A Multicentre, Randomised, Double-blind, Placebo-controlled, Repeat Dose, Dose-ranging Phase 2a/2b Study to Evaluate the Safety, Tolerability and Efficacy of an Anti-oncostatin M Monoclonal Antibody (GSK2330811) in Patients With Moderate to Severe Crohn's Disease

The study will include participants with moderate to severe Crohn's disease. The aim is to evaluate the safety, tolerability, and efficacy of anti-oncostatin M monoclonal antibody (mAb) GSK2330811. This is a parallel group study with Induction and Maintenance periods. During Induction, the first 100 participants randomised will receive a 450mg GSK2330811 SC loading dose followed by 150mg weekly (Q1W), or placebo for 12 weeks. Additional dose-ranging arms will open after the 100th participant is randomized and in addition to placebo and the highest dose arms will also include a 300mg subcutaneous (SC) loading dose followed by 150mg SC every 2 weeks (Q2W) arm, a 300mg loading dose followed by 150mg SC every 4 weeks (Q4W) arm and a 150mg SC every 8 weeks (Q8W) arm. Participants with a clinical response at Week 12 will continue into a 40-week blinded maintenance period and will receive either 150mg SC Q2W, 150mg SC Q4W, 150mg SC Q8W or placebo. Participants without a clinical response at Week 12 will be offered up to 40 weeks of open label treatment with GSK2330811. Approximately 560 participants will be screened to randomize 280.

开始日期2021-04-05

申办/合作机构

GSK Plc

NCT04138043

/ Completed临床1期

A Phase 1, Randomised, Double-blind, Placebo-controlled Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Subcutaneous Doses of GSK2330811 in Healthy Japanese Participants

This is a randomized, double-blind (sponsor-open), placebo-controlled, single-center study involving Japanese participants. The purpose of the study is to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity after a single subcutaneous (SC) dose of GSK2330811 in healthy Japanese participants. GSK2330811 is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that binds and inhibits the action of Oncostatin M (OSM) and is being developed for the treatment of Crohn's disease (CD) and Systemic sclerosis (SSc). Participants will be randomized to receive either GSK2330811 (450 milligram [mg]) or placebo in an approximate ratio of 7:3.

开始日期2019-12-05

申办/合作机构

GSK Plc

NCT03041025

/ Completed临床2期

A Multi-center, Randomized, Double-blind (Sponsor Open), Placebo-controlled, Repeat-dose, Proof of Mechanism Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Explore Efficacy of GSK2330811 in Participants With Diffuse Cutaneous Systemic Sclerosis

GSK2330811 is a humanized monoclonal antibody which is in development for systemic sclerosis (SSc), a rare autoimmune disease with high morbidity and mortality. Currently, there are no approved disease modifying therapies and it is an area of high unmet medical need. GSK2330811 has been shown to bind and neutralize Oncostatin M (OSM) that has been associated with fibrosis, vasculopathy and inflammation in a number of diseases. This multi-center, randomized, double-blind (sponsor open), placebo controlled, proof of mechanism study will be the first study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of repeat subcutaneous (SC) doses of GSK2330811 in male and female participants with diffuse cutaneous SSc (dcSSc). Participants with active disease and a disease duration of <= 60 months will be enrolled. Approximately 24 to 40 participants will be randomized across two sequential cohorts. Cohort 1 will evaluate a repeat-dose predicted to provide sub-maximal inhibition of OSM, leading to a dose escalation decision. Cohort 1 is planned to consist of at least 4 participants, randomized such that 3 participants will receive GSK2330811 100 milligram (mg) and 1 will receive placebo. Cohort 2 is planned to consist of at least 20 participants, randomized such that participants will receive GSK2330811 300 mg and placebo in a 3:1 ratio respectively. The duration of the study is up to 34 weeks including a screening period of up to 6 weeks, treatment period of 12 weeks and follow-up period of 16 weeks.

开始日期2017-06-05

申办/合作机构

GSK Plc

100 项与 GSK-2330811 相关的临床结果

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100 项与 GSK-2330811 相关的转化医学

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100 项与 GSK-2330811 相关的专利（医药）

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项与 GSK-2330811 相关的文献（医药）

2022-12-23·Rheumatology (Oxford, England)

Biological and clinical insights from a randomized phase 2 study of an anti-oncostatin M monoclonal antibody in systemic sclerosis

Article

作者: Wisniacki, Nicolas ; Khanna, Dinesh ; Csomor, Eszter ; Denton, Christopher P ; Flint, Shaun M ; Varga, John ; Reid, Juliet ; Temple, Jane ; Lee, Amy ; del Galdo, Francesco ; Vonk, Madelon C ; Johnson, Sindhu R ; Furst, Daniel E ; Zecchin, Chiara ; Chung, Lorinda

Abstract:

Objectives:

The cytokine oncostatin M (OSM) is implicated in the pathology of SSc. Inhibiting OSM signalling using GSK2330811 (an anti-OSM monoclonal antibody) in patients with SSc has the potential to slow or stop the disease process.

