitis with nasal polyps (CROWNS-1): a multicentre, randomised, double-blind, placebo-controlled phase 2 clinical trial, eClinicalMedicine 2023;61: 102076.5.https://akesobio.com/cn/media/akeso-news/230824/  近期活动  2023年11月24日，湖州申科将联合生物制品圈在上海举办“细胞基因治疗产品开发与质量控制研究”技术交流会。会议邀请到多位CGT领域专家,聚焦细胞基因治疗产品开发、生产和质控，共话技术研究，助力加速CGT产品商业化进程。点击”阅读原文“即可报名。识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

− The Study Met Its Primary Endpoint with 53.3% and 54.2% of Patients Treated With TAK-279 (15 mg and 30 mg Respectively) Achieving At Least an ACR 20 Response Compared to 29.2% in the Placebo Group at Week 12 (p = 0.002) 1 − TAK-279 Demonstrated Improvements in Key Secondary Endpoints and a Safety Profile Consistent with the Phase 2b Psoriasis Study 1 − Takeda Will Initiate Phase 3 Studies in Plaque Psoriasis in FY23 and Psoriatic Arthritis in FY24, While Exploring TAK-279 in Systemic Lupus Erythematosus, Inflammatory Bowel Disease and Other Indications OSAKA, Japan & CAMBRIDGE, MA, USA I November 07, 2023 I Takeda ( TSE:4502/NYSE:TAK ) today announced that the company will present positive results from its randomized, double-blind, placebo-controlled, Phase 2b trial evaluating TAK-279, an investigational oral allosteric tyrosine kinase 2 (TYK2) inhibitor with next generation selectivity, in patients with active psoriatic arthritis. These data ( Abstract #L12 ) will be presented on Tuesday, November 14 as part of the late-breaking poster session from 9:00 AM - 11:00 AM PT at the American College of Rheumatology (ACR) Convergence 2023 in San Diego, California. The study met its primary endpoint with a statistically significant proportion of patients, 53.3% (15 mg) and 54.2% (30 mg), treated with TAK-279 achieving at least an American College of Rheumatology 20 (ACR 20) response compared to 29.2% in the placebo arm at week 12 (p = 0.002). 1 The safety and tolerability profile of TAK-279 in the trial was consistent with that observed in the Phase 2b psoriasis study. 1 There was no statistically significant difference in ACR 20 seen in the TAK-279 5 mg arm (35.2%) compared to the placebo arm (29.2%). 1 “There remains a critical unmet need for psoriatic arthritis treatment options that not only improve the signs and symptoms of the condition, but are well tolerated and convenient for patients,” said Alan Kivitz, MD, MACR, the study’s principal investigator. “As psoriatic arthritis is a condition with diverse presentations of inflammation and skin involvement, the improvements seen with just 12 weeks of treatment in this Phase 2b study in patients with a low mean baseline C-reactive protein level are particularly encouraging. These results support the continued evaluation, across the psoriatic arthritis disease spectrum, of TAK-279, a once-daily oral TYK2 inhibitor with next generation selectivity.” The study also demonstrated improvements in key secondary endpoints: The most common treatment-emergent adverse events (TEAEs) in patients who received TAK-279 5 mg, 15 mg, or 30 mg versus placebo, respectively, were nasopharyngitis (8.5%, 9.3%, 9.7%, 4.2%), upper respiratory tract infections (11.3%, 4%, 9.7%, 2.8%), headache (2.8%, 8.0%, 5.6%, 4.2%) and rash (4.2%, 8%, 5.6%, 0%). 1 No opportunistic infections, major adverse cardiovascular events or differences in mean laboratory parameters of interest were observed, compared with placebo. There was no clinically significant difference in adverse event rates between doses of TAK-279. Serious and grade 3 or higher TEAEs occurred infrequently and at a similar rate in the TAK-279 and placebo groups. 1 “Based on these promising efficacy and safety results, achieved at 12 weeks, we plan to initiate a Phase 3 study of TAK-279 in psoriatic arthritis as well as commence a Phase 3 study in plaque psoriasis,” said Andy Plump, President, Research & Development, Takeda. “We are also advancing the development of TAK-279 in Crohn’s disease, ulcerative colitis and systemic lupus erythematosus and exploring a range of other potential indications. These opportunities are being explored in parallel with the psoriasis and psoriatic arthritis programs.” About TAK-279 TAK-279 is a highly selective, oral allosteric tyrosine kinase 2 (TYK2) inhibitor in late-stage development, 3 with approximately 1.3 million–fold greater selectivity for TYK2 as compared with JAK1. 