更新于：2024-11-01

IL-31RA

更新于：2024-11-01

基本信息

别名

CRL、CRL3、Cytokine receptor-like 3

+ [14]

简介

Associates with OSMR to form the interleukin-31 receptor which activates STAT3 and to a lower extent STAT1 and STAT5 (PubMed:11877449, PubMed:14504285, PubMed:15627637, PubMed:15194700). May function in skin immunity (PubMed:15184896). Mediates IL31-induced itch, probably in a manner dependent on cation channels TRPA1 and TRPV1 (By similarity). Positively regulates numbers and cycling status of immature subsets of myeloid progenitor cells in bone marrow in vivo and enhances myeloid progenitor cell survival in vitro (By similarity).

关联

项与 IL-31RA 相关的药物

Nemolizumab

尼莫利珠单抗

靶点

IL-31RA

作用机制

IL-31RA抑制剂

在研机构

Maruho Co., Ltd. [+3]

原研机构

Chugai Pharmaceutical Co., Ltd.

在研适应症

结节性痒疹 [+3]

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

日本

首次获批日期2022-03-28

项与 IL-31RA 相关的临床试验

JPRN-jRCT2021230034 / Suspended临床2期IIT

A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Nemolizumab in Patients with Acquired Reactive Perforating Collagenosis

开始日期2023-11-09

申办/合作机构-

JPRN-jRCT2031230174 / Recruiting临床3期IIT

A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-Center Study to Evaluate the Efficacy and Safety of nemolizumab in Japanese Infant and Pediatric Atopic Dermatitis Patients with moderate to severe pruritus

开始日期2023-06-25

申办/合作机构-

NCT05056779 / Withdrawn临床3期

A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Nemolizumab in Subjects With Moderate-to-Severe Atopic Dermatitis With Inadequate Response to or for Whom Cyclosporine A is Not Medically Advisable

The primary objective of this study is to investigate the efficacy of nemolizumab administered in combination with topical background therapy (topical corticosteroids [TCS] with or without topical calcineurin inhibitors [TCI]) in adult participants with moderate-to-severe atopic dermatitis (AD) who are not adequately controlled with or are not advised to use oral cyclosporine A (CsA) for medical reasons. The secondary objective is to investigate the safety of nemolizumab in adult participants with moderate-to-severe AD who are not adequately controlled with or are not advised to use oral CsA for medical reasons.
The study will be carried out in up to 70 different locations across Europe.

开始日期2023-01-01

申办/合作机构

Galderma Holding SA

100 项与 IL-31RA 相关的临床结果

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100 项与 IL-31RA 相关的转化医学

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0 项与 IL-31RA 相关的专利（医药）

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1,496

项与 IL-31RA 相关的文献（医药）

2025-01-01·Journal of Ethnopharmacology

Jieduquyuziyin prescription alleviates lupus development via inhibiting neddylation pathway to promote Bim-induced apoptosis of double negative T cells

Article

作者: Li, Yiping ; Wang, Chenxi ; Li, Suling ; Huang, Lin ; Jiang, Zhangsheng ; Zhang, Yun ; Duan, Qingchi ; Wen, Chengping ; Ruan, Xinyi ; He, Zhixing ; Du, Lijun