Methods:

This multicentre, randomized, double-blind, placebo-controlled study enrolled participants ≥18 years of age with active dcSSc. Participants were randomized 3:1 (GSK2330811:placebo) in one of two sequential cohorts to receive GSK2330811 (cohort 1: 100 mg; cohort 2: 300 mg) or placebo s.c. every other week for 12 weeks. The primary endpoint was safety; blood and skin biopsy samples were collected to explore mechanistic effects on inflammation and fibrosis. Clinical efficacy was an exploratory endpoint.

Results:

Thirty-five participants were randomized to placebo (n = 8), GSK2330811 100 mg (n = 3) or GSK2330811 300 mg (n = 24). Proof of mechanism, measured by coordinate effects on biomarkers of inflammation or fibrosis, was not demonstrated following GSK2330811 treatment. There were no meaningful differences between GSK2330811 and placebo for any efficacy endpoints. The safety and tolerability of GSK2330811 were not favourable in the 300 mg group, with on-target, dose-dependent adverse events related to decreases in haemoglobin and platelet count that were not observed in the 100 mg or placebo groups.

Conclusion:

Despite a robust and novel experimental medicine approach and evidence of target engagement, anticipated SSc-related biologic effects of GSK2330811 were not different from placebo and safety was unfavourable, suggesting OSM inhibition may not be a useful therapeutic strategy in SSc.

Trial registration number:

ClinicalTrials.gov, NCT03041025; EudraCT, 2016-003417-95.

2018-10-01·British journal of clinical pharmacology2区 · 医学

In vivo affinity and target engagement in skin and blood in a first‐time‐in‐human study of an anti‐oncostatin M monoclonal antibody

2区 · 医学

Article

作者: Fernando, Disala ; Feeney, Maria ; Reid, Juliet ; Edwards, Ken ; Zamuner, Stefano ; Nevin, Katherine ; Wisniacki, Nicolas ; Zecchin, Chiara ; Rumley, Sally‐Anne

Aims:

The oncostatin M (OSM) pathway drives fibrosis, inflammation and vasculopathy, and is a potential therapeutic target for inflammatory and fibrotic diseases. The aim of this first‐time‐in‐human experimental medicine study was to assess the safety, tolerability, pharmacokinetics and target engagement of single subcutaneous doses of GSK2330811, an anti‐OSM monoclonal antibody, in healthy subjects.

Methods:

This was a phase I, randomized, double‐blind, placebo‐controlled, single‐dose escalation, first‐time‐in‐human study of subcutaneously administered GSK2330811 in healthy adults (NCT02386436). Safety and tolerability, GSK2330811 pharmacokinetic profile, OSM levels in blood and skin, and the potential for antidrug antibody formation were assessed. The in vivo affinity of GSK2330811 for OSM and target engagement in serum and skin blister fluid (obtained via a skin suction blister model) were estimated using target‐mediated drug disposition (TMDD) models in combination with compartmental and physiology‐based pharmacokinetic (PBPK) models.

Results:

Thirty subjects were randomized to receive GSK2330811 and 10 to placebo in this completed study. GSK2330811 demonstrated a favourable safety profile in healthy subjects; no adverse events were serious or led to withdrawal. There were no clinically relevant trends in change from baseline in laboratory values, with the exception of a reversible dose‐dependent reduction in platelet count. GSK2330811 exhibited linear pharmacokinetics over the dose range 0.1–6 mg kg–1. The estimated in vivo affinity (nM) of GSK2330811 for OSM was 0.568 [95% confidence interval (CI) 0.455, 0.710] in the compartmental with TMDD model and 0.629 (95% CI 0.494, 0.802) using the minimal PBPK with TMDD model.

Conclusions:

Single subcutaneous doses of GSK2330811 were well tolerated in healthy subjects. GSK2330811 demonstrated sufficient affinity to achieve target engagement in systemic circulation and target skin tissue, supporting the progression of GSK2330811 clinical development.

