A Multicenter, Randomized, Double-Masked, Placebo-Controlled Phase 3 Study of the Efficacy, Safety, and Tolerability of Subcutaneously Administered Pozelimab in Combination With Cemdisiran or Cemdisiran Alone in Participants With Geographic Atrophy Secondary to Age-Related Macular Degeneration

This study is researching experimental (study) drugs called pozelimab and cemdisiran. The study is focused on participants who have geographic atrophy (GA) caused by age-related macular degeneration (AMD). Geographic atrophy is a medical term that refers to later-stage cases of AMD which is an eye condition affecting central vision (what one sees straight ahead).
The purpose of this study is to evaluate the progression rate of Geographic Atrophy in eyes of patients treated with cemdisiran alone or in combination with pozelimab compared to those treated with placebo.
The study is looking at several other research questions, including:
* What side effects may happen from taking the study drug(s)
* How much study drug(s) are in the blood at different times
* Whether the body makes antibodies against the study drug(s) (which could make the study drug(s) less effective or could lead to side effects)

开始日期2024-10-28

申办/合作机构

Regeneron Pharmaceuticals, Inc.

NCT06479863 / Recruiting早期临床1期IIT

Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Patients With Sporadic Inclusion Body Myositis

To evaluate the efficacy of Pozelimab/Cemdisiran combination therapy in patients with sIBM

开始日期2024-08-08

申办/合作机构

Regeneron Pharmaceuticals, Inc.

CTR20241295 / Recruiting临床3期

Pozelimab与Cemdisiran联合治疗在症状性全身型重症肌无力患者中的有效性和安全性

主要目的为：在症状性全身型重症肌无力（gMG）患者中评价pozelimab+cemdisiran对受体征和症状影响的日常功能的影响。本研究的次要目的为： 1. 评价pozelimab+cemdisiran（即联合治疗）和cemdisiran单药治疗对以下方面的影响：临床医生评估的重症肌无力（MG）体征和肌力；症状性gMG患者受体征和症状影响的日常功能（仅cemdisiran单药治疗）；受MG体征和症状影响的日常功能改善的患者比例；临床医生评估的MG体征和肌力改善的患者比例；健康相关的生活质量；出现极轻度MG症状的患者比例；患者和临床医生报告的MG体征和症状。 2. 评价pozelimab+cemdisiran联合治疗和cemdisiran单药治疗的安全性和耐受性。 3. 评估血清中总pozelimab的浓度 4. 评估血浆中总C5的浓度 5. 评估血浆中cemdisiran及其代谢物的浓度 6. 评估pozelimab的免疫原性 7. 评估cemdisiran的免疫原性 8.研究pozelimab+cemdisiran联合治疗和cemdisiran单药治疗对补体激活的影响

开始日期2024-07-19

申办/合作机构

再鼎医药（上海）有限公司

[+2]

100 项与 Cemdisiran 相关的临床结果

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100 项与 Cemdisiran 相关的转化医学

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100 项与 Cemdisiran 相关的专利（医药）

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项与 Cemdisiran 相关的文献（医药）

2023-12-04·Clinical kidney journal

Targeting complement in IgA nephropathy

Review

作者: Gutiérrez, Eduardo ; Caravaca-Fontán, Fernando ; Sevillano, Ángel M ; Praga, Manuel

ABSTRACT:

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Recent years have witnessed significant improvements in the understanding of the pathogenesis of IgAN and particularly, the pathogenic role of complement activation. The alternative complement pathway is the major complement cascade activator in IgAN, and glomerular C3 deposition has been shown to correlate with disease progression. In addition, several studies have provided insight into the pathogenic role of factor H–related proteins -1 and -5 in IgAN, as independent players in complement dysregulation. The lectin pathway has also been shown to be associated with the severity of IgAN. Glomerular deposition of C4d has been associated with increased histologic disease activity, faster decline in estimated glomerular filtration rate and higher risk of kidney failure. On the other hand, although overlooked in the Oxford classification, numerous studies have shown that the coexistence of thrombotic microangiopathy in IgAN is a significant indicator of a poorer prognosis. All the breakthroughs in the understanding of the contributing role of complement in IgAN have paved the way for the development of new complement-targeted therapies in this disease. Several ongoing trials are evaluating the efficacy of new agents against factor B (iptacopan, Ionis-FB-LRX), C3 (pegcetacoplan), factor D (vemircopan, pelecopan), C5 (ravulizumab, cemdisiran) and C5a receptor 1 (avacopan). In this study, we provide a comprehensive review of the role of complement in IgAN, including the emerging mechanisms of complement activation and the promising potential of complement inhibitors as a viable treatment option for IgAN.

