Prednisolone

Final results for the key secondary endpoint of overall survival (OS) from the PEACE-3 trial will be presented by the European Organization for Research and Treatment of Cancer (EORTC) coalition as an oral abstract at ASCO GU 2026. XOFIGO ® (radium-223 dichloride) in combination with enzalutamide reduced the risk of death by 24% (HR 0.76; 95% CI 0.60-0.96; p=0.0096) and a median OS of 38.2 months (95% CI 33.1-44.8) versus enzalutamide alone (32.6 months, 95% CI 29.3-38.2) in men with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. WHIPPANY, N.J.--(BUSINESS WIRE)--Final results from the pivotal investigational Phase III PEACE-3 trial demonstrate that first-line treatment with XOFIGO® (radium-223 dichloride) in combination with enzalutamide, an androgen receptor pathway inhibitor (ARPI), resulted in a significant overall survival (OS) benefit, reducing the risk of death by 24% versus enzalutamide alone (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.60-0.96; p=0.0096) in men with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases.1 These data will be presented by the European Organization for Research and Treatment of Cancer (EORTC) coalition in an oral session at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) 2026 (Oral abstract #15; February 26, 2026. 8:15 – 8:25 AM PST) and published simultaneously in Annals of Oncology. Updated results for radiological progression-free survival (rPFS), the primary endpoint of the trial, will also be shared. XOFIGO is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.2 XOFIGO is not approved in this investigational indication in combination with enzalutamide. “Despite recent advances in prostate cancer care, many men with mCRPC and bone metastases continue to face a poor prognosis and a high risk of disease progression,” said Enrique Gallardo, MD, Parc Tauli Hospital Universitari, Sabadell, Spain and First Author and Presenter of the EORTC 1333/PEACE-3 trial. “Results from PEACE-3 show that starting with a combination of radium-223 and enzalutamide, may help support treatment strategies that prioritize bone health.” The PEACE-3 trial is an international, randomized, open-label, Phase III trial designed to investigate the efficacy and safety of XOFIGO in combination with enzalutamide in patients with mCRPC and bone metastases. The primary endpoint was rPFS by investigator assessment, with key secondary endpoints including OS, time to subsequent systemic treatment, pain progression, and symptomatic skeletal events. At the time of the final OS analysis, men receiving XOFIGO plus enzalutamide demonstrated a statistically significant improvement in the key secondary endpoint of OS compared to those receiving enzalutamide alone, with a 24% reduction in risk of death (HR 0.76; 95% CI 0.60-0.96; p=0.0096). Median OS was 38.2 months with XOFIGO plus enzalutamide versus 32.6 months with enzalutamide alone. The final OS results build on the primary analysis, published in Annals of Oncology, which showed a significant improvement in the primary endpoint of radiological progression-free survival (rPFS) with the combination versus enzalutamide alone (19.4 vs. 16.4 months respectively; HR 0.69; 95% CI 