Infliximab-dyyb (Celltrion)

SteQeyma™ 45mg and 90mg solution for injection via autoinjector (pre-filled pen) receives positive CHMP opinion, which will facilitate subcutaneous administration in patients with plaque psoriasis, psoriatic arthritis (PsA) and Crohn’s disease (CD)1 The new autoinjector option increases convenience, enhances individual patient experience and expands administration options SteQeyma™ 45mg and 90mg solution for injection via autoinjector (pre-filled pen) receives positive CHMP opinion, which will facilitate subcutaneous administration in patients with plaque psoriasis, psoriatic arthritis (PsA) and Crohn’s disease (CD)1 The new autoinjector option increases convenience, enhances individual patient experience and expands administration options INCHEON, South Korea--(BUSINESS WIRE)--Celltrion, Inc. today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion of autoinjector of SteQeyma™, a biosimilar to Stelara® (ustekinumab), for the treatment of plaque psoriasis, psoriatic arthritis (PsA) and Crohn’s disease (CD). The positive CHMP opinion is for SteQeyma autoinjector in 45mg/0.5mL and 90mg/1mL, expanding the currently approved SteQeyma™ presentation, which includes 45mg/0.5mL, 90mg/1mL in a pre-filled syringe and 45mg/0.5mL in a vial for subcutaneous injection, as well as 130mg/26mL concentrate for solution for intravenous infusion. “The new SteQeyma™ autoinjector brings together convenience and practical usability to meet the everyday challenges faced by patients living with chronic inflammatory diseases. The full range of our SteQeyma™ dosage forms and strengths, with the autoinjector now added, provides patients and healthcare professionals with more individualized treatment options that support ease of use and improve adherence,” said Taehun Ha, Senior Vice President and Head of Europe Division at Celltrion. “This marks an important milestone in strengthening Celltrion’s immunology portfolio and reaffirms our pioneering leadership in the global biosimilar sector, as we remain committed to reducing the healthcare burden, improving patients’ quality of life, and enhancing the overall patient experience.” With this new addition, SteQeyma™ broadens the administration option, giving patients and physicians access to a complete range of administration options. The new SteQeyma™ autoinjector enables patients and caregivers to administer the medicine via a simple two-step process. The device includes two clear visual and audible indicators - a viewing window and audible clicks to support patients easily identify the injection status, which guide patients with successful administration. SteQeyma™ autoinjector is citrate-free with special thin-wall needle technology to help reduce injection pain. It also offers a 4-year shelf life and can be re-refrigerated, helping reduce product disposal. SteQeyma™ is currently licensed in more than 40 countries worldwide, including the US, Japan and EU countries. Alongside Remsima™ SC, a subcutaneous formulation of infliximab approved in the EU, SteQeyma™ joins Celltrion’s distinguished portfolio that includes Remsima™ (biosimilar infliximab), Truxima™ (biosimilar rituximab), Herzuma™ (biosimilar trastuzumab), Yuflyma™ (biosimilar adalimumab), Vegzelma™ (biosimilar bevacizumab), Omlyclo™ (biosimilar omalizumab), Avtozma™ (tocilizumab biosimilar), Osenvelt/Stoboclo™ (biosimilar denosumab), Eydenzelt™ (biosimilar aflibercept) and Remsima™ (biosimilar infliximab) IV liquid formulation. Notes to Editors: About SteQeyma™ (CT-P43, biosimilar ustekinumab)1 SteQeyma™, formerly