IL36B

2023年11月，生物制药公司Argenx宣布其皮下注射剂efgartigimod治疗原发免疫性血小板减少症（ITP）3期临床ADVANCE-SC研究未达到主要终点。一个月后，Argenx公布其用于治疗成人寻常型天疱疮(PV)和落叶型天疱疮(PF)的3期ADDRESS研究也未达到主要和次要终点，当天股价大跌25%。2008年，Argenx成立于荷兰，专注于开发治疗癌症和自身免疫性疾病的差异化治疗抗体。2014年7月，Argenx在布鲁塞尔泛欧交易所成功IPO，募集资金4000万欧元。自2017年上市以来，短短两年公司市值就突破百亿美元。即便是遭受挫折的2023年，公司产品净销售额也达11.91亿美元，全球产品收入年均复合增长率达21%。与2022年相比，产品净销售额的增速虽减缓，整体仍呈直线上升趋势。 产品净销售额变化图（图源：Argenx官网）3期临床试验迭遭失败，在多个适应症上折戟，Argenx的产品净销售额却仍能达到近12亿美元。Argenx到底秉承怎样的开发策略，能在市场“如鱼得水”？治疗性抗体开发先驱+业务开发“老手”Argenx由Tim Van Hauwermeiren与Hans de Haard共同创办，总部位于荷兰，在美国、日本、瑞士和比利时均设有办事处。创始人的全球“足迹”为Argenx的全球布局打下了基础。Tim具有20多年的综合管理和业务开发经验，是比利时根特大学（Ghent University）的生物工程理学硕士，也是弗勒里克管理学院（The Vlerick School of Management）的高级管理人员工商管理硕士。 Tim Van Hauwermeiren（图源：Argenx官网）而Hans是荷兰马斯特里赫特大学分子免疫学博士，也是法国弗朗什孔泰大学免疫学教授。Hans自1989年以来一直活跃在抗体工程领域，无疑是抗体平台的先驱。他在马斯特里赫特大学创建了一个大型非免疫人类Fab库，该库后来成为生物制药公司Dyax的核心资产，并开发出多种治疗性抗体，包括IMC-1F8、具有高亲和力的人源化抗IGF-1R单克隆抗体IMC-A12和人血管内皮生长因子受体2（VEGFR2）拮抗剂ramucirumab（IMC-1121B）等。1998年至2002年，Hans在联合利华负责开发基于VHH（骆驼体内存在天然的缺失轻链的重链抗体，克隆其可变区可以得到只有重链可变区组成的单域抗体）的产品。在加入Argenx之前，Hans曾就职于纳米抗体创新药企Ablynx公司（2018年被赛诺菲以39亿欧元收购），负责建立Nanobody®发现引擎，并作为核心成员，参与开发基于B细胞选择的Nanoclone®方法。 Hans de Haard（图源：Argenx官网）专有平台生成多样化抗体库，Fc工程化技术扩大治疗指数Argenx能够取得良好市场表现，技术优势是重要因素。其中包括SIMPLE Antibody™平台、三项Fc工程化技术（NHANCE®、ABDEG™和POTELLIGENT®）和ENHANZESC®给药技术。以下逐一介绍。· SIMPLE Antibody™平台被誉为“沙漠之舟”的骆驼能够在恶劣环境中生活，即便体内检测出较高的病毒载量，却也极少表现出病症。这不禁让人产生疑问，骆驼科是否具有在其他物种中未广泛观察到的独特的适应性免疫学特征？其实，在骆驼的免疫系统中存在着与传统抗体结构不同的重链抗体（HCAb）和常规抗体（IgG1）两种结构的抗体。全球唯一一个基于美洲驼IgG1抗体V区（可变区）进行治疗性抗体药物开发的平台是SIMPLE Antibody™，它是Argenx的专有平台。骆驼科动物的IgG1抗体具有以下优势：①多样性程度高且具有高亲和力：骆驼科动物近交繁殖的比例较少，遗传背景差异大，对外源性抗原的免疫应答强。②人源化程度高：骆驼科IgG1抗体V区与人的抗体V区具有高结构同源性，后期人源化改造更简单，具有极高的治疗潜力。当美洲驼的免疫系统与人类疾病靶点产生免疫反应时，会生成高度多样化的抗体库，进而能够开发利用新型和基于复杂疾病生物学的靶点。· 三项Fc工程化技术（NHANCE®、ABDEG™和POTELLIGENT®）IgG1抗体包含两条轻链（由VL和CL结构域组成）和两条重链（由VH、CH1、铰链、CH2和CH3结构域组成），NHANCE®、ABDEG™和POTELLIGENT®技术可以工程化改造抗体的Fc段（CH2和CH3结构域），进而增强其内在的治疗特性。此外，Argenx还获得了日本中外制药株式会社关于SMART-Ig和ACT-Ig技术的非独家研究许可和选择权。这些技术使Argenx能够通过调节候选药物的半衰期、组织渗透、清除率和效力来扩大候选药物的治疗指数。IgG1抗体示意图（图源：Argenx官网）· ENHANZESC®给药技术Argenx与药物递送技术公司Halozyme Therapeutics在2019年2月宣布达成全球合作和许可协议，并于2020年10月扩大协议，授予Argenx对FcRn、C2靶点以及4个其他靶点ENHANZE®技术的独家使用权。ENHANZE®技术可以缩短给药时间，具有给药灵活性和便捷性。  上市首年获超4亿美元，布局广泛的临床适应症目前，Argenx具有超20条药物管线，其中2款产品VYVGART®和VYVGART®HYTRULO已上市，VYVGART®在上市首年（2022年）的全球产品净销售额达4.007亿美元。 2022年全球产品净销售额（图源：Argenx官网）2021年12月，FDA批准了Efgartigimod（VYVGART®，efgartigimod alfa-fcab）上市，用于治疗AChR抗体阳性的成年患者的全身性重症肌无力（gMG）。2022年1月，日本PMDA批准（VYVGART®，efgartigimod alfa-fcab）用于治疗对类固醇或非类固醇免疫抑制疗法（ISTs）没有充分应答的全身型重症肌无力（gMG）成人患者。由此，VYVGART®成为美国和日本第一个也是唯一一个获批的FcRn抑制剂。 VYVGART®（图源：Argenx官网）VYVGART®HYTRULO是一种靶向FcRn的含有efgartigimod alfa和hyaluronidase（重组人透明质酸酶PH20）两种成分的复方制剂。在VYVGART®的基础上改良并添加了可增强皮下组织通透性的hyaluronidase，进而改静脉注射为皮下注射制剂。2023年6月获FDA批准，用于治疗乙酰胆碱受体（AChR）抗体阳性的全身性重症肌无力症（gMG）成人患者。2024年1月，Argenx公司宣布日本厚生劳动省已经批准VYVDURA®用于皮下注射治疗对类固醇或非类固醇免疫抑制剂（ISTs）没有充分应答的全身型重症肌无力（gMG）成人患者。基于此，efgartigimod已在日本获批静脉输注剂型和皮下注射剂型两种给药方式。