A Randomized, Double-Blind, Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of QPI-1002 for the Prevention of Major Adverse Kidney Events (MAKE) in Subjects at High Risk for Acute Kidney Injury (AKI) Following Cardiac Surgery

This trial is designed to evaluate QPI-1002 versus placebo for the prevention of Major Adverse Kidney Events (MAKE) in subjects at high risk for acute kidney injury following cardiac surgery. Half of the participants will receive QPI-1002 while the other half will receive placebo.

开始日期2018-06-29

申办/合作机构

Quark Pharmaceuticals, Inc.

NCT02610296

/ Completed临床3期

A Phase 3, Randomized, Double-blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of QPI-1002 for Prevention of Delayed Graft Function in Recipients of a Donation After Brain Death Older Donor Kidney Transplant

The purpose of this trial is to evaluate the reduction in incidence and severity of delayed graft function with kidney allografts from donors >45 years after brain death (DBD).

开始日期2016-03-01

申办/合作机构

Quark Pharmaceuticals, Inc.

NCT02610283

/ Completed临床2期

A Randomized, Double-Blind, Placebo Controlled , Phase 2 Study to Evaluate the Efficacy and Safety of QPI-1002 for the Prevention of Acute Kidney Injury in Subjects at High Risk for AKI Following Cardiac Surgery

This trial is designed to evaluate QPI-1002 versus placebo for the prevention of AKI in subjects who are at high risk for AKI following cardiac surgery. Half of the participants will receive QPI-1002 while the other half will receive placebo.

开始日期2015-12-01

申办/合作机构

Quark Pharmaceuticals, Inc.

100 项与 Teprasiran 相关的临床结果

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100 项与 Teprasiran 相关的转化医学

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100 项与 Teprasiran 相关的专利（医药）

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项与 Teprasiran 相关的文献（医药）

2021-10-05·Circulation1区 · 医学

Teprasiran, a Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Study

1区 · 医学

Article

作者: Molitoris, Bruce ; Mazer, C. David ; Lamy, Andre ; Squiers, Elizabeth C. ; Thielmann, Matthias ; Swaminathan, Madhav ; Corteville, David ; Atta, Mohamed G. ; Lehner, Lukas J. ; Erlich, Shai ; Brown, Craig D. ; Rothenstein, Daniel ; Szabo, Gabor ; Noiseux, Nicolas

Background::

Acute kidney injury (AKI) affects up to 30% of patients undergoing cardiac surgery, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA that temporarily inhibits p53-mediated cell death that underlies AKI.

Methods::

This prospective, multicenter, double-blind, randomized, controlled phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran versus placebo (1:1), in reducing the incidence, severity, and duration of AKI after cardiac surgery in high-risk patients. The primary end point was the proportion of patients who developed AKI determined by serum creatinine by postoperative day 5. Other end points included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite end point of major adverse kidney events at day 90, including death, renal replacement therapy, and ≥25% reduction of estimated glomerular filtration rate was assessed. Both serum creatinine and serum cystatin-C were used for estimated glomerular filtration rate assessments.

Results::

A total of 360 patients were randomly assigned in 41 centers; 341 dosed patients were 73±7.5 years of age (mean±SD), 72% were men, and median European System for Cardiac Operative Risk Evaluation score was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran- versus 50% for placebo-treated patients, a 12.8% absolute risk reduction, P =0.02; odds ratio, 0.58 (95% CI, 0.37–0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran- versus 6.7% of placebo-treated patients had grade 3 AKI; 7% teprasiran- versus 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the major adverse kidney events at day 90 composite in the overall population. No safety issues were identified with teprasiran treatment.

Conclusions::

The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced after teprasiran administration. A phase 3 study with a major adverse kidney event at day 90 primary outcome that has recently completed enrollment was designed on the basis of these findings (NCT03510897).

Registration::

URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02610283.

2021-07-01·Biochemical pharmacology2区 · 医学

The growth of siRNA-based therapeutics: Updated clinical studies

2区 · 医学

Review

作者: Manautou, José E ; Zhong, Xiao-Bo ; Bahal, Raman ; Rasmussen, Theodore P ; Zhang, M May

More than two decades after the natural gene-silencing mechanism of RNA interference was elucidated, small interfering RNA (siRNA)-based therapeutics have finally broken into the pharmaceutical market. With three agents already approved and many others in advanced stages of the drug development pipeline, siRNA drugs are on their way to becoming a standard modality of pharmacotherapy. The majority of late-stage candidates are indicated for rare or orphan diseases, whose patients have an urgent need for novel and effective therapies. Additionally, there are agents that have the potential to meet the need of a broader population. Inclisiran, for instance, is being developed for hypercholesterolemia and has shown benefit in patients who are uncontrolled even after maximal statin therapy. This review provides a brief overview of mechanisms of siRNA action, physiological barriers to its delivery and activity, and the most common chemical modifications and delivery platforms used to overcome these barriers. Furthermore, this review presents comprehensive profiles of the three approved siRNA drugs (patisiran, givosiran, and lumasiran) and the seven other siRNA candidates in Phase 3 clinical trials (vutrisiran, nedosiran, inclisiran, fitusiran, teprasiran, cosdosiran, and tivanisiran), summarizing their modifications and delivery strategies, disease-specific mechanisms of action, updated clinical trial status, and future outlooks.