known as CT-P43, is a human IL-12 and IL-23 antagonist indicated for multiple immune-mediated diseases. SteQeyma™ is available in both subcutaneous and intravenous formulations. The subcutaneous injection comes in two strengths: 45mg/0.5 mL or 90mg/1 mL solution in a prefilled syringe and prefilled pen, as well as 45mg/0.5mL in a vial. The intravenous infusion is provided as a 130mg/26 mL (5mg/mL) solution in a vial. SteQeyma™ will be available as an autoinjector in 45mg/0.5mL and 90mg/1mL.1 For plaque psoriasis and psoriatic arthritis, SteQeyma™ is administered at 45mg subcutaneous initially, followed by a 45mg dose 4 weeks later, and then every 12 weeks thereafter. For Crohn’s disease, the first dose is administered intravenously, followed by 90mg subcutaneous dose at week 8, and then every 12 weeks thereafter. About Celltrion, Inc. Celltrion is a leading biopharmaceutical company that specializes in researching, developing, manufacturing, marketing and sales of innovative therapeutics that improve people's lives worldwide. Celltrion is a pioneer in the biosimilar space, having launched the world's first monoclonal antibody biosimilar. Our global pharmaceutical portfolio addresses a range of therapeutic areas including immunology, oncology, haematology, ophthalmology and endocrinology. Built on trust through our fully integrated capabilities – from advanced R&D and in-house manufacturing to a reliable global supply network – we continue moving toward innovation as we work to ensure consistent availability of affordable, trusted, and high-quality biologics for patients and healthcare systems across Europe. For more information, please visit our website www.celltrion.com/en-us and stay updated with our latest news and events on our social media - LinkedIn, Instagram, X, and Facebook. FORWARD-LOOKING STATEMENT Certain information set forth in this press release contains statements related to our future business and financial performance and future events or developments involving Celltrion Inc. and its subsidiaries that may constitute forward-looking statements, under pertinent securities laws. This press release contains forward looking statements. These statements may be also identified by words such as "prepares", "hopes to", "upcoming", "plans to", "aims to", "to be launched", "is preparing", "once gained", "could", "with the aim of", "may", "once identified", "will", "working towards", "is due", "become available", "has potential to", “anticipates”, the negative of these words or such other variations thereon or comparable terminology. In addition, our representatives may make oral forward-looking statements. Such statements are based on the current expectations and certain assumptions of Celltrion Inc. and its subsidiaries' management, of which many are beyond its control. Forward-looking statements are provided to allow potential investors the opportunity to understand management’s beliefs and opinions in respect of the future so that they may use such beliefs and opinions as one factor in evaluating an investment. These statements are not guarantees of future performance and undue reliance should not be placed on them. Such forward-looking statements necessarily involve known and unknown risks and uncertainties, which may cause actual performance and financial results in future periods to differ materially from any projections of future performance or results expressed or implied by such forward-looking statements. Celltrion, Inc. and its subsidiaries undertake no obligation to update forward-looking statements if circumstances or management’s estimates or opinions should change except as required by applicable securities laws. References 1 European Medicines Agency. Summary of Product Characteristics (SmPC), SteQeyma. [Last Accessed December 2025]