ETHNOPHARMACOLOGICAL RELEVANCEJieduquyuziyin prescription (JP) is an empirical prescription approved for application to treat systemic lupus erythematosus (SLE) in hospital within China. Despite the prominent treatment effect of JP clinically, further investigation is imperative to explore its underlying mechanisms.AIM OF THE STUDYWe aim to investigate the impact of JP on DN T cell apoptosis in the treatment of SLE and the specific regulation mechanisms.MATERIALS AND METHODSFirstly, female MRL/lpr mice were treated with JP and the therapeutic efficacy of JP was evaluated via skin lesions, lymphoid organ enlargement, accumulation of autoantibodies and renal function. Then, flow cytometer analysis was performed to evaluate the proportions and the apoptosis of T cell subpopulations. Based on the above results, double-negative (DN) T cells were subjected to proteomic with subsequent differential screening. The expression of Ube2m and Bim was further validated using real-time PCR and Western blot. Subsequently, DN T cells were incubated with JP-contained serum in vitro, and cell apoptosis was quantified using flow cytometry. Additionally, the expression levels of Ube2m, Bim and other associated proteins were also assessed through western blotting. To further clarify whether Ube2m serves as the key target of JP in regulating DN T cell apoptosis, the mice that Ube2m was specific deleted in T cells with spontaneous lupus (Ube2m^-/-lpr) were utilized. JP was administered to WTlpr or Ube2m^-/-lpr mice, followed by assessment of the lupus condition and DN T cell apoptosis.RESULTSJP administration effectively ameliorated the lupus phenotype. Then flow cytometry assay showed that JP treatment enhanced DN T cell apoptosis to reduce their accumulation and restored the immune homeostasis. Proteomic analysis revealed a significant inhibition of Ube2m for JP treatment, which is essential for maintaining homeostasis of DN T cells. Further experiments confirmed that JP treatment effectively downregulated the expression of Ube2m and subsequently upregulated the level of pro-apoptotic protein Bim with decreased Bim degradation. In vitro experiments also confirmed that JP-contained serum significantly facilitated DN T cell apoptosis and reduced DN T cell accumulation by inhibiting Ube2m expression. Furthermore, Ube2m^-/-lpr mice were utilized and the impact of JP treatment on the apoptosis of DN T cells was found to be minimal in the absence of Ube2m. Mechanistic investigation reveals that JP exerts its effects by suppressing the expression of Ube2m, subsequently inhibiting CRL-dependent degradation of Bim, and ultimately promoting Bim-induced apoptosis in DN T cells. Furthermore, the blockade of Ube2m in T cells effectively prevents JP-induced apoptosis in DN T cells, underscoring Ube2m as one crucial therapeutic target of JP in mediating DN T cell apoptosis and managing SLE.CONCLUSIONSOur findings indicate that JP treatment effectively restores the homeostasis of DN T cells in SLE by inhibiting Ube2m expression, thereby reducing Bim ubiquitination degradation. This ultimately enhanced DN T cell apoptosis and alleviated lupus phenotype.

2024-12-01·Cytokine

Synthetic trimeric interleukin-6 receptor complexes with a STAT3 phosphorylation dominated activation profile

Article

作者: Floss, Doreen M. ; Floss, Doreen M ; Pudewell, Silke ; Lang, Alexander ; Weitz, Hendrik T. ; Weitz, Hendrik T ; Seibel, Christiane ; Scheller, Jürgen ; Rafii, Puyan ; Köhrer, Karl ; Petzsch, Patrick ; Ettich, Julia

In Interleukin (IL)-6 signalling, IL-6 site I binds to the IL-6 receptor (IL-6R) first, following by IL-6 site II interaction to domain 2/3 of gp130 to form premature trimeric IL-6:IL-6R:gp130 receptor complexes. Formation of the mature hexameric receptor complex is then facilitated by the inter-trimeric interaction of IL-6 site III with domain 1 of the opposing gp130. The two gp130-associated Janus kinases (JAKs) trans-phosphorylate when their spatiotemporal pairing is correct, which causes the activation of STAT, ERK, and AKT pathways in a balanced manner. Since the intracellular domain (ICD) of IL-6R is not needed for STAT/ERK/AKT phosphorylation, we investigated the conditions under which a chimeric IL-6R_ECD-gp130_TMD/ICD receptor protein confers biological activity. For IL-6R_ECD-gp130_TMD/ICD, the extracellular domain (ECD) of IL-6R was fused to the transmembrane domain (TMD) and ICD of gp130. Co-expression of IL-6R_ECD-gp130_TMD/ICD with signalling-deficient gp130 variants did not induce IL-6 signalling, suggesting that the assembly of hexameric complexes failed to dimerize the IL-6R-associated JAKs correctly. By mimicking the premature trimeric receptor complex, IL-6-mediated dimerization of IL-6R_ECD-gp130_TMD/ICD with the single-cytokine-binding variant gp130_ΔD1 induced signalling. Of note, IL-6 signalling via these synthetic gp130_ΔD1:IL-6R_ECD-gp130_TMD/ICD complexes resulted predominantly in STAT3 phosphorylation. A STAT3-dominated profile was also observed after IL-6-induced signalling mediated by a JAK-deficient IL-6R_ECD-gp130_TMD/ICDΔJAK variant in complex with the JAK-proficient but STAT/ERK/AKT-deficient gp130_JAKΔICD variant. Our data showed that effective ERK/AKT signalling could not be executed after intracellular domain swapping from gp130 to the IL-6R. Taken together, the chimeric IL-6R/gp130 receptor may be helpful in the creation of customized synthetic IL-6 signalling.