2018-05-01·Pediatric nephrology (Berlin, Germany)3区 · 医学

Acute kidney injury: emerging pharmacotherapies in current clinical trials

3区 · 医学

Review

作者: Devarajan, Prasad ; Benoit, Stefanie Woolridge

Acute kidney injury (AKI) is a significant source of morbidity and mortality in pediatric patients, affecting more than one quarter of critically ill children. Despite significant need, there are no targeted therapies to reliably prevent or treat AKI. Recent advances in our understanding of renal injury and repair signaling pathways have enabled the development of several targeted pharmaceuticals. Here we review emerging pharmacotherapies for AKI that are currently in clinical trials. Categorized by their general mechanism of action, the therapies discussed include anti-inflammatory agents (recAP, AB103, ABT-719), antioxidants (iron chelators, heme arginate), vasodilators (levosimendan), apoptosis inhibitors (QPI-1002), and repair agents (THR-184, BB-3, mesenchymal stem cells).

项与 Teprasiran 相关的新闻（医药）

2023-10-25

·SYNAPSE

Analysis on the Research Progress of p53 inhibitors

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.

2022-07-29

·行舟Drug

独家原创|全球基因治疗药物研发现状分析

点击上方的行舟Drug ▲ 添加关注全球基因治疗药物研发现状分析 PPS 朱凌峰，王中健*（药融云数字科技（成都）有限公司，四川成都610000）[摘要]随着DNA重组、基因克隆等技术的逐步成熟，基因治疗这一具有革命性的医疗技术不断发展，改变了单基因遗传病的治疗现状，为肿瘤、遗传性疾病、自身免疫性疾病等带来了新的选择。截至2022年2月，全球已有37款基因治疗药物获批上市。通过对1998年至2022年2月全球范围内获批上市的基因治疗药物进行数据监控与分析，包括药物分类、药物名称、适应证、批准日期、批准国家、研发公司等，并且对全球在研基因治疗药物的研发现状进行分析总结，以期为基因治疗药物的立项与研发提供参考。1基因治疗药物概述1968年，美国科学家迈克尔·布莱泽发表了《改变基因缺损：医疗美好前景》的文章，首次在医学界提出了基因治疗的概念[1]。基因治疗是以改变人的遗传物质为基础的生物医学治疗手段，是指将外源正常基因导入靶细胞，以纠正或补偿因基因缺陷或基因表达异常引起的疾病，从而达到治疗疾病的目的[2]。美国食品药品监督管理局（Food and Drug Administration，FDA）对基因治疗定义为：基因治疗是一种通过改变人的基因来治疗或治愈疾病的技术。基因治疗可以通过以下几种机制发挥作用：1）用一个正常基因来替换致病基因；2）使不能正常发挥作用的致病基因失活；3）将一种新的或经过修饰的基因导入体内以帮助治疗疾病。基因治疗药物，是指经过药物监管机构批准的用于治疗人体相关疾病的基因类产品[3]。从1998年全球首款基因治疗药物上市到2015年期间，断断续续有少量基因治疗药物获批；从2016年开始，每年都有多款基因治疗药物获批上市。截至2022年2月，全球共有37款基因治疗药物获批上市，从1998年到2022年2月，每年基因治疗药物获批上市的数量如图1所示。基因治疗药物按照结构可划分为核酸类药物、重组病毒类药物以及细胞治疗类药物。其中核酸药物按照种类又可划分为DNA药物（裸质粒等）、RNA药物[干扰RNA（RNAi）等]及反义寡核苷酸药物，其作用原理是借助一定载体将核酸药物传送进细胞内并进行复制转录继而从基因层面起到治疗效果；重组病毒类药物是利用人工修饰过的病毒选择性进攻人体病灶部位，以起到治疗疾病的目的，该类药物目前大多用于治疗癌症；细胞治疗类药物以细胞为主体通过基因工程技术对相关功能细胞进行改造，改造后的细胞直接输送回病人体内用以治疗相关疾病。已上市37款基因治疗药物中，核酸类药物共计15款，其中裸质粒2款，反义寡核苷酸9款，RNAi4款；重组病毒类药物9款；细胞治疗类药物13款（见图2）。从获批药物的疾病领域来看，近一半是罕见病，其次是肿瘤（见图3）。针对肿瘤的基因治疗主要是嵌合抗原受体T细胞免疫疗法（chimeric antigen receptor T-Cell immunotherapy，CAR-T）药物和溶瘤病毒药物。从获批药物使用的载体来看，裸质粒/寡核苷酸最多，其次是慢病毒和逆转录病毒载体（见图4）。本文将分别按照核酸类药物、重组病毒类药物和细胞治疗类药物对目前已经上市的基因治疗药物以及全球研发现状进行介绍。2核酸类药物2.1裸质粒截至2022年2月，全球共有2个裸质粒药物获批上市，分别为2011年在俄罗斯上市的Neovasculgen（cambiogenplasmid）和2019年在日本上市的Collategene（beperminogene perplasmid）（见表1）。Neovasculgen是一个编码血管内皮生长因子基因的质粒，注射到人体内后，表达出的血管内皮生长因子能够促进血管的生成，从而改善患者的生活质量[4]。Collategene是一种编码肝细胞生长因子基因的质粒，注射到人体内后，表达出的肝细胞生长因子能够促进血管的生成，从而治疗缺血性疾病。相关研究表明[5-6]，病毒载体介导的促血管生成因子基因的传递诱导了小鼠心脏血管瘤的形成，将表达血管内皮生长因子的基因工程细胞注入到正常肌肉中，术后24d后也可以观察到血管瘤的形成。