4 TAK-279 has the potential to become an important treatment option in multiple immune-mediated inflammatory diseases. In Phase 1 studies, TAK-279 showed a good tolerability profile, a dose-dependent trend in exploratory clinical activity and a pharmacokinetic profile allowing for once-daily solid oral dosing. 5 In a Phase 2b study in patients with moderate-to-severe psoriasis, a statistically significant greater proportion of patients receiving TAK-279 achieved Psoriasis Area and Severity Index (PASI) 75, 90 and 100 in the 5mg, 15mg and 30mg dosing arms compared to placebo at 12 weeks. 3 TAK-279 is an investigational compound that has not been approved for use by any regulatory authority. About the TAK-279 Phase 2b Study in Psoriatic Arthritis The Phase 2b study ( NCT05153148 ) is a randomized, multicenter, double-blind, placebo-controlled multiple-dosed trial designed to evaluate the efficacy, safety and tolerability of TAK-279 in patients with active psoriatic arthritis. 6 Eligible patients were aged ≥ 18 years, with psoriatic arthritis symptoms for ≥ 6 months prior to screening, met Classification criteria for Psoriatic Arthritis (CASPAR), and had ≥ 3 tender and ≥ 3 swollen joint counts (TJC/SJC) at enrollment despite prior NSAID, DMARD or biologic treatment. 6 In total, 290 patients were randomized and treated (1:1:1:1 ratio) to receive one of three doses of TAK-279 or placebo once daily for 12 weeks with a 4 week safety follow up period; 245 completed 12 weeks’ treatment. 1,6 Baseline characteristics were generally comparable across groups (except for a lower mean TJC in the 30 mg group); 58.6% had BSA ≥ 3% (of which mean baseline PASI score was 6.2), and 32.1% had prior biologic use (20.7% TNFis). 1 Mean baseline high-sensitivity C-reactive protein (hsCRP) was 7.0 mg/L; 45.9% had hsCRP ≥ 3 mg/L. 1 The primary endpoint was the proportion of patients achieving at least an ACR 20 response at week 12. 6 The ACR 20, ACR 50, and ACR 75 are composite measures defined as 20%, 50% and 75% improvement, respectively, in the number of tender and number of swollen joints, and in three of the following five criteria: patient global assessment of psoriatic arthritis, physician global assessment of psoriatic arthritis, patient pain scale, disability history questionnaire and an acute phase reactant. 6 The Psoriasis Area and Severity Index (PASI) is a scoring system to evaluate baseline and response of therapy in psoriasis. PASI 75 is a binary outcome that indicates a 75% or greater improvement in PASI from baseline. 7 About Psoriatic Arthritis Psoriatic arthritis is a chronic immune-mediated inflammatory disease, characterized by inflammation causing joint pain, stiffness, and swelling and occurs with the skin condition psoriasis. 8 Psoriatic arthritis affects approximately 10 million people globally. 9 Psoriatic arthritis is a heterogenous condition - affecting everyone differently. 10 Symptoms may be mild or severe, affect just a few or many joints, and symptoms can come and go. 10 Chronic inflammation seen in psoriatic arthritis may result in irreversible joint damage if not managed appropriately. 8 Progressive disease is associated with substantial physical disability 11 and significant mental health disorders, such as anxiety and depression. 12 About Tyrosine Kinase 2 (TYK2) Inhibitors Tyrosine kinase 2 (TYK2) is an intracellular enzyme that belongs to the Janus family of protein tyrosine kinases. 13 TYK2 is a member of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, which mediates signaling downstream of key immune cytokine receptors. 