Teprasiran

治疗急性肾损伤的新药 New drugs for acute kidney injury Citation: Hariri G, Legrand M. New drugs for acute kidney injury. J Intensive Med. 2024;5(1):3–11. doi: 10.1016/j.jointm.2024.08.001. 核心结论 急性肾损伤（AKI）在重症及围术期患者中发病率高达30%-60%，目前仍无高级别证据支持的预防或治疗药物。本文系统综述了基于最新病理生理机制（炎症应答、代谢重编程、血流动力学调节、补体活化及细胞凋亡/修复）的在研新药，涵盖碱性磷酸酶、Reltecimod、血管紧张素II、维生素B3类、CD39重组蛋白、Ravulizumab、siRNA QPI-1002及间充质干细胞等。多项II/III期临床试验正在评估其疗效，为降低AKI发生率及严重程度带来新希望。 正文 急性肾损伤（AKI）是全球性健康问题，每年影响超过1300万人，并导致约170万例死亡[1]。从病理生理角度看，AKI以肾小球滤过率（GFR）快速下降为特征，数小时或数日内表现为血清肌酐急剧升高。2004年之前由于缺乏统一定义，AKI的诊断标准从轻度肌酐升高至需要肾脏替代治疗（RRT）范围广泛[2]。RIFLE、AKIN及KDIGO分级系统的建立，依据血清肌酐和尿量变化提供了结构化诊疗路径，实现了早期识别与干预[3-5]。在重症监护环境中，AKI发病率异质性较大（15%-60%），且与死亡率升高、住院时间延长及慢性肾脏病（CKD）风险增加密切相关[6-8]。尽管过去二十年危重症患者管理取得显著进步，但预防或治疗AKI的有效药物干预仍十分缺乏。近期对AKI病理生理机制的深入理解揭示了炎症、代谢紊乱及细胞修复障碍等共同通路，为新型药物研发提供了方向（图1，表1）。 图1：重症及围术期急性肾损伤预防或治疗新药的作用机制概览。HGF: 肝细胞生长因子；MSC: 间充质干细胞。 基于上述机制，目前处于研发阶段的药物涵盖了免疫调节、血流动力学优化、细胞能量代谢支持、补体抑制及抗凋亡/促修复等多个维度。下文按照靶点分类逐一阐述代表性药物的临床证据。1. 炎症调控 碱性磷酸酶（ALP）可通过去磷酸化脂多糖（LPS）及胞外ATP/ADP，减轻Toll样受体介导的先天免疫反应。STOP-AKI试验（n=301）中，重组ALP（ilofotase alfa）虽未改善7天肾功能，但28天肌酐清除率提升18.5 mL/min（95%CI: 5.3-31.7），死亡率降低（14.4% vs 26.7%）[18]。然而后续III期REVIVAL试验（n=655）未显示28天全因死亡率获益，但MAKE90复合终点（56.7% vs 64.6%, P=0.02）提示可能降低RRT需求[19]。针对CSA-AKI的II期预防试验（NCT06168799）正在进行。 Reltecimod是一种靶向T细胞表面CD28的肽类，可调节脓毒症免疫应答。在坏死性软组织感染III期试验中虽未达到主要复合终点，但第14天SOFA评分改善（65.1% vs 52.6%, P=0.04）[24]。目前针对KDIGO 2-3期AKI合并腹腔脓毒症的III期试验（NCT03403751）正在评估28天AKI恢复率。 活性维生素D（骨化三醇）可通过下调核因子κB减轻炎症。但ACTIVATE-AKI试验（NCT02962102）未显示7天内死亡或RRT需求的显著差异。RBT-1（锡原卟啉+蔗糖铁）通过上调HO-1、铁蛋白发挥预适应保护，PROTECT III期研究（n=400）正在进行，主要终点为死亡、透析需求、ICU住院日及30天再入院复合指标。 TIN816（重组CD39）可水解胞外ATP/ADP，抑制炎症及血小板聚集。针对SA-AKI的II期试验（NCT05996835）以第1-8天时间校正肌酐清除率曲线下面积为主要终点；CSA-AKI预防试验（NCT05524051）计划纳入120例患者。2. 血流动力学调节 血管紧张素II选择性收缩肾出球小动脉，提升GFR。ATHOS-3试验显示，血管紧张素II显著提高顽固性血管扩张性休克患者3小时平均动脉压（69.9% vs 23.4%, OR=7.95）[46]，且在需RRT的亚组中28天生存率更高（53% vs 30%）[47]。预防CSA-AKI的可行性研究提示AKI发生率降低（25% vs 38%, P=0.31），III期试验（NCT05199493）正在开展。 血管加压素：心脏术后血管麻痹性休克患者中，血管加压素较去甲肾上腺素显著降低CSA-AKI（10.3% vs 35.8%, P<0.0001）[52]；但在脓毒性休克中未显示AKI预防获益。个体患者数据Meta分析提示可能降低RRT需求（RR=0.86）。两项RCT（NCT04602767, NCT06125184）将进一步明确。 左西孟旦：钙增敏剂兼有入球小动脉扩张作用。心脏手术Meta分析显示可减少CSA-AKI（OR=0.51）及RRT（OR=0.43），但大型RCT未证实获益[57]。LEVO-AKI试验（NCT02531724）正在评估已发生CSA-AKI的治疗效果。3. 细胞代谢与线粒体功能 维生素B3类（烟酰胺、烟酰胺核糖）通过补充NAD+保护肾小管。心脏手术II期试验显示烟酰胺使AKI发生率降低35%[59]。多项RCT正在验证其预防CSA-AKI（NCT04750616）、肾移植后移植物功能（NCT05513807）及脓毒性休克相关AKI（NCT04589546）的疗效。ASP1128（PPARδ调节剂）在心脏手术高危患者中未减少AKI发生率（24.6% vs 21%, P=0.595）[62]。SIRT1激活剂NRPT（烟酰胺核糖+紫檀芪）II期试验（NCT04342975）正在主动脉弓置换患者中评估预防效果。 表1：重症及围术期急性肾损伤预防/治疗新药汇总 药物 机制 靶点 相关临床试验 研究人群 Angiotensin II 血流动力学 肾出球小动脉 NCT05199493 预防CSA-AKI Angiotensin II 血流动力学 肾出球小动脉 NCT04592744 肝移植后AKI预防 Angiotensin II 血流动力学 肾出球小动脉 NCT04901169 肝移植后AKI预防 Vasopressin 血流动力学 V1a受体 NCT04602767 预防CSA-AKI Vasopressin 血流动力学 V1a受体 NCT06125184 预防SA-AKI(脓毒性休克) Levosimendan 血流动力学/正性肌力 肾入球小动脉 NCT02531724 CSA-AKI治疗 Reltecimod 免疫调节 CD28 NCT03403751 SA-AKI(腹腔脓毒症) Activated vitamin D 免疫调节 NF-κB NCT02962102 高危患者AKI预防 ALP (Ilofotase alfa) 免疫调节 TLR-4/LPS NCT06168799 预防CSA-AKI RBT-1 缺血预适应 HO-1/铁蛋白 PROTECT study 预防CSA-AKI TIN816 ATP/ADP水解 CD39 NCT05996835 SA-AKI TIN816 ATP/ADP水解 CD39 NCT05524051 预防CSA-AKI Vitamin B3 (Nicotinamide) 细胞代谢 NAD+合成 NCT04750616 预防CSA-AKI Nicotinamide 细胞代谢 NAD+ NCT05513807 肾移植后移植物功能延迟 NR (Nicotinamide riboside) NAD+前体 SIRT1 NCT04818216 COVID-19相关AKI ASP1128 PPARδ激动剂 脂肪酸氧化 II期(已停止) CSA-AKI高危 NRPT (NR+Pterostilbene) SIRT1激活 NAD+/SIRT1 NCT04342975 主动脉弓置换后AKI预防 Ravulizumab 补体C5抑制剂 C5 NCT05746559 预防CSA-AKI siRNA QPI-1002 抗凋亡 p53 NCT02610296 肾移植后移植物功能延迟 HGF-mimetic (BB3) 细胞修复/抗凋亡 cMet/Bcl-2 NCT02771509 预防CSA-AKI Mesenchymal Stem Cells 免疫调节/修复 多靶点 NCT04445220 COVID-19合并RRT Umbilical cord MSC 组织修复 多靶点 NCT04194671 AKI治疗 补体抑制剂Ravulizumab（长效C5单抗）在COVID-19相关AKI的小样本试验中显示透析需求降低（P=0.03），III期ARTEMIS试验（NCT05746559）正在心脏手术CKD患者中验证其预防CSA-AKI的效果。