因此，为避免促血管生成因子的长期表达，裸质粒是一个很好的选择。目前裸质粒的主要开发方向就是编码促血管生成因子基因。截至2022年2月，全球处于已上市及在研状态的裸质粒基因治疗药物共计39个（见图5）。目前处于Ⅲ期临床的2款药物的相关信息如表2所示。重组质粒-肝细胞生长因子注射液（pUDK-HGF）是由中国人民解放军军事医学科学院放射与辐射医学研究所研发，人福医药合作开发的裸质粒药物。其治疗严重下肢缺血性疾病导致的肢体静息痛的Ⅲ期临床试验（CTR20181274）正在进行中，首次公示日期为2018年8月9日，主要临床机构为首都医科大学宣武医院。由Helixmith公司研发的重组人肝细胞生长因子裸质粒注射液（NL-003）目前正在全球范围内开展临床试验，其在中国的开发由北京诺思兰德生物技术股份有限公司进行，目前治疗下肢缺血性疾病的Ⅲ期临床试验（CTR20190746和CTR20190750）正在进行中，首次公示日期为2019年4月17日，主要临床机构为北京协和医院。2.2 反义寡核苷酸反义寡核苷酸是一种单链寡核苷酸分子，通常包含15~25个核苷酸残基。其进入细胞后在核糖核酸酶H1的作用下通过碱基互补配对原则同与其互补的靶信使核糖核酸（messenger RNA，mRNA）结合，抑制靶基因的表达。截至2022年2月，全球共有9款反义寡核苷酸药物获批上市（见表3）。1998年，美国FDA批准了首款基因治疗药物Vitravene（fomivirsen），Vitravene是一种反义寡核苷酸，可用于治疗局部免疫缺陷患者（包括获得性免疫缺陷综合征患者）的巨细胞病毒视网膜炎，但是，由于更高效抗逆转录病毒治疗药物的开发，Vitravene于2002年退出欧洲市场，并于2006年退出美国市场[7]。2013年，美国FDA批准了一款包含载脂蛋白B-100的反义寡核苷酸药物Kynamro（mipomersen）用于治疗纯合子家族性高胆固醇血症[8]。2016年，有2个反义寡核苷酸药物获得美国FDA批准，分别为Spinraza（nusinersen）和Exondys51（eteplirsen）。Spinraza用于治疗脊髓性肌萎缩，Exondys51用于治疗杜氏肌营养不良症[9-10]。2018年7月，Tegsedi（inotersen）作为一款反义寡核苷酸药物获得欧盟药品管理局（European Medicines Agency，EMA）的批准，用于治疗遗传性甲状腺淀粉样变性[11]。2019年，Waylivra（volanesorsen）获得了EMA批准用于治疗成年人家族性乳糜微粒血症综合征[12]。Vyondys53（golodirsen）获得了FDA批准用于治疗杜氏肌营养不良症[13]。2020年，日本独立行政法人医药品医疗器械综合机构（Pharmaceuticals and Medical Devices Agency，PMDA）批准了Viltepso（viltolarsen），用于治疗杜氏肌营养不良症[14]。2021年，FDA批准了Amondys45（casimersen）用于治疗杜氏肌营养不良症[15]。从治疗领域来看，除了已经退市的Vitravene外，全部是罕见病治疗领域，其中有4个适应证为杜氏肌营养不良症。从开发公司来看，小核酸药物研发公司Ionis公司占5个，Sarepta公司占3个。截至2022年2月，全球处于已上市及在研状态的反义寡核苷酸基因治疗药物共计345个，临床前180个，进入临床阶段的共计90个（见图6）。其中，目前处于Ⅲ期临床的13款药物如表4所示。Alicaforsen是细胞间黏附分子-1的反义抑制剂，最新的针对结肠袋炎的Ⅲ期临床效果不佳，未达到预期主要终点，经内窥镜评估缓解率，与安慰剂相比并无改善（4.6% vs. 4.9%）。Sepofarsen是一种旨在解决CEP290基因中p.Cys998X突变引起的莱伯先天性黑内障的反义寡核苷酸，p.Cys998X突变会导致mRNA的异常剪接和中心体蛋白290（centrosomal protein of 290 kDa，CEP290）失去功能，sepofarsen通过结合到pre-mRNA的突变位置，使得产生正常的CEP290[16]。Imetelstat是一种端粒酶抑制剂，在治疗骨髓增生异常综合征的Ⅱ/Ⅲ期临床试验IMerge中，imetelstat取得了积极的临床效果，持续8周输血不依赖率达到34.3%，而其中未接受过低甲基化药物或来那度胺治疗，且无染色体5q缺失的持续8周输血不依赖率达到53.8%[17]。AKCEA-APOCIII-LRx是由Ionis公司专有的配体共轭反义技术平台开发的反义寡核苷酸药物，能够抑制载脂蛋白C-Ⅲ（apolipoprotein C-Ⅲ，ApoC Ⅲ）的产生。ApoC Ⅲ是一种在肝脏中产生的蛋白质，在血清三酰甘油的调节中发挥着核心作用。Trabedersen是TGF-β2基因mRNA区域的反义互补物，通过下调TGF-β2mRNA发挥抑制作用。在Ⅱ期临床研究中，与标准化疗治疗相比，使用10mmol·L-1trabedersen治疗的复发/难治性晚期胶质瘤患者的2年生存率更高。亨廷顿舞蹈症的主要机制为患者4号染色体上的亨廷顿基因CAG三核苷酸重复扩增，从而导致亨廷顿蛋白质具有延伸的聚谷氨酰胺束，并在细胞内积聚成大分子团，影响神经元的正常功能[18]。Tominersen可以在核糖核酸酶H1的作用下通过碱基互补配对原则与其互补的靶mRNA结合，抑制靶基因的表达。基于这一原理，tominersen可靶向相应的mRNA以防止蛋白质产生，基于非盲独立数据监测委员会对受试者的潜在风险/收益比提出了意见，罗氏于2021年3月宣布终止tominersen治疗显性亨廷顿舞蹈症的Ⅲ期GENERATION HD1临床的给药工作。携带肉瘤融合基因（fused in sarcoma，FUS）突变的患者会发展成罕见形式的肌萎缩侧索硬化症（amyotrophic lateral sclerosis，ALS），即FUS-ALS，FUS基因突变是青少年ALS最常见的病因。ION-363是一种靶向FUS mRNA的反义药物，以减少FUS蛋白质的产生。在FUS-ALS小鼠模型中，反义介导的突变FUS蛋白质减少可以防止运动神经元丢失。通过靶向FUS-ALS的根本病因，ION-363有潜力减少或防止患者的病情进展。Aganirsen可抑制胰岛素受体底物1（insulin receptor substrate 1，IRS1）的表达，被研究用于角膜和视网膜新生血管的治疗。