VYVGART®HYTRULO（图源：Argenx官网）Efgartigimod作为Argenx药物管线的“王牌”在研项目，是针对新生儿Fc受体(FcRn)设计的一类抗体片段。靶向FcRn的抗体，可以用于治疗存在致病性免疫球蛋白G（IgG）自身抗体的严重自身免疫性疾病患者。FcRn可以延长IgG的半衰期，Argenx的ABDEG™技术可以增强Efgartigimod与FcRn结合的亲和力，阻断IgG与FcRn结合，加速IgG降解，减少其再循环利用。如下图所示： Efgartigimod作用机制(图源：Argenx官网)与PD-1和TNF-α等有多个适应症的抗体药物相似，Efgartigimod具有“a pipeline in a drug”的潜质。这也就解答了文章开头所提出的问题，正是其广泛的临床适应症特性，能够让Argenx在gMG、慢性炎性脱髓鞘性多发性神经根神经病（CIDP）取得成功，但相继折戟ITP、PV和PF后，继续积极拓展其他多项适应症。 药物管线图（图源：Argenx官网）与多所高校共推免疫学创新计划（IIP），再鼎医药获独家授权合作据Argenx官网，其研发工作的主体不限于公司员工，还通过免疫学创新计划(IIP)与领先的学术研究人员合作，合作者包括哥伦比亚大学（Columbia University）、纽约大学医学院（NYU School of Medicine）及都灵大学（Turin University）等。IIP将免疫学领域的疾病生物学知识或疾病通路等学术突破转化为临床开发候选药物的途径，进而开发出新型抗体药物。如下图： 不完全IIP表（动脉网根据公开数据整理）除与学界的研发合作外，在当下的融资环境下，如License-out等的多种BD合作形式被Biotech看重。Argenx也不例外，公司探索出早期研发合作、成本分担合作及独家授权合作等合作方式。 近三年BD合作表（动脉网根据公开数据整理）2021年1月，Argenx与中国生物技术新锐再鼎医药（2017年9月在美国纳斯达克上市）就Efgartigimod达成独家授权合作。此后，再鼎医药不断加速Efgartigimod在我国的商业化进程。去年6月，Efgartigimod静脉注射剂型（商品名：卫伟迦®）获得中国国家药品监督管理局批准，与常规治疗药物联合，用于治疗AChR抗体阳性的成人gMG患者。去年7月，Efgartigimod皮下注射剂型用于治疗全身型重症肌无力的新药上市申请已获国家药品监督管理局受理。去年9月，国家药品监督管理局药品审评中心授予Efgartigimod皮下注射剂型突破性治疗认定，用于治疗慢性炎性脱髓鞘性多发性神经根神经病（CIDP）患者。卫伟迦®是国内首个、目前唯一获批的FcRn拮抗剂，并且于去年12月纳入我国医保。据《柳叶刀》（The Lancet）发表的研究数据，19种常见自身免疫病的发病率与患病率整体表现为随时间变化而增加的趋势，2017~2019年的整体患病率达11.0%。[1]自身免疫性疾病诱因众多，与年龄、性别、季节、共病等因素相关，难以采取预防措施。因此，靶向FcRn的新型抗体药物具有医疗需求。通过阻断FcRn与致病IgG抗体结合，可降低IgG抗体表达水平，进而达到治疗自身免疫疾病的目的。《“十四五”医药工业发展规划》中也提到了要推动医药创新产品产业化，重点发展针对自身免疫疾病等重大临床需求，以及罕见病治疗需求，具有新靶点、新机制的化学新药。在抗体药物领域，重点发展针对免疫类疾病等的新型抗体药物。去年6月，和铂医药宣布，国家药品监督管理局（NMPA）已受理公司在研药物巴托利单抗（HBM9161）治疗全身型重症肌无力（gMG）的生物制品许可申请（BLA）。今年2月，强生宣布，在研抗体nipocalimab在治疗成人全身性重症肌无力（gMG）成人患者的关键性3期临床试验VIVACITY中达到了主要终点，获得积极顶线结果。目前，我国在针对FcRn靶向新药这一赛道加码布局的企业不多，发展前景良好。参考文献：[1]Conrad N, Misra S, Verbakel JY, Verbeke G, Molenberghs G, Taylor PN, Mason J, Sattar N, McMurray JJV, McInnes IB, Khunti K, Cambridge G. Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK. Lancet. 2023 Jun 3;401(10391):1878-1890. 近期推荐声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。动脉网，未来医疗服务平台

今日（4月11日），中国国家药监局药品审评中心（CDE）官网公示，勃林格殷格翰（Boehringer Ingelheim）的BI655130注射液拟纳入突破性治疗品种，拟定适应症为预防泛发性脓疱性银屑病（GPP）发作。公开资料显示，BI655130注射液（即佩索利单抗，spesolimab）是勃林格殷格翰开发的一款靶向IL-36受体的单克隆抗体，此前已经在中国获批用于治疗成人GPP发作。 泛发性脓疱型银屑病（GPP）是一种罕见的、异质性的、危及生命的嗜中性粒细胞性皮肤病。患者的临床病程各不相同，有些患者的疾病复发并伴有反复急性发作，而另一些患者的疾病持续存在且间歇性急性发作。GPP急性发作若不及时治疗，出现败血症和多系统器官衰竭等并发症，可能会危及生命。 IL-36是树突细胞和T细胞的强效调节剂，参与树突细胞与辅助性T细胞的激活、抗原呈递和刺激促炎因子产生。研究表明，IL-36在皮肤中大量表达，并在银屑病等皮肤病发病机制中扮演重要角色。 佩索利单抗（曾用名：司柏索利单抗）是一种人源化拮抗性单克隆IgG1抗体，可与白介素-36受体（IL-36R）结合并阻断人IL-36α、IL-36β和IL-36γ诱导的IL-36R活化，从而抑制炎症性皮肤病中的促炎和促纤维化通路。根据勃林格殷格翰早前发布的新闻稿，佩索利单抗是专门靶向IL-36通路治疗GPP急性发作的在研疗法。2022年9月，该产品获FDA批准上市，用于治疗GPP发作。 同年12月，该产品在中国获批，用于治疗成人GPP发作。目前，佩索利单抗还在被开发用于预防GPP急性发作以及治疗其他嗜中性粒细胞性皮肤病，如掌跖脓疱病和化脓性汗腺炎。根据中国药物临床试验登记与信息公示平台，勃林格殷格翰已经完成一项国际多中心（含中国）2期临床研究，研究旨在评估佩索利单抗是否能够预防GPP患者病情急性发作。 2023年2月，勃林格殷格翰宣布佩索利单抗的一项2b期临床试验（EFFISAYIL 2试验）达到了主要和关键次要终点。该研究用于评估皮下注射佩索利单抗阻止青少年和成人GPP发作的疗效和持续控制GPP症状的有效性和安全性。