项与 GSK-2330811 相关的新闻（医药）

2026-02-12

·百度百家

「文献解读」抑瘤素M在皮肤免疫、炎症与肿瘤发生中的多面角色：机制与治疗前景

抑瘤素M（Oncostatin M, OSM）是白介素-6（IL-6）细胞因子家族中的一员，自1986年首次分离以来，其功能已超越最初的抑瘤活性，被广泛认识到在炎症、免疫调节及组织稳态中发挥核心作用。近期发表于《Journal of Investigative Dermatology》（2025）的这篇综述，系统阐述了OSM及其受体在皮肤免疫、多种炎症性皮肤病及皮肤肿瘤中的复杂作用，并评估了其作为治疗靶点的潜力与挑战。一、OSM的生物学基础与信号通路 1. 表达与调控： OSM主要由活化的免疫细胞产生，包括树突状细胞、巨噬细胞、中性粒细胞和T淋巴细胞。其基因表达受STAT蛋白调控，并可被前列腺素E2（PGE2）、脂多糖（LPS）等炎性信号强烈诱导。在皮肤微环境中，OSM是连接上皮细胞激活与炎症/屏障反应的关键桥梁。 2. 受体与信号传导： OSM通过两类受体复合物发挥作用： II型受体：由OSMRβ与gp130组成。 I型受体：由白血病抑制因子受体β（LIFRβ）与gp130组成。结合后，OSM主要激活JAK/STAT（尤其是STAT3）、MAPK（ERK、p38、JNK）和PI3K/Akt等信号通路。与IL-6家族其他成员不同，OSM还能激活STAT6，并与IL-4协同调节嗜酸性粒细胞趋化因子表达，显示了其功能的独特性。二、OSM在炎症性皮肤病中的作用 1. 特应性皮炎： OSM在AD患者皮损中高表达。它与IL-31共享OSMRβ受体亚基，构成复杂的调控网络：调节瘙痒：单独OSM不直接诱发瘙痒，但能与IL-31竞争性结合OSMRβ，在动物模型中表现出剂量依赖性地抑制IL-31诱导的瘙痒。加重炎症与屏障损伤：OSM可上调角质形成细胞中IL-4/IL-13受体表达，并加剧皮肤屏障功能障碍，促进Th2型炎症。治疗启示：靶向IL-4Rα的度普利尤单抗可降低相关疾病患者分泌物中的OSM水平，提示OSM与2型炎症轴紧密关联。 2. 银屑病： OSM在银屑病皮损中表达升高。它能与TNF-α、IL-17等细胞因子协同，强力诱导角质形成细胞活化、迁移及S100A9等炎症因子表达，促进银屑病样表型。然而，其作用似乎独立于经典的IL-23/Th17轴。 3. 结节性痒疹： OSM在PN患者真皮中表达显著升高，且与瘙痒严重程度正相关。靶向OSMRβ的单抗Vixarelimab在II期临床试验中显示出缓解瘙痒和皮肤结节的双重疗效，提示OSM信号通路在PN，尤其是伴有纤维化/结节表型的发病中至关重要。 4. 皮肤淀粉样变：家族性原发性局限性皮肤淀粉样变（PLCA）可由OSMRβ基因突变直接引起，这从遗传学角度确立了OSM信号通路在慢性瘙痒和皮肤病变中的根本性作用。 5. 伤口愈合： OSM由伤口处的巨噬细胞产生，能有效刺激角质形成细胞迁移，在糖尿病等慢性伤口模型中显示表达不足，补充OSM可促进再上皮化，表明其在组织修复中有积极功能。三、OSM在皮肤肿瘤中的双重作用 OSM在肿瘤微环境中的作用具有显著的情境依赖性和双重性，既可抑制也可促进肿瘤进展。 1. 黑色素瘤：抑瘤作用：在多数细胞系中，OSM通过激活STAT1/STAT3、上调细胞周期抑制剂p27等机制抑制增殖。促瘤与免疫逃逸：在某些情况下，OSM可促进增殖，并通过下调肿瘤细胞免疫原性抗原，使其对免疫系统“隐形”。来源：肿瘤微环境中的基质或免疫细胞是OSM的主要来源。 2. 皮肤鳞状细胞癌： OSM在cSCC中高表达，主要来源于肿瘤相关巨噬细胞。它通过激活STAT3和ERK通路，促进恶性角质形成细胞的增殖、迁移和上皮-间质转化（EMT），在动物模型中敲除OSM可减少约30%的肿瘤体积，明确其促癌角色。 3. 其他非皮肤癌种的启示：综述通过总结乳腺癌、结直肠癌、肝癌、肺癌、胶质母细胞瘤等多种肿瘤的研究，揭示了OSM信号通路的普遍双重性。其最终效应取决于肿瘤类型、微环境、激活的下游STAT亚型（STAT1通常抑瘤，STAT3通常促瘤）等多种因素。四、治疗靶向策略与挑战 1. 炎症性疾病：靶向OSMRβ：目前最有前景的策略。Vixarelimab（抗OSMRβ单抗）在PN中显示出疗效，并正在溃疡性结肠炎、系统性硬化症等疾病中进行II期试验。直接靶向OSM的困境：早期两款抗OSM单抗（GSK315234A, GSK2330811）在类风湿关节炎和系统性硬化症的临床试验中均未达主要终点，或因亲和力不足、脱靶率高，或因剂量限制性血液学毒性而失败。提示完全中和OSM可能存在技术挑战和功能代偿问题。 2. 肿瘤治疗：尽管临床前研究大量揭示了OSM/OSMR轴在多种癌症中的重要性，但由于其功能双重性及情境依赖性，直接靶向该轴的肿瘤治疗药物研发严重滞后，目前尚无相关生物制剂进入癌症临床试验。未来策略可能需要更精准地识别其发挥促瘤作用的特定情境，或靶向其上游调控因子或下游特异性效应分子。五、总结与展望 OSM是一个多功能的“枢纽”细胞因子，深刻参与皮肤免疫稳态、慢性炎症和肿瘤发生发展：桥梁作用：它贯穿于慢性炎症（如AD、PN）与肿瘤（如cSCC）之间，是连接免疫系统、上皮细胞和基质微环境的关键分子。功能双重性：尤其在肿瘤中，其抑瘤或促瘤作用高度依赖具体情境，这既是理解的难点，也是精准干预的潜在突破口。治疗前景：靶向其受体OSMRβ在炎症性皮肤病（特别是PN）中已显现明确疗效，是当前最具转化潜力的方向。然而，直接靶向OSM配体或将其应用于肿瘤治疗仍面临巨大挑战。未来研究需要：更深入阐明OSM在不同疾病、不同微环境中信号传导的精确图谱。开发更可靠的疾病模型（如更多人源化的动物模型或类器官）。探索基于患者分层（如特定基因型、肿瘤微环境特征）的精准靶向策略，以驾驭OSM双重功能的复杂性，最终实现对其有害活性的安全有效干预，同时保留或利用其有益的生理功能。 EnkiLife（恩玑生命）是一家深耕生命科学，专注细胞生物学和免疫学科研试剂的研发、生产与销售的生物技术企业，在全球100多个国家和地区开展业务，致力于为科研工作者提供高质量的产品和卓越的客户服务，推动生命科学的发展。 EnkiLife的产品线涵盖细胞系、原代细胞、细胞培养基、胎牛血清、细胞功能检测试剂盒、重组靶点蛋白、细胞因子、重组抗体、抗体标记试剂盒、WB试剂盒、IHC试剂盒、TSA多重免疫荧光试剂盒、ELISA试剂盒等，覆盖了生命科学研究的各大关键领域，包括细胞生物学、癌症、免疫学、神经科学、心血管疾病、干细胞、表观遗传学、内分泌、蛋白质组学、代谢组学等，全方位满足您的实验需求，让您享受科研的乐趣！参考文献 The multifaceted roles of oncostatin M and its receptor in skin immunity, inflammation, and tumorigenesis. Journal of Investigative Dermatology (2025)