4. 凋亡抑制与细胞修复 siRNA药物QPI-1002（靶向p53）在心脏手术高危患者中使AKI发生率降低13%（37% vs 50%, P=0.02）[75]，但MAKE90无差异；III期预防试验因无效而终止。HGF模拟物BB3在肾移植后未改善360天eGFR（P=0.32）[80]，GUARD试验（NCT02771509）正在评估其对CSA-AKI的预防效果。间充质干细胞（MSC）在CSA-AKI的II期试验中未显示获益，但体外扩增MSC可能具有免疫修复潜力，相关试验仍在进行（NCT04445220, NCT04194671）。 综上所述，目前尚无获批的AKI特效药，但基于精准病理生理靶点的多种药物已进入后期临床试验阶段，为改善重症及手术患者AKI结局带来了切实希望。 参考文献 Mehta R.L., Cerdá J., Burdmann E.A., Tonelli M., García-García G., Jha V., et al. 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p53 inhibitors are a class of chemical compounds that target and inhibit the function of the p53 protein. The p53 protein, also known as the tumor protein 53, is a critical regulator of cell cycle progression, DNA repair, and apoptosis (programmed cell death). It acts as a tumor suppressor by preventing the proliferation of cells with damaged DNA or mutations that could lead to cancer development. In normal conditions, the p53 protein is tightly regulated and maintained at low levels in the cell. However, in response to various stress signals such as DNA damage, oncogene activation, or hypoxia, the levels and activity of p53 can increase. Activated p53 induces cell cycle arrest, allowing time for DNA repair, or triggers apoptosis if the DNA damage is irreparable. This mechanism helps to maintain genomic stability and prevent the survival and propagation of cells with potentially harmful mutations. p53 inhibitors interfere with the normal function of the p53 protein and are primarily used as research tools to study the biological effects of p53 inactivation. By inhibiting p53, these chemicals allow researchers to investigate the consequences of p53 loss or reduced activity in cellular processes and disease models. There are several types of p53 inhibitors, and they can target different aspects of p53 function. One common approach is to disrupt the interaction between p53 and its negative regulator, MDM2 (mouse double minute 2). MDM2 binds to p53 and promotes its degradation, thereby regulating its levels in the cell. Inhibitors that interfere with the p53-MDM2 interaction prevent MDM2 from tagging p53 for degradation, leading to increased levels and activity of p53. Overall, the p53 pathway is highly complex and involves numerous interactions with other proteins and regulatory mechanisms. Many p53 inhibitors bind directly to the p53 protein and disrupt it's interaction with other proteins involved in p53 signaling pathways. These inhibitors can also interfere with the ability of p53 to activate downstream genes involved in cell cycle arrest or apoptosis. p53 is a crucial protein that plays a vital role in maintaining the integrity of the human body. It acts as a tumor suppressor by regulating cell division and preventing the formation of cancerous cells. p53 monitors DNA damage and initiates repair mechanisms, halting cell division if the damage is irreparable. Additionally, it promotes programmed cell death (apoptosis) to eliminate cells with severe DNA damage. p53 also regulates various cellular processes, including metabolism, angiogenesis, and immune response. Its significance in preventing cancer and maintaining genomic stability makes p53 an essential protein in the human body. p53 Competitive LandscapeAccording to Patsnap Synapse, as of 5 Oct 2023, there are a total of 136 p53 drugs worldwide, from 154 organizations, covering 107 indications, and conducting 211 clinical trials. 