结果显示，该产品能够避免青少年和成人泛发性脓疱性银屑病（GPP）的发作长达48周。 据勃林格殷格翰早先新闻稿介绍，令人感到疼痛的GPP的发作可能会突然发生，并因迅速加剧而需要紧急就医。这使得人们焦虑且对未来感到不确定。预防GPP发作使患者能够计划他们的生活，不再担心他们的疾病。 参考资料：[1]中国国家药监局药品审评中心（CDE）官网. Retrieved Apr 11， 2023, from https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c [2] Spesolimab meets primary and key secondary endpoint for prevention of generalized pustular psoriasis flares. Retrieved February 2, 2023, from https://www.businesswire.com/news/home/20230129005023/en 内容来源于网络，如有侵权，请联系删除。

INGELHEIM, Germany I December 13, 2022 I The European Commission (EC) granted a conditional marketing authorization for Boehringer Ingelheim’s spesolimab as first in class treatment for GPP flares in adults. 1 Spesolimab is a novel, selective antibody that blocks the activation of the interleukin-36 receptor (IL-36R), a signaling pathway within the immune system shown to be involved in the pathogenesis of GPP. 2, 4-7 “The symptoms of GPP are devastating and cause immense pain as well as hospitalization during a flare. Increased GPP awareness that leads to accurate and faster diagnosis is one important step to improving the quality of life for people living with GPP,” said Frida Dunger Johnsson, Executive Director, IFPA. “Now with a specifically developed treatment, people living with GPP can be offered a new lease of life by effectively managing the impact of GPP flares.” “We are delighted to be able to bring this much needed treatment to patients with GPP, whose options were incredibly limited until this year. This approval marks another significant milestone in the continued development of spesolimab in neutrophilic skin diseases which we are investigating in further clinical trials” commented Carinne Brouillon, Member of the Board of Managing Directors, responsible for Human Pharma, Boehringer Ingelheim. “Today’s news marks the first of what we hope will be a number of new treatment options from our accelerated late-stage portfolio with the potential to transform the lives of people for generations to come.” The EC’s conditional approval of spesolimab is based on results from the pivotal EFFISAYIL ® 1 Phase II clinical trial. 2 In the 12-week trial, patients experiencing a GPP flare were treated with spesolimab or placebo. Most patients at the outset of the trial had a moderate or severe pustulation of the skin. After one week, 54% of patients treated with a single dose of spesolimab showed no visible pustules compared to placebo (6%). 2 Adverse events were reported in 66% of patients treated with spesolimab and 56% of those receiving placebo after one week. 2 Infections were reported by 17% and 6% of patients in the spesolimab and placebo groups respectively (at week one). 2 Serious adverse events were reported in 6% of patients treated with spesolimab (at week one). 