0.54–0.87; p=0.0009).3,4 “PEACE-3 is a strong example of how academic cooperative research can help advance progress for complex diseases such as metastatic prostate cancer,” said Denis Lacombe, Chief Executive Officer, European Organization for Research and Treatment of Cancer (EORTC). EORTC is a non-governmental, non-profit organization, which unites clinical cancer research experts, throughout Europe, to coordinate and conduct international translational and clinical research. “These Phase III data provide important insights for clinicians and underline the value of international collaboration in generating evidence that supports clinical decision-making.” “These new PEACE-3 data reinforce Bayer’s leadership in prostate cancer care and our long term commitment to addressing the unmet medical needs of patients,” said Christine Roth, Executive Vice President, Global Product Strategy and Commercialization and Member of the Pharmaceuticals Leadership Team at Bayer. “By investigating combination approaches, we are building a growing prostate cancer portfolio with the potential to bring new treatment options to patients across different stages of the disease.” Grade 3 or higher treatment emergent adverse events (TEAE) were recorded in 69% of patients in the combination arm versus 58% of patients treated with enzalutamide alone. No individual TEAE Grade 3 or higher has increased by more than 5% in the combination arm compared to the enzalutamide arm alone.1 About PEACE-3 (EORTC GUCG-1333)5 The PEACE-3 trial is an international, randomized, open-label, Phase III trial designed to investigate the efficacy and safety of XOFIGO in combination with enzalutamide in asymptomatic or mildly symptomatic patients (Brief Pain Inventory score <4) with metastatic castration-resistant prostate cancer (mCRPC) and ≥2 bone metastases. A total of 446 patients were randomized 1:1 to receive either XOFIGO 55 kBq/kg as an intravenous injection monthly for six cycles in combination with enzalutamide 160mg orally daily or enzalutamide 160mg orally daily. The primary endpoint was radiological progression-free survival (rPFS) by investigator assessment. Key secondary endpoints included overall survival (OS), time to subsequent systemic treatment, pain progression, and symptomatic skeletal event. This trial was a collaboration with several cancer cooperative groups: the European Organization for Research and Treatment of Cancer (EORTC), Clinical Trial Ireland (CTI), the Canadian Urological Oncology Group (CUOG), the Latin American Cooperative Oncology Group (LACOG), and French UNICANCER Urogenital Tumor Study Group (GETUG). The trial is supported by Astellas and Pfizer who manufacture enzalutamide (Xtandi) in collaboration with Bayer. About XOFIGO® (radium-223 dichloride) Injection2 XOFIGO is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. Important Safety Information for XOFIGO® (radium-223 dichloride) Injection Warnings and Precautions: Bone Marrow Suppression: In the phase 3 ALSYMPCA trial, 2% of patients in the XOFIGO arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with XOFIGO bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the XOFIGO arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of XOFIGO-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with XOFIGO and placebo. Myelosuppression–notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia–has been reported in patients treated with XOFIGO. Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue XOFIGO in patients who experience life-threatening complications despite supportive care for bone marrow failure Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of XOFIGO. Prior to first administering XOFIGO, the absolute neutrophil count (ANC) should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue XOFIGO if hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with XOFIGO have not been established. Outside of a clinical trial, concomitant use of XOFIGO in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, XOFIGO should be discontinued Increased Fractures and Mortality in Combination With Abiraterone Plus Prednisone/Prednisolone: XOFIGO is not recommended for use in combination with abiraterone acetate plus prednisone/prednisolone outside of clinical trials. At the primary analysis of the Phase 3 ERA-223 study that evaluated concurrent initiation of XOFIGO in combination with abiraterone acetate plus prednisone/prednisolone in 806 asymptomatic or mildly symptomatic mCRPC patients, an increased incidence of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received XOFIGO in combination with abiraterone acetate plus prednisone/prednisolone compared to patients who received placebo in combination with abiraterone acetate plus prednisone/prednisolone. Safety and efficacy with the combination of XOFIGO and agents other than gonadotropin-releasing hormone analogues have not been established Embryo-Fetal Toxicity: The safety and efficacy of XOFIGO have not been established in females. XOFIGO can cause fetal harm when administered to a pregnant female. Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise male patients to use condoms and their female partners of reproductive potential to use effective contraception during and for 6 months after completing treatment with XOFIGO Administration and Radiation Protection: XOFIGO should be received, used, and administered only by authorized persons in designated clinical settings. The administration of XOFIGO is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations Fluid Status: Dehydration occurred in 3% of patients on XOFIGO and 1% of patients on placebo. XOFIGO increases adverse reactions such as diarrhea, nausea, and vomiting, which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia Injection Site Reactions: Erythema, pain, and edema at the injection site were reported in 1% of patients on XOFIGO Secondary Malignant Neoplasms: XOFIGO contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, XOFIGO may increase the risk of osteosarcoma or other secondary malignant neoplasms. However, the overall incidence of new malignancies in the randomized trial was lower on the XOFIGO arm compared to placebo (<1% vs 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow-up for patients on the trial Subsequent Treatment With Cytotoxic Chemotherapy: In the randomized clinical trial, 16% of patients in the XOFIGO group and 18% of patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with XOFIGO will tolerate subsequent cytotoxic chemotherapy Adverse Reactions: The most common adverse reactions (≥10%) in the XOFIGO arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of XOFIGO-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the XOFIGO arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%). Please see the full Prescribing Information for XOFIGO (radium Ra 223 dichloride). About Oncology at Bayer Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer includes seven marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated. About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. In line with its mission, “Health for all, Hunger for none,” the company’s products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2024, the Group employed around 93,000 people and had sales of 46.6 billion euros. R&D expenses amounted to 6.2 billion euros. For more information, go to www.bayer.com. © 2026 Bayer BAYER, the Bayer Cross and XOFIGO are registered trademarks of Bayer. Forward-Looking Statements This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments. References 1 Gallardo, E. et al. Final Overall Survival Results from the EORTC 1333/PEACE-3 Trial: Enzalutamide With or Without Radium-223 in Metastatic Castration-Resistant Prostate Cancer. Oral abstract #15. Presented at ASCO GU 2026. 2 Xofigo® (radium-223 dichloride) Injection [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, December 2019. 3 Gillessen, S., et al. A randomized multicenter open label phase III trial comparing enzalutamide vs a combination of Radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): First results of EORTC-GUCG 1333/PEACE-3. European Society of Medical Oncology 2025 (ESMO) LBA1. September 9, 2024 4 Tombal. B., et al. Enzalutamide plus Radium-223 in Metastatic Castration-Resistant Prostate Cancer: Results of the EORTC 1333/PEACE-3 trial. Annals of Oncology. May 30, 2025. DOI: 10.1016/j.annonc.2025.05.011 5 ClinicalTrials.gov NCT02194842. Phase III Radium 223 mCRPC-PEACE III (PEACE III). https://clinicaltrials.gov/study/NCT02194842. Accessed January 2026.

引言 受体相互作用丝氨酸/苏氨酸激酶2（Receptor-Interacting Serine/Threonine Kinase 2, RIPK2，又称RIP2）是先天免疫信号通路中的关键适配蛋白，作为NOD1/NOD2和Toll样受体（TLRs）的下游信号分子，在炎症性肠病（IBD）、自身免疫性疾病和肿瘤等多种疾病中发挥核心作用。近年来，针对RIPK2的小分子抑制剂研发取得了显著进展，多个候选药物已进入临床试验阶段，展现出良好的治疗前景。 01 RIPK2的生物学功能与信号机制 1.1 分子结构与激活机制 RIPK2是一种含有CARD（Caspase激活与募集结构域）的丝氨酸/苏氨酸激酶，其N端激酶结构域和C端CARD结构域通过中间连接区相连。2025年最新研究通过冷冻电镜技术解析了RIPK2-CARD的寡聚化结构，揭示了"RIPosome"复合物的形成机制：NOD1/NOD2的CARD结构域与RIPK2-CARD相互作用，诱导RIPK2发生寡聚化，从而启动下游信号传导。 1.2 信号通路整合 RIPK2处于多条先天免疫信号通路的交汇点： - NOD1/NOD2-RIPK2轴：识别细菌肽聚糖成分，激活NF-κB和MAPK通路，诱导促炎细胞因子（TNF-α、IL-6、IL-12/23p40）产生 - TLRs-RIPK2轴：Toll样受体通过RIPK2传递信号，在IBD中发挥促炎作用 - 泛素化调控：XIAP、cIAP1/2等E3泛素连接酶介导RIPK2的K63位泛素化，是信号激活的关键步骤 值得注意的是，最新研究表明RIPK2的激酶活性对于NOD2信号传导并非必需，而抑制剂主要通过阻断RIPK2与XIAP的相互作用、抑制RIPK2泛素化来发挥抗炎作用。 02 RIPK2与疾病关联 2.1 炎症性肠病（IBD） RIPK2在IBD发病机制中扮演双重角色： - 保护作用：NOD2-RIPK2通路通过激活IRF4和ATG16L1，抑制TLRs诱导的促炎反应，维持肠道免疫稳态 - 致病作用：TLRs-RIPK2通路驱动过度的炎症反应 临床研究显示，克罗恩病（CD）和溃疡性结肠炎（UC）患者结肠黏膜中RIPK2及其信号分子（cIAP2、TRAF6、TAK1）表达显著升高，且与炎症因子水平正相关。NOD2功能缺失突变与CD发病风险增加相关，但有趣的是，IBD患者炎症黏膜中NOD2表达并未升高，提示TLRs-RIPK2通路可能是更有效的治疗靶点。  