13 Inflammatory cytokine signaling is associated with several immune-mediated inflammatory diseases, including psoriasis, psoriatic arthritis, systemic lupus erythematosus and inflammatory bowel disease. 14 Selective allosteric inhibition of TYK2 may be a promising therapeutic approach to target immune-mediated inflammation while potentially decreasing the risk of JAK-related toxicity. 15 About Takeda Takeda is focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline. As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. For more information, visit https://www.takeda.com. 1 TAK-279 PsA Ph2b ACR abstract (TKPO011). Efficacy and safety outcomes of TAK-279, a selective oral tyrosine kinase 2 (TYK2) inhibitor, from a randomized, double-blind, placebo-controlled phase 2b trial in patients with active psoriatic arthritis. Presented at American College of Rheumatology (ACR) 2023 Convergence, November 10–15, 2023 San Diego, CA, USA. 2 Takeda Pharmaceuticals. Data on File. 3 Armstrong A, Lynde C, Forman S, et al. Efficacy and safety results from the randomized double-blind, placebo-controlled phase 2b trial of TYK2 inhibitor NDI-034858 in moderate-to-severe psoriasis. Presented March 17-21, 2023, New Orleans, Louisiana at the 2023 American Academy of Dermatology Annual Meeting. 4 Leit S, J, Greenwood Carriero S, et al. Discovery of a potent and selective tyrosine kinase two inhibitor: TAK-279. J Medicinal Chemistry.2023;66(15):10473-10496. doi.org/10.1021/acs.jmedchem.3c00600. 5 Gangolli EA, Carreiro S, Leit S, et al. Characterization of pharmacokinetics, pharmacodynamics, tolerability and clinical activity in Phase 1 studies of the novel allosteric tyrosine kinase 2 (TYK2) inhibitor NDI-034858. Presented May 18-21, 2022, Portland, OR at the 2022 Society for Investigative Dermatology Annual Meeting. 6 ClinicalTrials.gov. A Study to Evaluate the Efficacy, Safety, and Tolerability of NDI-034858 in Subjects With Active Psoriatic Arthritis. Available at: https://classic.clinicaltrials.gov/ct2/show/NCT05153148 . Last accessed: November 2023 7 Rodgers M, Epstein D, Bojke L, et al. Etanercept, Infliximab and Adalimumab for the Treatment of Psoriatic Arthritis: A Systematic Review and Economic Evaluation. Southampton (UK): NIHR Journals Library; 2011 Feb. (Health Technology Assessment, No. 15.10.) Appendix 18, Estimation of Psoriasis Area and Severity Index score for treatment responders in the decision model. Available at: https://www.ncbi.nlm.nih.gov/books/NBK109508/ . Last accessed: November 2023. 8 American College of Rheumatology. Psoriatic Arthritis. Available at: https://rheumatology.org/patients/psoriatic-arthritis . Last accessed: November 2023. 9 Scotti L, Franchi M, Marchesoni A, Corrao G. Prevalence and incidence of psoriatic arthritis: A systematic review and meta-analysis. Semin Arthritis Rheum. 2018 Aug;48(1):28-34. doi:10.1016/j.semarthrit.2018.01.003. 10 Arthritis Foundation. Psoriatic Arthritis. Available at: https://www.arthritis.org/diseases/psoriatic-arthritis . Last accessed: November 2023. 11 Mease P, Strand V, Gladman D. Functional impairment measurement in psoriatic arthritis: Importance and challenges. InSeminars in arthritis and rheumatism 2018 Dec 1 (Vol. 48, No. 3, pp. 436-448). WB Saunders. 12 Zhao SS, Miller N, Harrison N, Duffield SJ, Dey M, Goodson NJ. Systematic review of mental health comorbidities in psoriatic arthritis. Clinical Rheumatology. 2020 Jan;39:217-25. 13 Muromoto R, Oritani K, Matsuda T. Current understanding of the role of tyrosine kinase 2 signaling in immune responses. World J Biol Chem. 2022;13(1):1–14. doi:10.4331/wjbc.v13.i1.1. 14 Bunte K et al. Th17 Cells and the IL-23/IL-17 Axis in the Pathogenesis of Periodontitis and Immune Mediated Inflammatory Diseases. 2019 Intl J Molecular Sci. 15 Krueger JG, McInnes IB, Blauvelt A. Tyrosine kinase 2 and Janus kinase‒signal transducer and activator of transcription signaling and inhibition in plaque psoriasis. J Am Acad Dermatol. 2022;86(1):148-157. doi:10.1016/j.jaad.2021.06.869.. SOURCE: Takeda Pharmaceutical Co