Tofersen是一种反义寡核苷酸药物，旨在降低超氧化物歧化酶1（superoxide dismutase1，SOD1）的mRNA，从而降低SOD1蛋白，在对SOD1-ALS的Ⅲ期临床试验VALOR中，与安慰剂相比，tofersen在其主要终点上并没有取得统计上显著的改善。Eplontersen是一种靶向转甲状腺素的反义寡核苷酸药物。Pelacarsen是首个靶向脂蛋白（a）[lipoprotein（a），Lp（a）]的反义寡核苷酸降脂药，pelacarsen的Ⅱb期临床试验研究显示，98%的患者Lp（a）水平降至50mg·dL-1以下的适宜水平。ION-373是一种靶向胶质纤维酸性蛋白mRNA的反义寡核苷酸药物，FDA已授予ION-373孤儿药资格认定。Donidalorsen是一种抑制前激肽释放酶产生的反义寡核苷酸药物，前激肽释放酶在遗传性血管性水肿急性发作相关的炎症介质激活中起关键作用，该药物治疗遗传性血管性水肿的Ⅲ期临床正在进行中，Ⅱ期临床试验研究显示，与安慰剂组相比，donidalorsen可减少遗传性血管性水肿的发作。2.3 RNA干扰药物截至2022年2月，全球共有4款RNAi药物获批上市（见表5），4款RNAi药物都是小干扰RNA（small interfering RNA，siRNA）药物，siRNA进入细胞后，与解旋酶和其他因子结合，形成RNA诱导沉默复合物（RNA-induced silencing complex，RISC），RISC与mRNA结合，使得mRNA降解。2018年，Onpattro（patisiran）作为首个RNAi药物获得FDA和EMA的许可，用于治疗淀粉样变性[19]。2019年，Givlaari（givosiran）获得FDA批准用于治疗肝卟啉病。2020年，2款RNAi药物获批上市，Oxlumo（lumasiran）获得EMA和FDA批准用于治疗高草酸尿症[20]，Leqvio（inclisiran）获得EMA批准用于治疗高胆固醇血症。Leqvio的获批上市，也使得RNAi疗法的疾病领域不仅局限于罕见病[21]。载体上，除了Onpattro使用的纳米脂质体，后续3个药物都是使用靶向肝细胞的N-乙酰半乳糖胺（N-acetylgalactosamine，GalNAc）修饰。截至2022年2月，全球处于已上市及在研状态的RNAi基因治疗药物共计235项（见图7），其中临床前131项。已提交上市申请和Ⅲ期临床试验的7款药物如表6所示。RNAi疗法药物vutrisiran靶向和沉默特定的mRNA，从而阻止野生型和突变型甲状腺素转运蛋白（transthyretin，TTR）的产生，在Ⅲ期临床试验HELIOS-A中取得积极的临床结果，2021年6月，Alnylam宣布FDA已受理vutrisiran的新药申请[22]。Fitusiran使用siRNA来靶向并减少抗凝血酶，从而促进血友病A或B的患者有足够的凝血酶生成，以恢复止血功能和防止出血。然而于2020年11月，因发现新的不良反应事件，赛诺菲宣布fitusiran的研究暂时搁置。Tivanisiran是一种靶向香草酸受体（transient receptor potential cation channel subfamily V member 1，TRPV1）的小分子RNAi疗法药物，Sylentis公司发布的Ⅲ期临床试验HELIX显示，中央角膜染色的减少有改善（P=0.035）。Cosdosiran是一种靶向细胞凋亡相关基因caspase-2的mRNA的siRNA药物，拟用于治疗视网膜神经节细胞死亡相关的疾病。目前，cosdosiran用于非动脉性缺血性视神经病变治疗的Ⅱ/Ⅲ期临床试验已于2019年6月终止，原因是中期分析的结果不足以支持后续的患者入组。Teprasiran可通过暂时抑制P53介导的细胞死亡，减少急性肾损伤（acute kidney injury，AKI）发生，41个临床试验中心共360例患者随机分为给药组（10mg·kg-1）和安慰剂组，给药方式为术后4h内单次静脉推注，术后7d内每日随访，第30、90和365d时再进行3次随访观察。结果显示，teprasiran可显著降低心脏术后患者AKI的发生率、严重程度及持续时间，90d内主要不良事件的发生率与安慰剂组无统计学差异[23]。Nedosiran是一种正在开发用于原发性高草酸尿症（primary hyperoxaluria，PH）1、PH2和PH3型的RNAi候选药物，旨在抑制肝乳酸脱氢酶（lactate dehydrogenase，LDH）的产生，该酶可催化乙醛酸代谢途径的最后一步，可以导致PH1、PH2或PH3患者草酸过量产生，在治疗PH患者中的关键临床试验PHYOX2中取得了积极顶线结果。ARO-APOC3是一种靶向ApoC Ⅲ的RNAi药物，其治疗家族性乳糜微粒血症的Ⅲ期临床试验正在进行中。3重组病毒类药物病毒因其良好的感染效率和在体内外靶细胞中持久表达的潜力被用于生物研究领域重组细胞的构建以及作为医药领域基因治疗技术的重要载体。而现在，病毒除了可以作为细胞和基因治疗药物的主要工具外，重组病毒也已经作为一类药物进入临床使用[24]。目前，主要应用的病毒包括腺病毒及腺相关病毒、逆转录病毒、单纯疱疹病毒等。截至2022年2月，全球共有9款重组病毒类基因治疗药物获批上市（见表7）。2003年，我国批准一款重组腺病毒载体表达p53治疗头颈癌的基因治疗药物——今又生（重组人p53腺病毒注射液）。今又生被认为是我国首个商品化的基因治疗药物[25]。2005年，我国批准了用于治疗鼻咽癌的世界首个溶瘤病毒药物安柯瑞（重组人5型腺病毒注射液）[26]。2007年，菲律宾批准了Rexin-G（Mx-dnG1）用于治疗软组织肉瘤和骨肉瘤，Rexin-G也是一种溶瘤病毒药物，所用的病毒载体为逆转录病毒[27]。2009年，拉脱维亚批准了Rigvir（VirusECHO-7）用于治疗黑色素瘤，Rigvir也是一款溶瘤病毒药物，所用的病毒载体为ECHO-7肠道病毒[28]。2012年，EMA批准了Glybera（alipogene tiparvovec）用于治疗家族性脂蛋白脂酶缺乏症，Glybera所用的载体为重组腺相关病毒。Glybera的获批上市是整个基因治疗领域的里程碑，促进了基因治疗的发展。但是，由于高昂的价格以及市场需求有限，Glybera已经撤市[29]。2015年，Imlygic（talimogene laherparepvec）获得FDA批准用于治疗黑色素瘤，这是FDA批准的首个溶瘤病毒药物，使用的载体为单纯疱疹病毒[30]。2017年，腺相关病毒载体药物Luxturna（voretigene neparvovec-rzyl）获得FDA批准上市用于治疗经证实的双等位基因RPE65突变相关的视网膜营养障碍性疾病[31]。2019年，美国FDA批准Zolgensma（onasemnogene abeparvovec-xioi）用于治疗脊髓性肌萎缩症[32]。