2.2 肿瘤 2025年4月发表在《Cell Death & Disease》的最新研究揭示了RIPK2在结直肠癌转移中的新机制：RIPK2通过保护YAP蛋白免受ITCH介导的泛素化降解，促进肿瘤转移。这一发现拓展了RIPK2抑制剂在肿瘤治疗中的应用前景。  2.3 其他自身免疫疾病 RIPK2还参与类风湿性关节炎、多发性硬化症、银屑病等疾病的发病过程，使其成为广谱抗炎治疗的潜在靶点。 2.4 代谢性疾病 2026年Endocrine Connections发表的一项研究利用棕榈酸诱导的大鼠L6肌管胰岛素抵抗模型，结果显示，在胰岛素抵抗状态下，RIPK2表达显著升高，而X连锁凋亡抑制蛋白（XIAP）表达降低。 该研究揭示的XIAP-RIPK2调控轴为2型糖尿病的干预提供了新靶点，上述发现提示RIPK2可能也适用于代谢性疾病。通过恢复RIPK2的泛素化修饰或抑制其激酶活性，或可改善胰岛素敏感性和葡萄糖稳态。这一概念的提出拓展了RIPK2靶点的应用场景，从炎症性疾病延伸至代谢紊乱领域。 03 RIPK2抑制剂研发进展 3.1 第一代抑制剂：多靶点激酶抑制剂 早期RIPK2抑制剂多为已上市药物的重新定位： 关键发现：Canning等人（2015）首次证明Type II激酶抑制剂（结合DFG-out构象）对RIPK2的抑制效果比Type I抑制剂提升两个数量级，并解析了RIPK2-Ponatinib共晶结构，发现变构位点可用于选择性抑制剂设计。  3.2 第二代抑制剂：高选择性RIPK2抑制剂  3.2.1 GSK系列（葛兰素史克） - GSK583：高选择性RIPK2抑制剂，能有效抑制CD患者结肠活检样本中自发性促炎细胞因子释放 - GSK2983559：GSK583的前药，在TNBS诱导的结肠炎模型中显示出与泼尼松龙相当疗效，曾进入I期临床试验（NCT03358407），但因毒理学发现和安全性边际不足而终止开发  3.2.2 大环类抑制剂 OD36和OD38（Tigno-Aranjuez等，2014）： - IC50分别为5.3 nM和14.1 nM - 高选择性（366激酶谱中仅抑制少数激酶） - 在SAMP1/YitFc CD模型中下调MDP诱导的炎症因子 - 提出9基因RIPK2激活标志物（GPR84、ICAM1、IRG1等）用于预测患者响应  3.3 临床阶段候选药物  BI 706039（勃林格殷格翰） - 通过高通量筛选优化获得，结构未公开 - 285激酶谱中仅抑制18个激酶（3 μM浓度） -正在开展与Ustekinumab联合治疗CD的临床试验（NCT04978493） 04 新兴治疗策略  4.1 PROTAC降解剂 除传统抑制剂外，基于PROTAC（蛋白降解靶向嵌合体）技术的RIPK2降解剂在IBD临床前模型中展现出卓越疗效，为克服激酶抑制剂耐药性问题提供了新思路。  4.2 靶向蛋白-蛋白相互作用 目前所有RIPK2抑制剂均靶向激酶结构域的ATP结合位点。鉴于RIPK2的CARD-CARD相互作用是信号启动的关键步骤，开发阻断NODs与RIPK2相互作用的变构调节剂代表了一个尚未探索但极具吸引力的方向，有望实现更高的选择性和更少的脱靶效应。  4.3 组织特异性递送 由于RIPK2在多种组织中广泛表达，系统性抑制可能导致副作用。针对IBD等肠道疾病的局部递送策略（如直肠给药的siRNA载体）已在动物模型中验证有效，未来可结合纳米技术实现炎症部位的精准靶向。 05 结论 RIPK2作为先天免疫信号网络的核心节点，在IBD、自身免疫病和肿瘤等多种疾病中展现出显著的治疗潜力。随着结构生物学研究的深入（如RIPosome复合物解析）和药物化学的进步，从早期多靶点抑制剂到高选择性Type II抑制剂，再到新兴的PROTAC降解剂和变构调节剂，RIPK2靶向治疗正快速走向成熟。BI 706039等候选药物进入临床试验标志着该领域进入转化医学的关键阶段。未来通过解决组织选择性、机制精细调控等挑战，RIPK2抑制剂有望成为炎症性疾病治疗的重要武器。 06 相关产品推荐 货号 产品名称 UA085022 RIPK2 Flag Tag Protein, Human UA085035 RIPK2 GST Tag Protein, Human 部分数据分享 RIPK2 Flag Tag Protein, Human（UA085022） The specific activity of RIPK2 Flag Tag Protein, Human was determined to be >35 pmol/min/ug. 纯度＞90% by SDS-PAGE &＞95% by HPLC 参考文献： 1. Amélie Barczyk; Perrine Six; Morgane Rivoal; C. Devos; Xavier Dezitter; et al. 4-Anilinoquinazoline Derivatives as the First Potent NOD1-RIPK2 Signaling Pathway Inhibitors at the Nanomolar Range. Journal of Medicinal Chemistry.2024. 2. Matouš Hrdinka; Lisa Schlicher; Bing Dai; Daniel M. Pinkas; Joshua C. Bufton; et al. Small molecule inhibitors reveal an indispensable scaffolding role of RIPK 2 in NOD 2 signaling. The EMBO Journal.2018. 3.  Anh‐Tuan Pham; Amanda Franceschini Ghilardi; Lijun Sun. Recent advances in the development of RIPK2 modulators for the treatment of inflammatory diseases.  Frontiers in Pharmacology.2023. 4.  Chen Lu; Hongda Liu; Tianyu Liu; Sizheng Sun; Yanan Zheng; et al. RIPK2 promotes colorectal cancer metastasis by protecting YAP degradation from ITCH-mediated ubiquitination. Cell Death & Disease.2025. 5. Chunnan Zhao; Zezhi Zhang; Ran Li; Xueli Geng. XIAP down-regulation inhibits RIPK2 ubiquitination-mediated insulin resistance. Endocrine Connections.2026. 关于我们 优爱蛋白是优宁维集团旗下品牌，始终专注于为药物研发、细胞治疗、基因治疗及基础科研等领域提供全面的蛋白类试剂与技术服务。我们的产品涵盖药物靶点蛋白、细胞因子、工具酶、药物筛选与激酶检测试剂盒，同时承接蛋白定制表达、全长跨膜蛋白开发等项目。 优爱蛋白秉持"品质驱动创新，服务赋能科研"的理念，致力于为客户提供优质可靠的科研产品与高效定制化服务，持续推动生命科学前沿发展，矢志成为具有国际竞争力的高新技术企业。 南京优爱生物科技研发有限公司 邮箱：order@ua-bio.com 官网：买重组蛋白，找南京优爱 (ua-bio.com)