2024-11-01·Phytomedicine

Chaiqin chengqi decoction treatment mitigates hypertriglyceridemia-associated acute pancreatitis by modulating liver-mediated glycerophospholipid metabolism

Article

作者: Cai, Wenhao ; Liu, Tingting ; Windsor, John A. ; Wang, Qiqi ; Luo, Wenjuan ; Mukherjee, Rajarshi ; Xia, Qing ; Wang, Wen ; Zhong, Shaoqi ; Yao, Linbo ; Huang, Lijia ; Li, Yuying ; Phillips, Anthony R. ; Phillips, Anthony R ; Xue, Jing ; Hong, Jiwon ; Deng, Dan ; Yang, Xinmin ; Sutton, Robert ; Jin, Tao ; Sun, Xin ; Windsor, John A ; Li, Fei ; Huang, Wei ; Wen, Yongjian

BACKGROUNDThe incidence of hypertriglyceridemia-associated acute pancreatitis (HTG-AP) is increasing globally and more so in China. The characteristics of liver-mediated metabolites and related key enzymes are rarely reported in HTG-AP. Chaiqin chengqi decoction (CQCQD) has been shown to protect against AP including HTG-AP in both patients and rodent models, but the underlying mechanisms in HTG-AP remain unexplored.PURPOSETo assess the characteristics of liver-mediated metabolism and the therapeutic mechanisms of CQCQD in HTG-AP.METHODSMale human apolipoprotein C3 transgenic (hApoC3-Tg; leading to HTG) mice or wild-type littermates received 7 intraperitoneal injections of cerulein (100 μg/kg) to establish HTG-AP and CER-AP, respectively. In HTG-AP, some mice received CQCQD (5.5 g/kg) gavage at 1, 5 or 9 h after disease induction. AP severity and related liver injury were determined by serological and histological parameters; and underlying mechanisms were identified by lipidomics and molecular biology. Molecular docking was used to identify key interactions between CQCQD compounds and metabolic enzymes, and subsequently validated in vitro in hepatocytes.RESULTSHTG-AP was associated with increased disease severity indices including augmented liver injury compared to CER-AP. CQCQD treatment reduced severity and liver injury of HTG-AP. Glycerophospholipid (GPL) metabolism was the most disturbed pathway in HTG-AP in comparison to HTG alone. In HTG-AP, the mRNA level of GPL enzymes involved in phosphocholine (PC) and phosphatidylethanolamine (PE) synthesis (Pcyt1a, Pcyt2, Pemt, and Lpcat) were markedly upregulated in the liver. Of the GPL metabolites, lysophosphatidylethanolamine LPE(16:0) in serum of HTG-AP was significantly elevated and positively correlated with the pancreas histopathology score (r = 0.65). In vitro, supernatant from Pcyt2-overexpressing hepatocytes co-incubated with LPE(16:0) or phospholipase A2 (a PC- and PE-hydrolyzing enzyme) alone induced pancreatic acinar cell death. CQCQD treatment downregulated PCYT1a and PCYT2 enzyme levels in the liver. Hesperidin and narirutin were identified top two CQCQD compounds with highest affinity docking to PCYT1a and PCYT2. Both hesperidin and narirutin reduced the level of some GPL metabolites in hepatocytes.CONCLUSIONLiver-mediated GPL metabolism is excessively activated in HTG-AP with serum LPE(16:0) level correlating with disease severity. CQCQD reduces HTG-AP severity partially via modulating key enzymes in GPL metabolism pathway.