2 People living with GPP often do not receive a correct or timely diagnosis and may have their symptoms identified as other forms of psoriasis. A Global Delphi Consensus Project classified GPP as phenotypically, genetically, immunologically and histopathologically distinct from psoriasis vulgaris / plaque psoriasis based on a systematic literature review. 3 The growing list of regulatory approvals for spesolimab for the treatment of GPP flares underlines that the Delphi panel’s vision of improved diagnosis and treatment for people with GPP is increasingly achievable. About SPEVIGO ® SPEVIGO ® (spesolimab) is a novel, humanized, selective antibody that blocks the activation of the interleukin-36 receptor (IL-36R), a signaling pathway within the immune system shown to be involved in the pathogenesis of several autoinflammatory diseases, including GPP. 2, 4-7 It is the first treatment to specifically target the IL-36 pathway for the treatment of GPP flares that has been evaluated in a statistically powered, randomized, placebo-controlled trial. Spesolimab is also under investigation for the prevention of GPP flares and for the treatment of other neutrophilic skin diseases. 8,9 About the EFFISAYIL ® 1 clinical trial 2 EFFISAYIL ® 1 (NCT03782792) was a 12-week, Phase II trial investigating patients with a GPP flare (N=53), randomly assigned 2:1 to a single 900 mg intravenous dose of spesolimab or placebo. 2 After one week, 54% of patients treated with spesolimab showed no visible pustules, compared to 6% of patients treated with placebo. 2 After 12 weeks more than 4 out of 5 patients (84.4%) had no visible pustules and clear/almost clear skin (81.3%). 9 Adverse events were reported in 66% of patients treated with spesolimab and 56% of those receiving placebo after one week. Infections were reported by 17% and 6% of patients in the spesolimab and placebo groups respectively (at week one). Serious adverse events were reported in 6% of patients treated with spesolimab (at week one). 2 About generalized pustular psoriasis (GPP) GPP is a rare, heterogenous and potentially life-threatening neutrophilic skin disease, which is clinically distinct from plaque psoriasis. 4, 11 GPP is caused by neutrophils (a type of white blood cell) accumulating in the skin, resulting in painful, sterile pustules all over the body. 4, 11 The clinical course varies, with some patients having a relapsing disease with recurrent flares, and others having a persistent disease with intermittent flares. 11 While the severity of GPP flares can vary, if left untreated they can be life-threatening due to complications such as sepsis and multisystem organ failure. 4 This chronic, systemic disease has a substantial quality of life impact for patients and places an increased burden on healthcare systems. 12 GPP has a varied prevalence across different geographical regions and more women are affected than men. 4, 12-14 There is a high unmet need for treatments with an acceptable safety profile that can rapidly resolve the symptoms of GPP flares and prevent their reoccurrence. 