2023-11-01·Drugs

Pozelimab: First Approval

Review

作者: Hoy, Sheridan M

Pozelimab (pozelimab-bbfg; VEOPOZ™) is a fully human immunoglobulin (Ig) G4^P (i.e. IgG4 with a proline substitution to promote stabilization of the disulfide bonds between the two heavy chains) monoclonal antibody developed by Regeneron Pharmaceuticals Inc., to block the activity of complement factor 5 (C5) and prevent diseases mediated by the complement pathway. In August 2023, pozelimab received its first approval for the treatment of adults, and paediatric patients aged ≥ 1 year with CD55-deficient protein-losing enteropathy (PLE), also known as CHAPLE disease, in the USA. It is the first US FDA-approved treatment for this disease. In the USA, pozelimab has been granted orphan drug designations for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) [both as a monotherapy and in combination with cemdisiran] and for the treatment of myasthenia gravis (in combination with cemdisiran). Pozelimab is also undergoing clinical development in several other countries worldwide for the treatment of CD55-deficient PLE, PNH and myasthenia gravis. This article summarizes the milestones in the development of pozelimab leading to this first approval for the treatment of adults, and paediatric patients aged ≥ 1 year with CD55-deficient PLE, also known as CHAPLE disease, in the USA.

2023-08-01·EJHaem

Results of a phase 1/2 study of cemdisiran in healthy subjects and patients with paroxysmal nocturnal hemoglobinuria.

Article

作者: Borodovsky, Anna ; Bhan, Ishir ; Bush, Jim ; Taubel, Jorg ; Urbano-Ispizua, Alvaro ; Badri, Prajakta ; Gaya, Anna ; Garg, Pushkal ; Wang, Yue ; Griffin, Morag ; Munir, Talha

Complement dysregulation underpins the physiopathology of paroxysmal nocturnal hemoglobinuria (PNH). Cemdisiran, an RNA interference investigational treatment, silences complement component 5 (C5) expression in the liver. Previously reported results showed sustained reduction in C5 levels following cemdisiran monotherapy, with >90% reduction in patients with PNH. This phase 1/2 study evaluated single (Part A, n = 32; 50-900 mg) or multiple (Part B, n = 24; 100-600 mg) ascending doses of cemdisiran or placebo (double-blind, randomized 3:1) in healthy adults, or cemdisiran in patients with PNH who were naive to, or receiving, eculizumab (Part C, n = 6; 200 or 400 mg weekly; open-label). The primary objective was to assess the safety and tolerability of cemdisiran. Other assessments included change in complement activity, lactate dehydrogenase levels, and inhibition of hemolysis following cemdisiran treatment. Cemdisiran was generally well tolerated in this study. Overall, 75%, 89%, and 100% of subjects in Parts A, B, and C, respectively, experienced ≥1 non-serious adverse event (AE). Most events were Grade 1 or 2 in severity and the most common AEs included nasopharyngitis and headache. Cemdisiran elicited robust, sustained reductions in the complement activity in healthy adults and patients with PNH. In Part C, exploratory analyses showed that cemdisiran monotherapy was insufficient to prevent hemolysis in patients with PNH as measured by serum lactate dehydrogenase levels. Cemdisiran and eculizumab combination therapy reduced the dose of eculizumab required to provide adequate control of intravascular hemolysis. These results demonstrate a potential benefit of cemdisiran coadministration in patients who are inadequate responders to eculizumab alone.

项与 Cemdisiran 相关的新闻（医药）

2024-09-02

·PRNewswire

Roche's PIASKY Approval for Paroxysmal Nocturnal Hemoglobinuria Treatment Will Give Tough Competition to AstraZeneca and Other Pharma Companies | DelveInsight