2021年6月，PMDA宣布授予Delytact（teserpaturev）许可，在一定的条件及时限内，允许被应用于治疗恶性胶质瘤患者。目前已上市的9款重组病毒类药物中，5款为溶瘤病毒，说明这种借由病毒的“以毒攻毒”的溶瘤病毒疗法已经逐渐取得成功。治疗领域来看，肿瘤治疗有6款，罕见病治疗有3款。使用最多的载体为腺相关病毒载体。截至2022年2月，全球处于已上市及在研状态的病毒载体药物共计980项，其中临床前570项，药物发现147项，临床阶段共计250项（见图8）。溶瘤病毒疗法已上市及在研状态共计212项（占全部重组病毒的21.6%），其中临床前101项（占临床前重组病毒的17.8%），药物发现38项（占比25.9%），临床阶段68项（占临床阶段重组病毒的27.2%）。目前提交上市申请的4款药物如表8所示。Lenadogene nolparvovec是一款重组腺相关病毒的基因治疗药物，病毒内包含编码人野生型线粒体烟酰胺腺嘌呤二核苷酸脱氢酶4蛋白（nicotinamide adenine dinucleotide dehydrogenase4，ND4）的基因，该化合物专为治疗ND4基因突变相关的Leber遗传性视神经病变而开发。GenSight公司根据Ⅰ/Ⅱa期临床试验研究（CLIN-01）、2项关键性Ⅲ期的有效性研究（CLIN-03A：RESCUE和CLIN-03B：REVERSE）以及RESCUE和REVERSE的长期随访研究，同时结合统计学的间接比较方法，确立基因疗法与自然病史对比的药效和获益-风险比，并以此为基础提交上市申请[33]。Valoctocogene roxaparvovec是一种使用腺相关病毒来递送凝血因子Ⅷ功能基因，用以恢复凝血因子Ⅷ的产生，从而起到治疗A型血友病的基因治疗药物，Ⅲ期临床研究结果显示，年化出血率下降84%。Eladocagene exuparvovec是一种基于腺相关病毒提供芳香族L-氨基酸脱羧酶（amino acid decarboxylase，AADC）基因的基因治疗药物[34]。Nadofaragene firadenovec是一款重组腺病毒的基因治疗药物，含有干扰素α-2b基因，每3个月1次通过导管灌注膀胱。腺病毒进入膀胱壁细胞后，释放出活性基因，经转录和翻译后，使膀胱壁细胞分泌大量的干扰素α-2b蛋白，从而增强抗肿瘤活性[35]。4细胞治疗4.1自体细胞治疗细胞治疗是利用患者自体或异体的成体细胞或干细胞对组织、器官进行修复的治疗方法。FDA对来自于患者自体的细胞基因治疗的定义是：从患者体内取出细胞、基因改造（通常使用病毒载体），然后回输到患者体内。细胞治疗给患有无法治愈的疾病的患者带来了希望。截至2022年2月，全球共有11款自体细胞基因治疗药物获批上市（见表9）。2016年，EMA批准Strimvelis用于治疗由于腺苷脱氨酶缺失导致的重症联合免疫缺陷。Strimvelis是一种表达人腺苷脱氨酶的CD34+自体细胞，是全球首个获批上市的细胞基因治疗药物[36]。2017年，FDA批准了全球首款及第2款CAR-T产品Kymriah（tisagenlecleucel）和Yescarta（axicabtagene ciloleucel）。2款药物都是在体外将CD19基因导入到患者自体的T细胞中。Kymriah可用于治疗25岁以下的复发或难治性B细胞急性淋巴细胞白血病；Yescarta被用来治疗成年患者复发或难治愈的大B细胞淋巴瘤[37-38]。2019年，EMA批准了Zynteglo用于治疗12岁及以上的输血依赖性β-地中海贫血症，Zynteglo是一种含有造血干细胞的用慢病毒载体转导了βA-T87Q球蛋白基因的CD34+自体细胞[39]。2020年，2款自体细胞治疗药物上市，分别为FDA批准的用于治疗套细胞淋巴瘤的CAR-T产品Tecartus（brexucabtagene autoleucel）以及EMA批准的用于治疗异染性脑白质营养不良的药品Libmedly。Libmedly是一种含有造血干细胞和祖细胞的用慢病毒载体转导了人芳基硫酸酯酶A基因的CD34+自体细胞[40]。2021年，3款CAR-T产品和1款自体细胞治疗药物获得批准上市，FDA批准了用于治疗弥漫性大B细胞淋巴瘤的Breyanzi（lisocabtagene maraleucel）和治疗多发性骨髓瘤的Abecma（idecabtagene vicleucel）[41-42]，我国批准了倍诺达（瑞基奥仑赛注射液）用于治疗经过二线或以上系统性治疗后复发或难治性大B细胞淋巴瘤的成人患者，倍诺达成为我国首个获批为1类生物制品的CAR-T产品。EMA批准了Skysona用于治疗携带ABCD1基因突变的、18岁以下的早期脑性肾上腺脑白质营养不良患者。2022年2月28日，FDA批准Carvykti（ciltacabtagene autoleucel）用于复发或难治性多发性骨髓瘤患者，Carvykti是一款靶向B细胞成熟抗原（B-cell maturation antigen，BCMA）的CAR-T产品，Carvykti是首款由我国自主研发获得FDA批准上市的CAR-T产品[43]。截至2022年2月，全球处于已上市及在研状态的CAR-T药物共计797项，临床阶段共计376项（见图9），适应证以肿瘤为主。4.2 异体细胞治疗在异体细胞基因治疗中，提供基因修饰细胞的供体与接受基因修饰细胞的受体是不同的人。从生产制造的角度来看，异体细胞治疗产品可以形成商业化的现成品，相较于自体细胞治疗，这可以大大降低生产成本[44]。截至2022年2月，全球共有2款异体细胞基因治疗产品获批上市（见表10）。2016年，EMA批准Zalmoxis（nalotimagene carmaleucel）用于造血干细胞移植后辅助恢复患者的免疫系统。2017年，韩国批准Invossa（tissuegene-c）治疗中度骨性关节炎，这是韩国的首款基因治疗药物[45-46]。5结语与展望目前已上市基因治疗药物包括核酸类药物、重组病毒类药物和细胞治疗类药物，核酸类药物细分为裸质粒、反义寡核苷酸和RNAi。裸质粒药物目前的主要应用方向为编码促血管生成因子基因，进一步优化方向为提高其在体内的稳定性与利用度。反义寡核苷酸药物近年来取得了良好的市场表现，美国渤健公司年报披露，2021年Spinraza全球销售额达到20.52亿美元，2021年12月3日该品种正式纳入我国医保，进入医保后，Spinraza在我国的市场规模预计达到30亿元人民币。已上市反义寡核苷酸药物适应证主要是罕见病，我国因人口基数庞大，罕见病人数相对较多，市场需求较高，反义寡核苷酸药物在我国具有相当大的市场潜力。