项与 IL-31RA 相关的新闻（医药）

2024-10-22

·EndPoints

FDA hits Camurus with CRL for acromegaly therapy over manufacturing issues

The FDA handed a CRL to the Swedish biotech Camurus for its hormone disorder therapy over “facility-related deficiencies” at a third-party manufacturer. The therapy, dubbed CAM2029, had a PDUFA date of Oct. 21 for acromegaly, but production issues were found at a third-party factory in September. There were no issues with the candidate’s efficacy or safety, Camurus said in a Tuesday release. CAM2029 does not have a new decision date, but Camurus said “timely resolution of the CRL” will depend on the unnamed third-party manufacturer’s responses. Labeling discussions for the asset were already in the final stages when the CRL was given, the company said. Acromegaly occurs when the body makes too much growth hormone, which leads to abnormally large hands and feet. Subcutaneously administered CAM2029 features a peptide inhibitor of growth hormones called octreotide. Camurus announced data from a pair of Phase 3 trials investigating CAM2029 in June and July 2023, showing acromegaly symptoms improved in patients. In May, Camurus said the EMA had received its regulatory application. Jefferies analysts said the delay could lead to Camurus launching its drug later than expected. Crinetics Pharmaceuticals has its own acromegaly candidate and announced the submission of its FDA application last month. CAM2029 is also being investigated for gastroenteropancreatic neuroendocrine tumors and polycystic liver disease.