Following achievements in Asia, Roche's PNH treatment drug PIASKY (crovalimab) received its first FDA approval. This approval has spiked the competition between Roche and current market leader AstraZeneca. Additionally, the other pharma companies also geared up to launch their respective lead assets. LAS VEGAS, Sept. 2, 2024 /PRNewswire/ -- Paroxysmal nocturnal hemoglobinuria (PNH), a rare disorder, shows a triad of features: intravascular hemolysis, thromboembolic events, and cytopenia. Manifestations vary among patients, making classification based on typical presentations challenging due to the disease's unpredictable nature. In 2023, the Paroxysmal Nocturnal Hemoglobinuria diagnosed prevalent cases were ~12,000 cases in the 7MM, which might reach ~13,000 cases by 2034. In the 7MM, the highest number of paroxysmal nocturnal hemoglobinuria diagnosed prevalent cases were observed in the US. Until 2007, PNH was a devastating disease without treatment for hemolysis and thrombosis, the leading cause of death in patients. However, the last decade saw a revolutionary shift with the advent of the anti-C5 agent eculizumab. It significantly reduced hemolysis, decreased transfusion dependency, and, crucially, lowered the thrombosis rate. The disease-modifying therapeutic strategy for paroxysmal nocturnal hemoglobinuria includes complement inhibition therapy, with drugs like SOLIRIS, ULTOMIRIS, and EMPAVELI approved by the FDA, and considered the gold standard. SOLIRIS, the pioneering therapy for PNH, was succeeded by ULTOMIRIS, both developed by Alexion Pharmaceuticals, offering C5 inhibitors as essential therapeutic options. Recent approvals of factor B and D inhibitors like FABHALTA (iptacopan) in the US and VOYDEYA (danicopan) in Japan aim to offer improved treatment with fewer side effects. Learn more about the FDA-approved paroxysmal nocturnal hemoglobinuria drugs @ Drugs for Paroxysmal Nocturnal Hemoglobinuria Treatment The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) recommended crovalimab for treating PNH in adults and adolescents aged 12 and above in June 2024, based on findings from the global Phase III COMMODORE 2 clinical trial. The FDA accepted a biologics license application for crovalimab in September 2023 and subsequently approved it in June 2024 for treating PNH in adults and adolescents aged 13 years and older. Genentech, a subsidiary of Roche, has made the drug available in the US. In Japan, Chugai Pharmaceutical submitted a new drug application for PiaSky to the Japan Ministry of Health, Labour, and Welfare (MHLW) in June 2023. The drug was approved in March 2024 and launched in May 2024 for patients with PNH aged 12 years and above. In February 2024, China's National Medical Products Administration (NMPA) approved crovalimab for treating PNH in adults and adolescents aged 12 years and older who have not previously received complement inhibitor treatment, following a priority review that began in August 2022. PiaSky is also undergoing review by other regulatory authorities, including those in Europe and Taiwan. To know more about paroxysmal nocturnal hemoglobinuria treatment options, visit @ New Treatment for Paroxysmal Nocturnal Hemoglobinuria The paroxysmal nocturnal hemoglobinuria market is crowded with so many companies working in the domain. Emerging PNH therapies include Pozelimab (REGN3918) + Cemdisiran, OMS906, NM8074 (ruxoprubart), and others, reflecting a dynamic evolution in treatment strategies. Discover which therapies are expected to grab major paroxysmal nocturnal hemoglobinuria market share @ Paroxysmal Nocturnal Hemoglobinuria Market Report Pozelimab is a novel, fully human monoclonal antibody currently under investigation. It aims to inhibit complement factor C5, thereby preventing the destruction of red blood cells (hemolysis) responsible for symptoms in conditions like Paroxysmal Nocturnal Haemoglobinuria (PNH) and other diseases influenced by complement pathway activity. This IgG4 antibody binds tightly to both wild-type and variant forms of human C5, effectively blocking its function. In its ongoing development, pozelimab is also being studied in combination with Alnylam's cemdisiran, a siRNA C5 inhibitor. This investigational combination therapy is aimed at treating various