3 GPP flares can lead to hospitalization with serious complications, including heart failure, renal failure and sepsis, with the unpredictability and severity of these flares greatly affecting a person’s quality of life. 4 About Boehringer Ingelheim Boehringer Ingelheim is working on breakthrough therapies that transform lives, today and for generations to come. As a leading research-driven biopharmaceutical company, the company creates value through innovation in areas of high unmet medical need. Founded in 1885 and family-owned ever since, Boehringer Ingelheim takes a long-term perspective. More than 52,000 employees serve over 130 markets in the three business areas, Human Pharma, Animal Health, and Biopharmaceutical Contract Manufacturing. Learn more at www.boehringer-ingelheim.com . References 1.    EC approval statement (data on file) 2.    Bachelez H et al. Trial of Spesolimab for Generalized Pustular Psoriasis. NEJM . 2021;385:2431-40. 3.    Puig L, et al. Global consensus on the clinical course, treatment and management of generalized pustular psoriasis (GPP). Presented at the European Academy of Dermatology and Venereology (EADV) Congress, Milan, Italy, 7–10 September 2022: P1203.B. 4.    Crowley JJ, et al. A brief guide to pustular psoriasis for primary care providers, Postgrad Med. 2021;133(3):330-344. 5.    Federal Drug Administration. New Drug Approvals for 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761244s000lbl.pdf . Accessed September 2022. 6.    Furue K, et al. Highlighting Interleukin-36 Signalling in Plaque Psoriasis and Pustular Psoriasis. Acta Derm Venereol . 2018;98:5–13. 7.    CHMP positive opinion. Available at: https://www.ema.europa.eu/en/medicines/human/summaries-opinion/spevigo . Accessed November 2022. 8.    ClinicalTrials.gov. A Study to Test Whether Spesolimab Helps People With a Skin Disease Called Hidradenitis Suppurativa. Available at: https://clinicaltrials.gov/ct2/show/NCT04762277 . Accessed October 2022. 9.    Elewski B, et al. Sustained treatment effect of spesolimab over 12 weeks for generalized pustular psoriasis flares; results from the Effisayil 1 study. AAD Congress 2022 , Poster 32924. 10.    Navarini AA, et al. European consensus statement on phenotypes of pustular psoriasis. JEADV . 2017;31:1792-1799. 11.    Hanna M, et al. Economic burden of generalized pustular psoriasis and palmoplantar pustulosis in the United States. Curr Med Res Opin . 2021. 37(5):735-742. 12.    Augey F, et al. Generalized pustular psoriasis (Zumbusch): a French epidemiological survey. Eur J Derm . 2006; 16(6):669-673. 13.    Jin H, et al. Clinical features and course of generalized pustular psoriasis in Korea. J Dermatol . 2015; 42(7):674-678. SOURCE: Boehringer Ingelheim