100 项与 GSK-2330811 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
克罗恩病	临床2期	-	GSK Plc	2021-04-05
弥漫性硬皮病	临床2期	美国	GSK Plc	2017-06-05
弥漫性硬皮病	临床2期	加拿大	GSK Plc	2017-06-05
弥漫性硬皮病	临床2期	荷兰	GSK Plc	2017-06-05
弥漫性硬皮病	临床2期	英国	GSK Plc	2017-06-05

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04138043 (CTgov)	临床1期	系统性硬皮病 \| 克罗恩病	9	Placebo (Placebo)	襯蓋壓壓獵蓋獵淵積廠 = 鑰鏇構選夢膚範艱製積築壓廠憲餘廠顧廠積艱 (製糧鏇蓋醖夢膚網齋夢, 築鬱構選鹽膚鹽觸顧壓 ~ 蓋窪餘廠醖繭築簾簾憲) 更多	-	2021-05-24
				GSK2330811 (GSK2330811 450 mg)	襯蓋壓壓獵蓋獵淵積廠 = 衊膚醖夢蓋艱蓋顧繭鑰築壓廠憲餘廠顧廠積艱 (製糧鏇蓋醖夢膚網齋夢, 積鬱觸鹽餘鑰鬱顧淵選 ~ 鑰艱構襯衊夢繭獵選糧) 更多
NCT03041025 (CTgov)	临床2期	弥漫性硬皮病	35	placebo (Placebo)	廠顧製廠顧觸艱膚憲窪 = 製選網繭遞鑰窪簾淵積淵網壓蓋繭壓壓襯鏇淵 (簾衊壓鑰鏇鏇鹽鹽製壓, 憲鹽簾鹽獵鏇鹽積願壓 ~ 壓鏇廠製鏇築夢願鹹窪) 更多	-	2021-05-24
				GSK2330811 (GSK2330811 100 mg)	廠顧製廠顧觸艱膚憲窪 = 顧簾夢簾廠鹹夢範願憲淵網壓蓋繭壓壓襯鏇淵 (簾衊壓鑰鏇鏇鹽鹽製壓, 齋廠築觸壓繭構觸鏇齋 ~ 壓齋窪鹽顧觸製壓願壓) 更多