👇Please click on the picture link below for free registration or login directly if you have freemium accounts, you can browse the latest research progress on drugs , indications, organizations, clinical trials, clinical results, and drug patents related to this target. The analysis of the current competitive landscape and future development of target p53 reveals a diverse and dynamic pharmaceutical industry. Aprea Therapeutics, Inc. is a key player in the development of drugs targeting p53, with a strong focus on advancing their drugs through clinical trials. The indications for target p53 cover a wide range of diseases and conditions, indicating its potential in various therapeutic areas. The presence of multiple drug types and the intense competition around biosimilars suggest a diverse and innovative approach to targeting p53. China, the United States, and other countries/locations are actively involved in the development of drugs targeting p53, with China showing significant progress. Overall, the future development of target p53 holds promise for advancements in the treatment of various diseases and conditions. Key drug：TeprasiranTeprasiran is a small interfering RNA (siRNA) drug that targets the p53 protein. It is being developed by Silence Therapeutics Plc, a pharmaceutical company specializing in RNA interference (RNAi) therapeutics. The drug is currently in Phase 3, which is the final stage of clinical trials before seeking regulatory approval. Teprasiran is primarily being investigated for its potential use in treating urogenital diseases and other diseases. Specifically, it is being studied for its efficacy in treating acute kidney injury and delayed graft function. These conditions are characterized by damage to the kidneys, which can lead to impaired kidney function and potentially life-threatening complications. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. One notable aspect of Teprasiran is its regulatory status as an orphan drug. Orphan drugs are medications developed to treat rare diseases or conditions that affect a small number of patients. The designation provides certain incentives and benefits to the drug developer, such as extended market exclusivity and financial support for clinical trials. siRNA drugs like Teprasiran work by interfering with the expression of specific genes, in this case, the p53 gene. The p53 protein is known as the "guardian of the genome" and plays a crucial role in regulating cell growth and preventing the formation of tumors. By targeting p53, Teprasiran aims to modulate its activity and potentially provide therapeutic benefits in the treatment of urogenital diseases and other conditions. As Teprasiran is currently in Phase 3, it is undergoing rigorous testing to evaluate its safety and efficacy in a larger patient population. The results of these trials will determine whether the drug can proceed to regulatory approval and ultimately be made available to patients. In summary, Teprasiran is a siRNA drug developed by Silence Therapeutics Plc that targets the p53 protein. It is being investigated for its potential use in treating urogenital diseases and other conditions, specifically acute kidney injury and delayed graft function. With its orphan drug designation and current Phase 3 status, Teprasiran holds promise as a potential therapeutic option for patients in need.