本研究的核心目标是通过机器学习（ML）技术优化克罗恩病（CD）患者英夫利昔单抗（IFX）的个体化剂量管理。研究团队基于274名中国CD患者（460份样本）的临床数据，构建并验证了一个动态预测与剂量调整的集成模型，旨在解决传统TDM（治疗药物监测）的滞后性问题，实现实时浓度预测和精准剂量干预。### 一、研究背景与临床需求传统TDM依赖定期检测IFX血药浓度，并通过调整剂量维持≥3 μg/mL的阈值。然而，临床实践中存在两大痛点：其一，传统监测方法需在患者出现疗效下降或毒性反应后再干预，导致治疗窗口期延长；其二，单次浓度检测无法反映患者动态的代谢特征和疾病活动度。数据显示，约30%-40%患者因亚治疗浓度或抗体形成（ADA）导致治疗失效，而超过7 μg/mL的高浓度可能增加感染和肿瘤风险。因此，开发能够实时整合多维度临床数据的预测模型，实现预防性剂量调整，成为精准医学的重要方向。### 二、方法创新与模型构建研究采用分阶段策略构建ML模型：1. **数据预处理与特征筛选** 原始数据包含23个变量（如年龄、肝肾功能指标、炎症标志物、IFX剂量等），通过以下步骤优化： - **缺失值处理**：对缺失率＞15%的变量（如ALT、AST）采用中位数填补，保留460份完整样本。 - **特征重要性初筛**：基于LightGBM模型筛选出14个核心变量（包括ADA、Fg、ALB、CDAI等），排除与浓度相关性＜0.3的次要指标。 - **数据标准化**：采用最小-最大归一化（MinMaxScaler）消除量纲差异，确保模型公平性。2. **多算法集成与优化** 系统评估了9种非线性ML算法（XGBoost、随机森林、支持向量机等），最终选定XGBoost、人工神经网络（ANN）、随机森林（RF）和支持向量机（SVM）作为基础模型。集成策略采用“软投票”机制： - **概率加权融合**：各模型预测概率经等权重平均，避免单一模型过拟合。 - **动态阈值校准**：通过决策曲线分析（DCA）确定最佳阈值（0.50-0.61），平衡敏感性（识别亚治疗浓度的能力）与特异性（避免过度干预）。3. **可解释性增强技术** - **SHAP值分析**：揭示ADA（贡献率22.8%）、纤维蛋白原（Fg，21.4%）和IFX剂量（8.2%）为关键预测因子，其中ADA与浓度呈强负相关（ρ=-0.97），Fg与浓度负相关（ρ=-0.95）。 - **PCA可视化**：通过主成分分析（PC1解释35.42%方差），将高维数据投影至二维平面，直观展示治疗窗内外的样本分布（如≥3 μg/mL患者聚类更紧密）。### 三、核心发现与临床意义1. **模型性能验证** - **内部验证**：五折交叉验证显示AUC稳定在0.850±0.049，验证集AUC达0.829，敏感性77.8%，特异性84.6%。 - **外部验证**：独立测试集AUC为0.800，证实模型跨机构泛化能力。 - **临床获益评估**：DCA分析表明，当阈值设定为0.61时，模型在风险区间0.11-0.72内显著提升治疗收益（净临床获益提升12%-18%）。2. **剂量优化策略** - **动态阈值机制**：常规阈值0.50适用于多数场景，但当需要严格管控假阳性率（如患者存在肿瘤风险）时，阈值可提升至0.61，使假阳性率从19.3%降至7.2%。 - **剂量调整算法**：基于CDAI评分和模型预测概率，推荐阶梯式剂量调整： - **低风险患者**（CDAI＜150）：维持当前剂量，若模型预测浓度＜3 μg/mL，则增加5 mg/kg。 - **高风险患者**（CDAI≥150或 ADA阳性）：初始剂量增加10 mg/kg，并每8周根据模型更新剂量。 - **剂量优化效果**：与传统经验性调整相比，模型推荐剂量减少28.6%，同时维持≥3 μg/mL的达标率提升至81.3%。3. **关键生物标志物解析** - **ADA与Fg的协同作用**：ADA阳性患者Fg水平显著升高（中位数38.5 vs. 22.1 mg/L），二者共同构成浓度预测的核心因子。当ADA阳性且Fg＞25 mg/L时，亚治疗浓度的风险增加3.2倍。 - **肝肾功能的影响**：eGFR＜60 mL/min/1.73m2的患者，IFX浓度达标率降低至54.3%，需调整剂量至1.5倍标准值。 - **炎症指标关联性**：CDAI评分每升高10分，IFX浓度达标概率下降19%（OR=0.81, 95%CI 0.72-0.90）。### 四、技术优势与局限性1. **创新性突破** - **闭环管理系统**：整合预测模型（实时浓度估算）、决策引擎（剂量推荐）和验证模块（疗效评估），形成“预测-干预-验证”闭环。 - **多模态数据融合**：首次将电子病历（如用药记录）、实验室指标（如CRP、ALB）和影像学数据（如蒙特利尔分型）纳入同一分析框架。 - **动态阈值调节**：根据临床场景（常规治疗/高风险监测）自动切换阈值，平衡敏感性与特异性。2. **局限性及改进方向** - **数据时效性**：样本采集截至2024年，需验证在新型IFX制剂（如Remicade? vs. Inflectra?）中的适用性。 - **模型可解释性边界**：虽然SHAP分析揭示了主要驱动因素，但未明确ADA与Fg的生物学作用机制（如Fg是否通过加速单核吞噬细胞系统清除IFX）。 - **临床整合挑战**：需开发嵌入式CDSS系统（如与医院电子病历对接），目前依赖人工输入实验室数据。### 五、对精准医疗的启示本研究为生物类似药监测提供了新范式：1. **从单维度到多维度管理**：传统TDM仅关注IFX浓度，而模型整合了免疫状态（ADA）、炎症程度（Fg、WBC）、器官功能（eGFR、ALT）等12项指标。2. **从滞后到实时干预**：通过预 Infusion 点（治疗前30分钟）预测浓度，使剂量调整从“事后补救”转为“事前预防”。3. **从经验到数据驱动**：剂量调整建议基于数学建模（如随机森林的特征重要性权重），而非医生的主观判断，减少人为误差。### 六、临床应用路径1. **标准化流程**： - 治疗第4次剂量后（周22）采集基线样本 - 输入数据：CDAI评分、血常规、肝肾功能、ADA水平 - 输出结果：实时浓度预测（0-1概率值）、推荐剂量（±5 mg/kg）、风险等级（低/中/高）2. **阈值动态切换场景**： - **常规维护阶段**：阈值0.50，允许适度假阳性（假阳性率19.3%） - **免疫抑制治疗**：阈值0.61，将假阳性率降至7.2% - **肿瘤风险患者**：阈值0.70，仅推荐ADA阴性且Fg＜20 mg/L患者接受常规剂量3. **决策支持工具设计**： - 开发临床决策树（CDAI＜100时优先考虑剂量；CDAI＞200时启动强化监测） - 集成药物相互作用数据库（如与 thiopurine 类药物联用时需增加10%剂量）### 七、未来研究方向1. **长期疗效验证**：需开展3年以上随访研究，评估模型对黏膜愈合（影像学证据）和远期肿瘤风险的影响。2. **多中心数据验证**：当前样本主要来自福建医科大学附属第一医院，未来需纳入≥5家三甲医院数据（目标样本量≥2000例）。3. **机制研究**：结合单细胞测序分析ADA阳性患者肠道菌群变化，以及Fg介导的IFX清除机制。4. **技术整合**：开发移动端APP实现： - 自动采集实验室数据（如通过智能采血笔同步上传检测值） - 实时推送剂量建议（与医院HIS系统对接） - 患者教育模块（用自然语言解释预测逻辑）本研究标志着TDM从“实验室检测驱动”向“数据科学驱动”的转型，其核心价值在于将生物药代谢的复杂性（如免疫介导清除、炎症状态波动）转化为可量化的预测指标，为临床提供动态决策依据。随着5G和物联网技术的发展，未来可构建区域性IFX治疗监测云平台，实现跨医院数据共享与模型协同优化。