RNAi药物起步较晚，首个药物于2018年获批，RNAi药物对于载体的要求较高，因此构建载体技术平台是开发RNAi药物的关键。重组病毒药物已为肿瘤及罕见病带来突破性的疗效，诺华的Zolgensma只要注射1次就可治愈脊髓性肌萎缩症，展现出基因治疗药物巨大的优势，诺华年报披露2021年Zolgensma全球销售额达到13.51亿美金。细胞治疗药物中自体细胞治疗药物开发较多，异体细胞治疗药物开发较少，然而从生产成本的角度考虑，使用自体细胞生产流程较长，成本远远高于异体细胞，但是使用异体细胞目前效果不佳且副作用较大，仍需技术上的突破。从发展阶段来看，基因治疗正处迅速发展期，越来越多的基因治疗药物进入到临床试验阶段。相信在不久的将来，基因治疗会给更多的疾病带来颠覆的解决方案，给患者带来更多的用药选择。数据说明本文中的上市药物数据和研发管线数据主要来源于：1）全球权威期刊所发表的与基因治疗相关学术文献，该部分已分别标注于文中；2）中国国家药品监督管理局网站（www.nmpa.gov.cn）、美国食品药品监督管理局网站（www.fda.gov）、欧洲药品管理局网站（www.ema.europa.eu）、英国药品与保健品监管局网站（http://www.mca.gov.uk/home.htm）、日本药品与医疗器械管理局网站（www.pmda.go.jp）等；3）中国临床试验登记与信息公开平台（www.chinadrugtrials.org.cn）、美国临床试验（clinicaltrials.gov）、澳大利亚临床试验（www.australianclinicaltrials.gov.au）等；4）国内外制药企业官网：辉瑞（www.pfizer.com）、诺华（www.novartis.com）、百济神州（www.beigene.com）、人福医药（www.humanwell.com.cn）等；5）各大综合类及医药类新闻网站，如美通社（www.prnasia.com）、商业资讯（services.businesswire.com）、世界医药新闻（www.worldpharmanews.com）、Drugs.com（www.drugs.com）、新浪医药新闻（med.sina.com）。基于上述数据源，以医药知识为核心，结合药融云公司人工智能团队，利用 Python 语言的数据采集与数据分析功能建立了药融云数据库，实时监控了全球范围内已上市、临床、临床前、药物发现各阶段的基因治疗药物信息，同时通过医药专业人员对智能化监控的数据进行了标准化处理、统计、分析和校对。参考文献：[1] 邓洪新 , 魏于全 . 肿瘤基因治疗的研究现状和展望 [J]. 中国肿瘤生物治疗杂志 , 2015, 22(2): 170-176.[2] Gruntman A M, Flotte T R. 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Targeted therapy for high[1]grade glioma with the TGF-β2 inhibitor trabedersen: results of a randomized and controlled phase IIb study[J]. Neuro Oncol, 2011, 13(1): 132-142.[19] Müschen L H, Krner G, Gingele S, et al. Treatment with patisiran of a patient with hereditary transthyretin-mediated amyloidosis with stage 3 polyneuropathy[J]. Muscle Nerve, 2021, 64(3): E11-E13.[20] Shah V N, Pyle L. Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1[J]. N Engl J Med, 2021, 384(13): 1216-1226.[21] Nambi V, Agha A. Inclisiran: a game changer in a changing game? [J]. J Am Coll Cardiol, 2021, 77(9): 1194-1196.[22] Benbrahim M, Norman K, Sanchorawala V, et al. A review of novel agents and clinical considerations in patients with attrcardiac amyloidosis[J]. J Cardiovasc Pharmacol, 2021, 77(5): 544-548.[23] Thielmann M, Corteville D, Szabo G, et al. Teprasiran, a small interfering RNA, for the prevention of acute kidney injury in high-risk patients undergoing cardiac surgery: a randomized clinical study[J]. Circulation, 2021, 144(14): 1133-1144.[24] Ginn S L, Alexander I E, Edelstein M L, et al. Gene therapy clinical trials worldwide to 2012 – an update[J]. J Gene Med, 2013, 15(2): 65-77.[25] Peng Z H. Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers[J]. Hum Gene Ther, 2005, 16(9): 1016-1027.[26] Liang M. Oncorine, the world first oncolytic virus medicine and its update in China[J]. Curr Cancer Drug Targets, 2018, 18(2): 171-176.[27] Gordon E M, Hall F L. Rexin-G, a targeted genetic medicine for cancer[J]. Expert Opin Biol Ther, 2010, 10(5): 819-832. [28] Doniņa S, Strēle I, Proboka G, et al. Adapted ECHO-7 virus rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study[J]. Melanoma Res, 2015, 25(5): 421-426.