临床3期申请上市

2024-08-27

·CPHI制药在线

结节性痒疹新药Nemluvio获FDA批准创新预充式皮下注射装置

关注并星标CPHI制药在线 2024年8月13日，全球知名医疗科技公司Galderma官方宣告，美国食品药品监督管理局（FDA）已正式接纳并授权Nemluvio（学名nemolizumab）投入市场，专项应用于治疗罹患结节性痒疹（PN）的成人患者群体。先前的第3期临床试验数据彰显了显著疗效——在接受Nemluvio治疗短短四周后，患者们的瘙痒感受即迎来了大幅度减轻的积极转变。这一公告中还提到，Nemluvio是首款获FDA批准的靶向IL-31信号途径的单克隆抗体疗法。结节性痒疹作为一种复杂的神经性免疫皮肤疾患，以其慢性和极具削弱性的特质，给患者的日常生活带来深远影响。它不仅涉及到难以忽视的二型炎症反应，更是在众多炎症性皮肤问题中，位列对生活质量负面冲击的顶尖位置。受结节性痒疹困扰的人们往往面临着持续剧烈的瘙痒折磨以及身体多处出现的皮肤增生结节（亦称结节性病变），且这一现象严重扰乱了他们的睡眠质量。以往，为缓解这一痛苦，患者不得不长期依赖于高强度的外用类固醇类药物，但这同样伴随着长期用药安全性的隐患与顾虑。在科学研究的探索中，IL-31被识别为包括过敏性皮炎和结节性痒疹等多种皮肤病发病机制中的核心分子之一。它不仅能直接作用于引发瘙痒的感觉神经，诱发并加剧炎症反应，同时还会对皮肤的防御屏障功能造成破坏。因此，IL-31作为免疫系统与神经系统之间的关键媒介或“桥梁”，其在调控作用上的特殊性使其成为了对抗炎症性皮肤病症的一大创新靶点。而Nemluvio的诞生，正是针对这一重要机制的精准施策，标志着皮肤科治疗领域的一大进展。关于结节性痒疹结节性痒疹，又称prurigo nodularis（PN），是一种顽固的慢性皮肤病症，其典型特征为多发性、质地坚硬、颜色从肤色到淡红色的结节状皮损，尤好发于四肢伸展部位。此病症常见于各个年龄层，且常伴随强烈瘙痒感，往往与特应性皮炎等皮肤过敏反应紧密相连。确诊依据主要依赖于临床表现，并需排除其他类似症状的疾病。PN不仅关乎皮肤健康，还常伴随显著的身心困扰，如治疗抵抗、睡眠障碍、社交隔阂以及情绪问题如焦虑和抑郁，严重影响患者的生活质量。关于PN的成因，目前仍缺乏明确答案。主流观点认为，其源于神经系统与免疫系统功能的不平衡，形成了慢性瘙痒与反复搔抓的恶性循环，进而诱发皮肤上的继发性反应。约半数患者此前即患有其他皮肤病，特别是特应性皮炎，偶尔也见于淤积性皮炎、单纯性苔藓等疾病。同时，约三分之一的病例与代谢异常有关，涵盖营养不良、肝功能障碍、尿毒症、甲状腺失衡、高钙血症、神经系统病变及淋巴瘤等。此外，还有部分患者可能因精神因素而罹患PN，如抑郁症、焦虑症等。值得注意的是，约5%的HIV感染者也会出现PN症状。流行病学数据显示，在美国约有181,000人正受到结节性痒疹的困扰；而在中国，该疾病的患者数量相对稳定，从2017年至2021年间约有190万人受其影响，并预测至2030年将达到约210万例。对于缓解PN患者的剧烈瘙痒，常见治疗方案包括使用局部药物如抗组胺药膏、类固醇软膏及局部麻醉剂，以及口服抗组胺药、类固醇药物和阿片受体激动剂。然而，鉴于局部类固醇和麻醉剂等治疗手段可能带来的副作用，建议在使用时应严格控制时间与剂量。关于Nemolizumab Nemolizumab，作为一款创新的预充式皮下注射装置，其核心功能在于特异性地阻断IL-31细胞因子信号路径，从而在结节性痒疹的病理过程中发挥作用，包括炎症反应的调节、表皮分化异常的改善以及纤维化（皮肤结缔组织的硬化）的缓解。该药物的研发最初由中外制药引领，随后于2016年，Galderma公司取得了在全球范围内（除日本与中国台湾外）独家开发并销售该药物的权益。至2022年3月，nemolizumab在日本市场上获得批准，以Mitchga为商品名，专门用于治疗结节性痒疹，同时扩展至治疗儿童及成年患者因特应性皮炎引发的瘙痒症状。值得一提的是，该药物早在2019年12月便荣获美国FDA的突破性疗法认定，并在接下来的2024年2月进一步获得了优先审评的地位，这一系列的进展均基于其III期临床试验OLYMPIA的显著成效。 OLYMPIA研究包括OLYMPIA 1（为期16周）和OLYMPIA 2（为期24周）两项子研究，它们共同评估了nemolizumab每四周皮下注射一次对于超过500名结节性痒疹患者的疗效与安全性。