complement-mediated disorders, including PNH and myasthenia gravis. OMS-906 is currently being developed to treat paroxysmal nocturnal hemoglobinuria (PNH), complement 3 glomerulopathy (C3G), idiopathic immune complex-mediated glomerulonephritis (ICGN), and arthritis. It can be administered either subcutaneously or intravenously. This drug candidate is a monoclonal antibody designed to target mannan-binding lectin serine protease 3 (MASP-3) to exert its therapeutic effects. Discover more about drugs for paroxysmal nocturnal hemoglobinuria in development @ Paroxysmal Nocturnal Hemoglobinuria Clinical Trials The anticipated launch of these emerging therapies for paroxysmal nocturnal hemoglobinuria are poised to transform the market landscape in the coming years. As these cutting-edge therapies continue to mature and gain regulatory approval, they are expected to reshape the paroxysmal nocturnal hemoglobinuria market landscape, offering new standards of care and unlocking opportunities for medical innovation and economic growth. DelveInsight estimates that in 2023, the total paroxysmal nocturnal hemoglobinuria market size in the 7MM was USD ~1.4 billion, which is expected to reach USD ~2.5 billion by 2034. This growth can be attributed to the advances in disease mechanisms that drive new diagnostics and therapeutics, fueling drug development. Additionally, the PNH market foresees positive growth, propelled by increasing cases and upcoming therapies in the forecast period. DelveInsight's latest published market report titled as Paroxysmal Nocturnal Hemoglobinuria Market Insight, Epidemiology, and Market Forecast – 2034 will help you to discover which market leader is going to capture the largest market share. The report provides comprehensive insights into the paroxysmal nocturnal hemoglobinuria country-specific treatment guidelines, patient pool analysis, and epidemiology forecast to help understand the key opportunities and assess the market's underlying potential. The paroxysmal nocturnal hemoglobinuria market report proffers epidemiological analysis for the study period 2020–2034 in the 7MM segmented into: Total Diagnosed Prevalent Cases of PNH Gender-specific Cases of PNH The report provides an edge while developing business strategies by understanding trends shaping and driving the 7MM paroxysmal nocturnal hemoglobinuria market. Highlights include: 11-year Forecast 7MM Analysis Epidemiology-based Market Forecasting Historical and Forecasted Market Analysis upto 2034 Emerging Drug Market Uptake Peak Sales Analysis Key Cross Competition Analysis Industry Expert's Opinion Access and Reimbursement Download this paroxysmal nocturnal hemoglobinuria market report to assess the epidemiology forecasts, understand the patient journeys, know KOLs' opinions about the upcoming treatment paradigms, and determine the factors contributing to the shift in the paroxysmal nocturnal hemoglobinuria market. Also, stay abreast of the mitigating factors to improve your market position in the paroxysmal nocturnal hemoglobinuria therapeutic space. Related Reports Paroxysmal Nocturnal Hemoglobinuria Epidemiology Forecast Paroxysmal Nocturnal Hemoglobinuria Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted paroxysmal nocturnal hemoglobinuria epidemiology in the 7MM, i.e., the United States, EU5 (Germany, Spain, Italy, France, and the United Kingdom), and Japan. Paroxysmal Nocturnal Hemoglobinuria Pipeline Paroxysmal Nocturnal Hemoglobinuria Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key paroxysmal nocturnal hemoglobinuria companies, including Biocad, AKARI Therapeutics, Amgen, MorphoSys, Ra Pharmaceuticals, Alnylam Pharmaceuticals, Arrowhead Pharmaceuticals, among others. Aplastic Anemia Market Aplastic Anemia Market Insights, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key aplastic anemia companies, including Pfizer, BioLineRx Ltd., Regeneron Pharmaceuticals, Gamida Cell, Elixirgen, Hangzhou Zede Pharmaceutical Technology, Cellenkos, Hemogenyx Pharmaceuticals, among others. Aplastic Anemia Pipeline Aplastic Anemia Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key aplastic anemia companies, including Pfizer, BioLineRx, Ltd., Regeneron Pharmaceuticals, Gamida Cell, Elixirgen, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP

上市批准优先审批临床3期

2024-08-19

·药融圈

Alnylam 心脏病RNAi疗法3期研究成功

▲8月15-16日 NDC2024生物医药创新者峰会扫码立即报名注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需得到授权。 2024年6月24日，全球领先的RNAi疗法公司Alnylam Pharmaceuticals（纳斯达克股票代码：ALNY）公布了vutrisiran的HELIOS-B 3期研究达到了主要终点和所有次要终点，包括基线tafamidis使用情况、ATTR疾病类型和疾病严重程度。根据此积极结果，Alnylam将使用优先审评券向美国FDA递交补充新药申请。消息公布后，Alnylam股价大涨35%，市值超过280亿美元。 AMVUTTRA®（vutrisiran）是一种RNAi治疗药物，可快速敲低突变型和野生型转甲状腺素（TTR），解决转甲状腺素（ATTR）淀粉样变性的根本原因。AMVUTTRA每季度通过皮下注射给药，已在15多个国家获得批准并上市，用于治疗成人遗传性转甲状腺素介导的淀粉样变性（hATTR-PN）的多发性神经病。 HELIOS-B是一项全球多中心、随机、双盲、安慰剂对照的3期研究，旨在评估vutrisiran在ATTR-CM患者中减少全因死亡率和复发性心血管事件的效果和安全性（主要终点）。该研究将655名成人ATTR淀粉样变性（遗传型或野生型）伴心肌病患者随机分组。在长达36个月的双盲治疗期内，患者被1:1随机分组，每三个月皮下接受一次25mg vutrisiran或安慰剂。双盲期结束后，所有仍在研究中的符合条件的患者都可以在开放标签延长期内接受vutrisiran治疗。结果显示，在双盲期间，总体患者（n=654；HR：0.718，p=0.0118）和接受单药治疗患者（即基线时未接受ATTR-CM获批疗法tafamidis治疗的患者，n=395；HR：0.672，p=0.0162）分别实现了全因死亡率和复发性心血管事件综合指标28%和33%的降低。研究还显示，总体和单药治疗患者在所有次要终点均有显著改善，包括疾病进展的关键指标：6分钟步行测试（6-MWT）、堪萨斯城心肌病问卷（KCCQ）和第30个月时纽约心脏协会（NYHA）分级（所有指标的p值均<0.025）。重要的是，使用vutrisiran治疗还降低了总体患者（HR：0.645，p<0.025）和单药治疗患者（HR：0.655，p<0.05）第42个月时的全因死亡率，这是一项预定的意向性治疗分析，包括来自开放标签扩展阶段最长六个月的数据。在HELIOS-B研究中，vutrisiran显示了令人鼓舞的安全性和耐受性，与其已知的安全特性一致。Vutrisiran和安慰剂组的不良事件（AE）、严重不良事件（SAE）和导致停药的不良事件的发生率相似。Vutrisiran组中没有任何不良事件的发生率比安慰剂组高出3%以上。 "HELIOS-B研究获得了压倒性的积极数据，表明vutrisiran有望满足ATTR淀粉样变性伴心肌病患者的需求，这是一种持续进展、使人衰弱并最终致命的疾病，"Alnylam公司首席医学官、医学博士Pushkal Garg说，"研究结果显示，vutrisiran改善了ATTR心肌病所有患者组的心血管预后，包括存活率、功能和生活质量。我们正抓紧向监管机构提交这些令人信服的数据，以便将这种药物带给世界各地的患者。" Alnylam公司首席执行官、医学博士Yvonne Greenstreet说："HELIOS-B研究的结果令我欣喜若狂，它表明vutrisiran有可能成为ATTR淀粉样变性伴心肌病患者的变革性药物。如果监管审查通过，vutrisiran 有可能成为治疗这种疾病的新标准，推动 Alnylam 进入下一个大幅增长的时代。" 总结 Alnylam是siRNA领域的领导者，由Alnylam与赛诺菲合作开发的皮下注射RNAi疗法Fitusiran、由Alnylam和再生元合作开发的皮下注射RNAi疗法Cemdisiran都已处于收获阶段，即将递交上市申请。 siRNA领域已成为生物制药公司的兵家必争之地，国外Ionis、Alnylam引领发展；国内目前致力于小核酸药物的研发企业约有40家，包括舶望制药、瑞博生物、圣诺医药、思合基因、中美瑞康、圣因生物、维亚臻生物等，通过自主研发和合作引进，迅速成长。参考资料：公司公告版权声明：本文转自细胞基因治疗前沿，如不希望被转载的媒体或个人可与我们联系，我们将立即删除 [ 重磅苏州新药峰会推荐 ] 8月16日论坛4：临床开发论坛 09:00-09:30新质生产力引领临床试验高质量发展 09:30-09:50临床试验数字化的现状与未来 09:50-10:10基因治疗产品的早期临床研究及案例分享 10:10-10:30临床试验创新设计与实施 10:30-10:50抗肿瘤药物临床试验中的终点选择 10:50-11:10创新药国际多中心临床试验的策略定制与考量 11:10-11:30 中国临床试验出海的机遇与挑战 11:30-11:50真实世界数据在临床研究中的应用 11:50-13:30午餐 13:30-14:00监管科学视角下临床研究设计和质量的重大意义 14:00-14:30新法规时代对药品临床试验的科学监管 14:30-15:00数字化助力监管决策——面向药品现代化监管的智能化服务平台 15:00-15:20从患者角度出发看DCT临床实践的融合与落地 15:20-15:40 临床试验的“质”与“量”的博弈 — 付出越大，环节越多，质量就越好吗？ 15:40-16:00临床试验不良事件的损害赔偿与风险管理确认嘉宾邓晓宇，希毅医学，创始人/总经理侯艳，北京大学，教授胡皓，医数康成，总经理吕华，天泽云泰，高级副总裁任以中，葆元医药，医学事务高级总监汤在详，苏州大学生物统计学，教授田少雷，国家局食品药品审核查验中心原学术委员会副主任委员、处长王维玉，北京灵迅医药科技公司，联合创始人夏素琴，创达医药，总经理张淼，南京麦普斯医药科技有限公司，创始人郑航，重庆医科大学药学院，教授周焕，中国药理学会药物临床试验专委会青年主任委员扫码报名参会【关于药融圈】药融圈PRHub旨在帮助生物医药科技型企业进行品牌推广及商务拓展服务，针对客户的真实需求制定系统化解决方案，通过“翻译-降维-场景化”将客户的品牌信息以直白易懂的方式被公众知悉，同时在流量渠道覆盖100万+垂直用户基础上实现合作目的，帮助合作伙伴完成从品牌开始到商务为终的闭环营销服务。我们已经完成了数十场线下1000人规模的生物医药研发类会议，涵盖小分子新药，大分子新药，改良型新药，BD跨境交易等多个领域，服务了百余家上市/独角兽/生物技术/制药企业。