[29] Ferreira V, Petry H, Salmon F. Immune responses to AAV-vectors, the glybera example from bench to bedside[J/OL]. Front Immunol, 2014, 5: 82[2022-03-01]. https://doi-org.libproxy1.nus.edu.sg/10.3389/fimmu.2014.00082.[30] Garnock-Jones K P. Talimogene laherparepvec: a review in unresectable metastatic melanoma[J]. BioDrugs, 2016, 30(5): 461- 468.[31] Prado D A, Acosta-Acero M, Maldonado R S. Gene therapy beyond luxturna: a new horizon of the treatment for inherited retinal disease[J]. Curr Opin Ophthalmol, 2020, 31(3): 147-154.[32] Cappella M, Ciotti C, Cohen-Tannoudji M, et al. Gene therapy for ALS—a perspective[J]. Int J Mol Sci, 2019, 20(18): 4388[2022-03- 01]. https://doi-org.libproxy1.nus.edu.sg/10.3390/ijms20184388.[33] Biousse V, Newman N J, Yu-Wai-Man P, et al. Long-term follow-up after unilateral intravitreal gene therapy for leber hereditary optic neuropathy: the restore study[J]. 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Regulators' advice can make a difference: European Medicines Agency approval of zynteglo for beta thalassemia[J]. Clin Pharmacol Ther, 2020, 107(3): 492-494.[40] Han D L, Xu Z H, Zhuang Y, et al. Current progress in CAR-T cell therapy for hematological malignancies[J]. J Cancer, 2021, 12(2): 326-334.[41] Abramson J S, Siddiqi T, Garcia J, et al. Cytokine release syndrome and neurological event costs in lisocabtagene maraleucel–treated patients in the transcend NHL 001 trial[J]. Blood Adv, 2021, 5(6): 1695-1705.[42] Munshi N C, Anderson L D, Shah N. Idecabtagene vicleucel in relapsed and refractory multiple myeloma[J]. N Engl J Med, 2021, 384(8): 705-716.[43] Berdeja J G, Madduri D, Usmani S Z, et al. Ciltacabtagene autoleucel, a b-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (cartitude-1): a phase 1b/2 open-label study[J]. Lancet, 2021, 398(10297): 314-324.[44] Harrison R P, Zylberberg E, Ellison S, et al. Chimeric antigen receptor-T cell therapy manufacturing: modelling the effect of offshore production on aggregate cost of goods[J]. Cytotherapy, 2019, 21(2): 224-233.[45] Farkas A M, Segundo M, Stoyanova-Beninska V, et al. Advanced therapy medicinal products for rare diseases: state of play of incentives supporting development in Europe[J]. Front Med, 2017, 4: 53[2022-03-01]. https://doi-org.libproxy1.nus.edu.sg/10.3389/fmed.2017.00053.[46] Lee H, Kim H, Seo J, et al. Tissuegene-c promotes an anti[1]inflammatory micro-environment in a rat monoiodoacetate model of osteoarthritis via polarization of m2 macrophages leading to pain relief and structural improvement[J]. Inflammopharmacology, 2020, 28(5): 1237-1252文章信息源于公众号药学进展，登载该文章目的为更广泛的传递行业信息，不代表赞同其观点或对其真实性负责。文章版权归原作者及原出处所有，文章内容仅供参考。本网拥有对此声明的最终解释权，若无意侵犯版权，请联系小编删除。学如逆水行舟，不进则退；心似平原走马，易放难收。行舟Drug每日更新欢迎订阅+医药大数据|行业动态|政策解读