这两项研究均不仅实现了预先设定的主要疗效终点，还显著达成了所有的关键次要终点，其规模之大在结节性痒疹（PN）研究领域内前所未有，且是唯一包含了长期随访扩展计划的临床试验。特别是在疗效评估上，OLYMPIA 1和OLYMPIA 2均展现出令人鼓舞的结果：接受Nemluvio（nemolizumab的另一种称谓）治疗的患者中，分别有56%和49%在第16周时，其瘙痒严重程度根据峰值瘙痒数值评定量表衡量，下降了至少4分，相比之下，两个安慰剂组的改善比例仅为16%，统计学差异极为显著（p<0.001）。此外，在早期疗效观察中，即从治疗第4周开始，就有高达41%的患者报告了至少4分的瘙痒减轻，而在相应的安慰剂组中，这一比例仅为6%和7%，同样展现出显著的统计学差异（p<0.001）。在OLYMPIA 1及OLYMPIA 2临床研究中，接受Nemluvio治疗的群体，于第16周时，分别有26%及38%的患者实现了皮肤结节的完全清除（基于IGA评分为0）或近乎完全清除（IGA评分为1），相较之下，安慰剂组的数据分别为7%和11%，差异显著（p<0.001），从而达到了预设的主要疗效里程碑。同时，针对睡眠障碍的改善，Nemluvio治疗组中50%至52%的患者在第16周时，其睡眠障碍数值评定量表上的得分至少下降了4个单位，相比之下，安慰剂组仅12%至21%的患者达到此改善程度（p<0.001），成功达成了另一项关键的次要疗效指标。值得注意的是，两项试验均迅速显现出对结节性痒疹引起的瘙痒和睡眠障碍的显著改善，这种改善在治疗的最初四周内便已显现，并满足了所有其他关键次要疗效终点。Nemluvio展现出良好的耐受性，其在OLYMPIA 1与OLYMPIA 2中的安全性表现与之前的2期临床试验结果相吻合。作为一类创新性的单克隆抗体，Nemluvio通过特异性地结合IL-31受体α，有效阻断了IL-31的信号传递路径。这款药物由中外制药株式会社率先研发，在日本以Mitchga为商品名上市，专用于治疗结节性痒疹及相关瘙痒症状，覆盖儿童、青少年及成人患者群体。Nemluvio已赢得美国FDA的突破性疗法认定（BTD）并于今年早些时候获得了治疗结节性痒疹的优先审评地位。此外，Nemluvio针对中度至重度特应性皮炎的生物制品许可申请亦在美国FDA的审评流程中，预计今年稍后时间将揭晓结果。与此同时，Galderma正积极推动Nemluvio在全球范围内的上市进程，包括向欧洲药品管理局（EMA）、加拿大卫生部，以及澳大利亚、新加坡、瑞士和英国等国的监管机构提交上市许可申请。展望2024年，更多国家和地区的监管机构将成为Nemluvio申请的下一个目标。关于IL-31 IL-31，隶属于IL-6细胞因子家族的关键成员，其核心产生源头聚焦于CD4+ T淋巴细胞。科学研究表明，除T细胞外，单核/巨噬细胞系列、树突状细胞、肥大细胞及嗜酸、嗜碱性粒细胞，乃至成纤维细胞和角质细胞等多类免疫与结构细胞均能分泌此因子。IL-31行使其生物功能的主要路径是通过与特定受体——即由IL-31受体A(IL-31RA)与瘤抑素M受体β(OSMRβ)组成的异二聚体复合物结合而实现的。这种受体复合体在多个系统如皮肤、神经、呼吸及消化系统中广泛且高量表达，且紧密关联于多种病理状态如AD（特应性皮炎）、PN（神经性皮炎）、哮喘及原发性胆管炎的发生与演进过程。在功能上，IL-31展现了多重调节作用，涵盖促进细胞增殖分化及诱导多种细胞因子的表达，从而影响免疫及神经细胞的行为。特别值得注意的是，其在引发瘙痒方面的角色，这一过程通常不通过组胺介导，而是直接与目标瘙痒感觉神经上的IL-31RA亚单位结合，触发OSMRβ的异构活化，并通过一系列复杂的信号传导通路（如JAK/STAT、PI3K/AKT、MAPK-JNK/p38）来上调TRPV1与TRPA1的表达水平，从而增强神经元对刺激的反应性。尽管这种机制的响应时间较为延迟，需要数小时才能显著显现，但IL-31确以此为主要模式推动了慢性或后期瘙痒的发展。此外，作为一类关键的炎症介质，IL-31还参与调节免疫细胞间的交互作用。研究揭示，它能够激励人角质细胞分泌诸如CCL17、CCL22的趋化因子，进而引发IL-6、IL-8、IL-32及血管内皮生长因子等一系列细胞因子与基质金属蛋白酶的释放。这些反应共同指向了IL-31在召集炎症细胞、加速血管生成以及促进炎症反应方面的潜在贡献，彰显了其在炎症反应调节网络中的重要地位。