优先审批临床3期临床结果临床2期上市批准

2024-08-11

·BiG生物创新社

Nature：一篇6000字「RNAi疗法」报告

RNA干扰(RNAi)疗法的发展始于1998年发表在Nature杂志上的一篇题为“Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans”重要论文。Andrew Fire、Craig C. Mello等科学家发现，使用长双链RNA (dsRNA)能够沉默秀丽隐杆线虫中特定基因的表达。在该研究的基础上，Thomas Tuschl等在2001年发表的另一篇Nature论文中揭示，使用小干扰RNA (small-interfering RNAs,siRNAs)在哺乳动物细胞中实现了序列特异性RNAi，且不会诱导使用长双链RNA (dsRNA)引发的免疫反应。基于这些重要发现，siRNA在科研及治疗领域的应用开始发展。来源：Nature Biotechnology 与单链反义寡核苷酸(antisense oligonucleotides，ASO)不同，siRNA是短的双链RNA (dsRNA)，由一条与靶RNA具有相同序列的正义链，及一条互补引导(反义)链组成。在被细胞摄取后，siRNA与RNA诱导沉默复合物（RISC，一个由AGO2内切酶、反式激活应答RNA结合蛋白2和DICER1组成的多蛋白系统）相互作用，正义链被清除，引导链（反义链）充当识别靶序列的模板，介导互补靶mRNA的结合及降解，从而终止靶蛋白的翻译。反义寡核苷酸(ASO)是首个获监管部门批准的寡核苷酸药物，合成ASO可以被设计成靶向剪接信号序列并调节pre-mRNA剪接(图1a)，也可以被设计成结合靶mRNA中的互补序列，并招募核糖核酸酶H1 (RNase H1)以降解靶mRNA(图1b)。外源性siRNA是内源性miRNA的“表亲”，利用siRNA诱导沉默复合物（siRISC）介导基因沉默(图1c)。miRNA利用miRNA诱导沉默复合物(miRISC)通过使mRNA脱帽或缩短poly(A)尾巴介导基因沉默（图1d）。（来源：Nature Biotechnology）目前，全球已有6款RNAi药物获批上市，验证了RNAi疗法在人类中的应用。随着RNAi不断取得治疗突破，该赛道的产业热度也在急剧上升。2023年以来，制药巨头BD之风也吹到了RNAi领域，罗氏牵手Alnylam（潜在交易总额28亿美元）、BI牵手瑞博生物（潜在交易总额超20亿美元）、诺华牵手舶望制药（潜在交易总额41.65亿美元）……MNC已毫不掩饰对RNAi疗法的兴趣。此外，从管线来看，医药魔方NextPharma®数据库显示，截至2024年7月26日，全球有超620个RNAi项目同步在研。已获批上市的RNAi疗法来源：Nature Biotechnology RNAi疗法具有特异性沉默几乎任何治疗靶点的潜力。然而，将这类创新性疗法带给更多患者仍面临巨大的挑战，其中递送问题最为突出。过去几年，RNAi疗法递送技术进展如何？RNAi疗法的靶点选择有何讲究？临床开发有哪些注意点？未来的优势发展方向在哪？近日，来自University of Massachusetts Chan Medical School的两位科学家在Nature Reviews Drug Discovery 杂志发表一篇综述文章，就以上问题展开了深入探讨。来源：Nature Reviews Drug Discovery 01 递送突破 siRNA向靶组织或细胞类型的功能性递送受到多种因素的影响，包括给药途径、生物屏障、外渗、组织或细胞摄取和内体逃逸。目前获批用于递送siRNA的技术包括LNP和基于GalNAc的偶联技术（肝脏递送）。其中，偶联介导的递送是目前临床上递送siRNA的主要平台。在LNP和GalNAc介导肝脏递送取得成功后，目前适合递送的组织正在扩大。其中，中枢神经系统(CNS)、眼睛、肺、肌肉和皮肤递送显示出可喜的进展，其他组织（包括肾脏、心脏、脂肪、胎盘和胰腺等）的递送也正在积极探索中。这些进步主要归因于最近递送平台和给药模式的创新。例如，通过局部给药（local administration）可将siRNA选择性递送至中枢神经系统（CNS）、眼睛、肺和皮肤；通过系统递送（systemic delivery）可以使siRNA到达肌肉、肾脏、心脏、脂肪、胎盘和胰腺，虽然这种方法没有选择性，但siRNA在可接受的剂量水平下会优先在这些组织中的某些细胞类型中积累。在不同组织中实现治疗性RNAi递送的技术来源：Nature Reviews Drug Discovery ▌系统性递送偶联介导的递送 GalNAc偶联siRNA结合细胞表面去唾液酸糖蛋白受体（ASGPR），通过内吞作用，促进肝细胞摄取。已获批上市的6款RNAi疗法有5款使用了GalNAc系统。GalNAc介导的肝细胞递送是一种独特的情况，肝脏的天然过滤功能、高血流量、开窗内皮以及ASGPR的快速循环共同导致了强大的疗效和持久性。目前，一些靶向偶联物，包括抗体、工程蛋白、肽、适体和脂质，正在开发用于siRNA肝外递送(图2a)。肝外递送改变药代动力学特征以改善siRNA全身分布和促进肝外疗效的策略（来源：Nature Reviews Drug Discovery ） siRNA向非肝组织的系统递送在概念上是复杂的，需要更好地理解驱动清除和生物分布的原理。