基因疗法寡核苷酸信使RNA细胞疗法免疫疗法

100 项与 Teprasiran 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15064

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适应症	最高研发状态	国家/地区	公司	日期
急性肾损伤	临床3期	美国	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	澳大利亚	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	奥地利	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	比利时	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	加拿大	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	捷克	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	法国	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	德国	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	新西兰	Quark Pharmaceuticals, Inc.	2018-06-29
急性肾损伤	临床3期	西班牙	Quark Pharmaceuticals, Inc.	2018-06-29

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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


NCT02610283 (Pubmed \| J Am Coll Cardiol \| Circulation) 人工标引	临床3期	急性肾损伤	341	Teprasiran	願齋築齋鬱範醖壓築願(淵壓鑰積繭顧簾膚膚廠) = 觸網蓋鬱繭壓鹽製餘夢壓憲淵膚顧憲願糧鹹夢 (製壓衊膚壓獵淵膚憲繭 ) 更多	积极	2021-10-05
				Placebo	願齋築齋鬱範醖壓築願(淵壓鑰積繭顧簾膚膚廠) = 醖艱鹹襯糧觸構簾選窪壓憲淵膚顧憲願糧鹹夢 (製壓衊膚壓獵淵膚憲繭 ) 更多
NCT02610283 (ASN2018)	临床2期	急性肾损伤 SCysC \| SCr \| eGFRCys ... 更多	341	QPI-1002	鹽齋憲餘壓築簾醖窪積(築鹹壓鏇製築鑰夢鬱積) = 衊網壓壓積淵鏇簾齋獵遞選顧齋襯網餘願鏇製 (簾襯鬱繭鬱網鹽鹹簾獵 )	积极	2018-10-23
				Placebo	鹽齋憲餘壓築簾醖窪積(築鹹壓鏇製築鑰夢鬱積) = 膚積衊壓蓋積簾鑰衊糧遞選顧齋襯網餘願鏇製 (簾襯鬱繭鬱網鹽鹹簾獵 )
NCT00554359 (Pubmed \| Kidney Int Rep) 人工标引	临床1期	急性肾损伤	16	Teprasiran	餘壓夢襯顧鬱獵簾選膚(醖觸築獵遞鏇餘積範醖) = 鑰鹹鏇壓蓋觸簾鑰衊淵齋齋獵齋積艱齋衊夢製 (醖選範製網觸觸糧獵顧 )	积极	2017-04-25
				Placebo	餘壓夢襯顧鬱獵簾選膚(醖觸築獵遞鏇餘積範醖) = 鹹鏇齋鑰獵膚構獵淵選齋齋獵齋積艱齋衊夢製 (醖選範製網觸觸糧獵顧 )