参考资料 [1]公司官网 [2]孙小洁,林彤.IL-31及其受体在皮肤病发生及治疗中的研究进展[J].中国皮肤性病学杂志,2024,38(06):696-699+704.DOI:10.13735/j.cjdv.1001-7089.202212022. [3] approval for Nemluvio® (nemolizumab) for adult patients living with prurigo nodularis. Retrieved August 13, 2024 from https://www.galderma.com/news/galderma-receives-us-fda-approval-nemluvior-nemolizumab-adult-patients-living-prurigo [4] A Phase 3, Placebo-controlled, Double-blind Study Assessing Rocatinlimab in Prurigo Nodularis. Retrieved August 13, 2024 from https://clinicaltrials.gov/study/NCT06527404?term=rocatinlimab&intr=prurigo%20nodularis&rank=1 [5] Collaborating to Address Moderate to Severe Atopic Dermatitis. Retrieved August 13, 2024 fromhttps://www.amgen.com/stories/2023/01/collaborating-to-address-moderate-to-severe-atopic-dermatitis [6] A Study to Evaluate the Efficacy and Safety of Ruxolitinib Cream in Participants With Prurigo Nodularis (PN) (TRuE-PN2). Retrieved August 13, 2024 from https://clinicaltrials.gov/study/NCT05764161?term=ruxolitinib%20&intr=prurigo%20nodularis&rank=2 [7] A Study to Evaluate the Safety and Efficacy of Ruxolitinib Cream in Participants With Prurigo Nodularis (PN) (TRuE-PN1). Retrieved August 13, 2024 from https://clinicaltrials.gov/study/NCT05755438?term=ruxolitinib%20&intr=prurigo%20nodularis&rank=3 [8] Incyte Presents New Late-Breaking Data from Phase 2 Study Evaluating Povorcitinib in Patients with Prurigo Nodularis. Retrieved August 13, 2024 from https://investor.incyte.com/news-releases/news-release-details/incyte-presents-new-late-breaking-data-phase-2-study-evaluating [9] A Study to Evaluate the Efficacy and Safety Study of Povorcitinib in Participants With Prurigo Nodularis (STOP-PN1). Retrieved August 13, 2024 from https://clinicaltrials.gov/study/NCT06516952?term=INCB-054707&intr=prurigo%20nodularis&rank=2 END END END 【智药研习社直播预告】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~