siRNA的生物分布可能受到给药途径、核酸酶稳定性和清除器官生理特性的影响。肝脏和肾脏是系统注射siRNA的主要清除器。肝脏较高的血流速率、不连续的内皮以及肾脏的天然过滤功能会在达到充足的系统积累之前就清除大部分注入的化合物。一般来说，骨架（scaffold）的整体亲疏水比决定了siRNA的清除模式。高疏水性siRNA在肝脏中被清除较多，高亲水性siRNA在肾脏中被过滤较多。事实上，与肌肉和中枢神经系统等组织(通常1–2 μg g−1就足够了)相比，肾脏中的靶向沉默需要高近两个数量级的siRNA积累(>100 μg g−1)。因此，对于肾脏，需要额外的化学改造，如增强稳定性和内体逃逸，以提高疗效。肾脏是许多肾脏疾病的重要器官，siRNA成功递送到肾小球内皮细胞和足细胞等细胞类型，将开启前所未有的机会。有研究显示，脂质偶联物（如docosanoic acid，phosphocholine (PC)–DCA）能够显著改善了siRNA的系统分布，在包括肌肉、心脏和脂肪在内的几种肝外组织中显示出疗效。除了表现出更好的肝外摄取外，这类化合物还显出更好的安全性。一项治疗先兆子痫的I期临床试验正在评估PC–DCA偶联siRNA对sFLT1的调节作用。此外，2′-O-hexadecyl (C16)脂质偶联siRNA正在临床前和临床研究中被广泛评估。显示出强大系统肝外效用的其他类型偶联物包括抗体、抗体片段和工程蛋白。这类偶联同时显著增加了siRNA药物的总体大小，从而通过降低肾脏清除率促进系统分布。抗体偶联siRNA进展最快的是使用靶向转铁蛋白受体1 (TfR1)的单抗，可用于骨骼、心脏和平滑肌递送。在一项临床前研究中，靶向SSB mRNA(编码小RNA结合外切酶保护因子La)，单次静脉注射6 mg kg - 1剂量的anti-TfR1–siRNA偶联物导致高达75%的靶点下调。一项针对人类患者的I/II期研究表明，使用anti-TfR1–siRNA靶向肌张力蛋白激酶(DMPK)治疗1型强直性肌营养不良，可显著改善疾病预后。 Centyrins是一类小的，工程化的人类蛋白质衍生物，也被用于siRNA肝外递送。centyrin-siRNA偶联平台显示出有希望的系统递送特性。一项使用centycin -conjugated siRNA (ABX1100)用于肌肉递送，以沉默糖原合成酶1 (GYS1)基因以治疗庞贝病的I期试验正在进行中。肽偶联也有望发展为siRNA的递送平台。肽可以合成，因此CMC相对不那么复杂。胰高血糖素样肽1（GLP1)是GLP1受体的一种配体，已被成功地用于将ASO递送到胰岛细胞。许多学术实验室和制药公司正在进一步探索肽偶联作为一种有前途的siRNA递送策略的潜力。适配体是第一批被探索用于递送siRNA和其他寡核苷酸疗法的偶联物之一，但可能由于早期的一些尝试观察到的持久性有限，目前还没有在转化领域获得太多的关注。不过，最近适配体在疾病动物模型中取得了显著进展，特别是靶向肿瘤相关的某些生物标志物，因此具有临床转化的潜力。另一种改善系统递送的策略是使用纳米结构（nanoconstruct）作为siRNA的载体。不过，某些包含大量siRNA的高载荷设计可能会触发不希望的免疫反应。因此，为了更好地利用纳米结构递送siRNA，需要增强对如何避免潜在免疫原性和改善有效载荷释放的理解。 ▌局部递送经优化的siRNA局部给药到中枢神经系统、眼睛、肺和皮肤已显示出强大的疗效。将化合物直接递送到这些相对封闭或易于进入的组织中，可以增强滞留，并确保化合物的充足供应以供细胞摄取。如前文所述，siRNA的分子性质（如疏水性、分子大小）也能够降低清除，并促进摄取。举例来说，偶联C16脂质链到siRNA正义链上可以在啮齿动物和非人灵长类动物(NHPs)的中枢神经系统、眼睛和肺中实现安全、有效和数月的沉默。此外，当siRNA进行局部给药时，可以测试多种优化骨架结构的设计，不同的骨架可以产生不同的细胞类型摄取谱。 siRNA局部递送（来源：Nature Reviews Drug Discovery ）中枢神经系统通过直接注射到脑区或注入脑脊液(CSF)，将siRNA治疗药物递送到中枢神经系统是可行的。给药方案是向中枢神经系统递送siRNA的重要考虑因素。将二价siRNA注射到脑脊液中支持广泛分布：在脑脊液高暴露区域(如海马体、丘脑、皮质和脊髓)积累水平高，而在更深区域(如尾状核和壳核)积累水平较低。因此，CSF注射治疗性siRNA可能适用于治疗累及皮质、海马体和脊髓的神经退行性疾病，如肌萎缩侧索硬化症和阿尔茨海默病。皮肤皮肤是siRNA局部递送最大和最容易接近的人体组织。但局部递送大分子（如siRNA）穿过皮肤屏障的最外层(即角质层)是具有挑战性的。皮内注射是一种可行的siRNA递送方法，在临床上通常用于局部皮肤病适应症的治疗。疏水偶联物可以显著改善局部注射后siRNA在皮肤中的滞留。未来的研究重点包括在猪模型（更接近人类皮肤）中测试不断优化的siRNA平台的皮内注射效果，以促进临床转化。体外移植将siRNA递送到离体器官用于移植是一个潜在的令人兴奋的应用。机器灌注递送siRNA沉默参与缺血再灌注损伤的基因有助于保持移植器官的质量。递送沉默免疫因子的siRNA可能有助于减少快速的移植排斥反应。这绝对是一个值得关注的领域。 