临床3期

2024-08-14

·凯莱英药闻

全球首款IL-31药物获FDA批准上市！结节性痒疹患者终迎创新疗法

欢迎关注凯莱英药闻 2024年8月13日，Galderma公司宣布，美国食品药品监督管理局 (FDA) 已批准Nemluvio (nemolizumab)的上市申请，用于治疗结节性痒疹（PN）成人患者。该药物是首个获FDA批准上市的IL-31药物。关于Nemolizumab Nemolizumab是一种预充式皮下注射笔，通过特异性抑制 IL-31 细胞因子信号传导，参与结节性痒疹的炎症、表皮分化改变和纤维化（皮肤组织硬化）。该药物最初由中外制药开发，2016 年，Galderma 获得了除日本和台湾以外全球范围内开发和销售nemolizumab 的独家权利。2022年3月，nemolizumab在日本获批（商品名：Mitchga），用于治疗结节性痒疹以及儿童、青少年和成人患者的特应性皮炎相关瘙痒症。2019 年 12 月，该药物获得FDA 突破性疗法认定，并于 2024 年 2 月获得优先审查资格。此次批准是基于 III 期 OLYMPIA 临床试验的积极结果。 OLYMPIA 1（16周）和 OLYMPIA 2（24周）III 期临床试验评估了每四周皮下注射一次nemolizumab对 500 多名结节性痒疹患者的疗效和安全性，试验均达到了主要终点和关键次要终点；这是迄今为止在PN领域开展的规模最大的临床试验，也是唯一包含长期扩展研究计划的试验。具体数据包括：在OLYMPIA 1 和 2 中，分别有 56% 和 49% 接受Nemluvio 治疗的患者在第 16 周的瘙痒强度至少降低了4 个百分点，而两个安慰剂组均为 16%（p<0.001）；在OLYMPIA 1 和 2 中，分别有 41% 接受 Nemluvio 治疗的患者在第 4 周的瘙痒强度至少降低了 4 个百分点，而安慰剂组分别为 6% 和 7% （p<0.001）；在 OLYMPIA 1 和 2 中，分别有 26% 和 38% 接受Nemluvio 治疗的患者在第 16 周达到皮肤结节清除或几乎清除（IGA 1），安慰剂组分别为 7% 和11%（p<0.001）；在 OLYMPIA 1 和 2 中，分别有 50% 和 52% 接受Nemluvio 治疗的患者在第 16 周的睡眠障碍减少了至少四个百分点，而安慰剂组分别为 12% 和 21%（p<0.001）；试验还满足了所有其他关键次要终点，证实了痒疹引起的瘙痒迅速减少；治疗开始后四周内，Nemluvio 的耐受性通常良好。除PN外，FDA 还接受了 Nemluvio 用于治疗中度至重度特应性皮炎的生物制品许可申请的审查，预计将于今年晚些时候做出决定。关于IL-31 IL-31是IL-6 细胞因子家族成员之一，主要来源于CD4 + T 淋巴细胞，研究发现，单核/巨噬细胞、树突状细胞、肥大细胞、嗜酸性粒细胞、嗜碱性粒细胞、成纤维细胞、角质形成细胞等均可分泌IL-31。IL-31 主要通过与IL-31受体A (IL-31RA) 和瘤抑素M 受体β(OSMRβ) 偶联形成的异二聚体受体复合体结合，发挥相应的生物学作用。IL-31 受体复合体高表达于皮肤、神经系统、呼吸系统、消化系统等组织，与AD、PN、哮喘、原发性胆管炎等疾病的发生发展密切相关。 IL-31 具有多种生理功能，可通过促进细胞增殖分化、诱导相关细胞因子表达等参与调节免疫细胞及神经细胞活动；研究者们认为IL-31 主要经组胺非依赖途径诱导瘙痒形成。有研究发现， IL-31 与瘙痒感觉神经纤维表面IL-31RA 亚基结合，激活OSMRβ 亚基发生异构，主要通过JAK/STAT、PI3K/AKT、MAPK-JNK/p38通路，上调瞬时受体电位香草酸受体1 (TRPV1)及瞬时受体电位受体A1( TRPA1) 表达，增强神经元兴奋性，但该反应应答通常需要数小时，故IL-31 主要经上述方式促进晚期及慢性瘙痒形成。除了参与免疫细胞与神经细胞间相互作用，促进瘙痒形成; 作为一种炎症因子，IL-31 也参与调节免疫细胞之间相互作用。据报道， IL-31 可以刺激人角质形成细胞分泌CCL17、CCL22 等趋化因子，诱导IL-6、IL-8、IL-32、血管内皮生长因子等细胞因子以及基质金属蛋白酶的分泌，提示IL-31 可能参与招募炎症细胞、促进血管生成，促进炎症发生发展。据不完全统计，目前在研的IL-31药物不足十种，涵盖的种类包括单抗、双抗。关于结节性痒疹结节性痒疹（PN）是一种慢性皮肤疾病，其特征是出现硬而极痒的肿块，称为结节，通常出现在容易抓伤的部位，如手臂、腿、上背部和腹部。患者往往由于难以控制的剧烈瘙痒，出现严重影响睡眠、社会孤立以及焦虑和抑郁等情况，生活质量明显下降。根据流行病统计，美国有多达 181,000 人患有结节性痒疹；中国结节性痒疹的患病率保持稳定，2017 年至2021年约为190 万例，且预计于2030 年将增至约210 万例。缓解瘙痒的典型结节性痒疹治疗包括局部乳膏，例如局部抗组胺药、类固醇及麻醉剂，以及全身药物，例如抗组胺药、类固醇及阿片受体激动剂。然而，由于局部类固醇和局部麻醉剂等若干结节性痒疹治疗具有副作用，故建议仅在有限的时间内使用。度普利尤单抗（Dupixent）为唯一获FDA 批准用于治疗PN的药物；在PRIME和PRIME2 临床实验中的药效：治疗第24 周时，瘙痒较基线有临床意义减轻的患者比例，Dupixent治疗组（60%和58%）大约是安慰剂组的3 倍（18%和20%）；治疗第12 周时，瘙痒较基线有临床意义减轻的患者比例，Dupixent治疗组（44%和37%）高于安慰剂组（16%和22%）；治疗第24 周时，皮损达到完全清除或几乎完全清除的患者比例，Dupixent 治疗组（48%和45%）是安慰剂组的2 倍多（18%和16%）。 2023年9 月，度普利尤单抗用于结节性痒疹的适应症获得NMPA批准，成为中国首个且唯一治疗中度至重度成人结节性痒疹的创新药物。中国结节性痒疹药物市场预计将进入快速发展阶段。 2020年，中国结节性痒疹药物潜在市场规模约11.8亿元人民币，随着患病人群的增长，叠加未来应用于结节性痒疹的创新型外用及口服药物上市，预计未来此市场将会以3.70%的复合年增长率增长，并于2025年达到约14.1亿元人民币。2025至2030年，中国结节性痒疹药物潜在市场规模将会以3.40%的复合年增长率增长并达到约16.7亿元人民币。参考资料 1、公司官网 2、孙小洁,林彤.IL-31及其受体在皮肤病发生及治疗中的研究进展[J].中国皮肤性病学杂志,2024,38(06):696-699+704.DOI:10.13735/j.cjdv.1001-7089.202212022. 3、兴业证券、中金企信感谢关注、转发，转载授权、加行业交流群，请加管理员微信号“hxsjjf1618”。 “在看”点一下

优先审批临床结果突破性疗法上市批准临床3期