02 临床开发五大“关键点” siRNA药物的开发与传统的小分子和生物制剂有很大的不同，主要区别在于siRNA的PK特性和靶向特异性可以独立优化：PK特性由整体化学骨架和偶联定义，而靶向特异性主要由向导链序列定义(图2a)。值得注意的是，平均而言，siRNA候选药物的设计和开发走向临床验证的成功率大大高于传统管道的成功率，但依然有一些关键因素需要重视：靶点选择 RNAi药物开发的临床适应症和靶点选择（来源：Nature Reviews Drug Discovery ）成功开发用于某一临床适应症的siRNA药物需要选择相关靶点。考虑靶点选择的基本因素是将siRNA递送到靶组织的能力（具有强大的有效性和可接受的安全性）。如前所述，当前肝脏递送已经经过充分验证，中枢神经系统、肺、眼睛、肌肉和皮肤递送也有可靠的动物数据。第二个关键因素是了解递送系统的分布。举例来说，大多数肌肉靶向偶联物也会递送到心脏和肝脏病诱导靶点沉默。因此，对于治疗应用，开发人员应确保靶点优先在预期组织中表达，或者off-tissue调控是良性的。此外，需要注意的一点是，如果某个疾病的靶点过度上调，那可能会超过RNAi机制的能力。一个替代策略是靶向与该靶点相互作用的上游信号因子。另一个方法是，使用多靶向siRNA再额外靶向其它靶点，或者联合其它药物类型实现协同效应。同时，靶点选择还需要考虑mRNA turnover率对siRNA药效的影响。研究表明，高turnover率的mRNA更能抵抗RNAi介导的沉默。靶点表达细胞类型的增殖速率也会显著影响siRNA的效力和持久性。随着时间的推移，快速分裂的细胞会稀释内化siRNA的细胞浓度。因此，活跃分裂细胞（例如肿瘤细胞和表皮角质形成细胞）中的RNAi活性可能会降低，需要重复给药以维持沉默效果。相比之下，siRNA的持久性通常在非分裂状态的细胞类型中持续更长时间，比如神经元。另一个重要的考虑因素是临床有效性。在很长一段时间里，人们认为siRNA不能与小分子和生物制剂竞争，因此，没有考虑已经有有效药物的靶点。然而，一年两次或一年一次给药频率的潜力，支持实际的便利性和患者依从性，现在使siRNA成为一种非常有吸引力的替代modality。最明显的例子是inclisiran，它靶向PCSK9，降低失调的胆固醇水平，尽管市场上已经有几种获批的生物制剂。 on-tissue靶向选择性为了避免off-tissue沉默带来的潜在副作用，一个有用的策略是关注在siRNA递送组织中优先表达的治疗靶点。例如，由MSTN编码的myostatin是一种主要在骨骼肌中产生的肌肉因子，作用于肌细胞抑制肌肉生长。靶向调节myostatin可能对治疗肌肉萎缩症有益。在跨多个组织普遍表达基因的情况下，系统靶向需要通过安全性研究进行仔细评估，因为off-tissue靶向沉默可能会带来潜在的风险。先导化合物优化先导化合物优化是连接体外筛选和体内验证的关键步骤。骨架和核苷酸修饰能够显著影响siRNA活性，因此优化过程中的任何重大变化都必须进行测试，以与亲本化合物进行活性比较。先导化合物的优化重点是改善体内递送、效力和持久性。先导化合物应仔细纯化和做好质量控制。在进行全面的临床前安全性和有效性研究之前，对优化的先导化合物物进行快速体内验证以确认靶点沉默情况将有所帮助。临床前评价理想情况下，先导化合物的疗效应在相关疾病模型中进行评估。然而，许多人类疾病缺乏动物模型，或者相关模型可用性有限，带了较大挑战。此外，动物模型的相关性——也就是说，它是否准确地反映了人类疾病的特征——是至关重要的，特别是对于炎症性疾病和癌症，这些疾病的确切原因可能是未知的。对于其他疾病，如亨廷顿病和肌强直性营养不良，其潜在机制在遗传水平上得到明确定义，因此，siRNA的设计和临床前评估更加“有利”，特别是当建立了人源化转基因模型时。临床验证尽管siRNA在啮齿类动物和NHP中具有良好的临床前安全性，但在临床验证中仍可能存在不确定性，如在revusiran的III期试验中所见，该试验导致了意外死亡率。尽管进行了广泛的调查，但确切原因仍不清楚，这强调了siRNA药物开发的所有阶段都需要进行彻底的安全性评估。值得注意的是，siRNA药物先导化合物的鉴定和临床前开发的时间较短，这一特点支持针对罕见遗传疾病或对现有治疗无响应的晚期癌症个体化患者开展临床试验的高可行性。这些N-of-1研究（一种基于单个病例进行的随机对照试验）为siRNA药物的快速临床验证和开发提供了绝佳的机会。 03 未来四大优势方向与传统药物相比，siRNA具有明显的优势，包括它们能够沉默以前被认为不可成药的靶点，开发时间更短，临床持久性更长等。未来，这类药物形式在以下几个领域极具前景： siRNA药物极具前景的未来应用方向（来源：Nature Reviews Drug Discovery ）调节疾病相关mRNA异构体转录后过程，如选择性剪接是固有的细胞机制，这会产生来自单个基因的多种调控和编码RNA转录本异构体（ transcript isoform）。这一过程可能导致在生物学功能和病理作用上不同的调节性RNA和蛋白质亚型。由于缺乏RNA或蛋白质异构体的结构特性表征，通过传统的小分子和生物制剂对它们进行特异性调节非常具有挑战性。相比之下，基于寡核苷酸的方法提供了在转录后水平上精准靶向疾病相关异构体的解决方案。异构体特异性siRNA的设计需要靶转录本有独特的序列延伸，将其与非靶向（non-targeted）异构体区分开来。使用新兴的强大工具，如长读测序，来确定疾病状态下的异构体表达谱，将极大地增加设计siRNA的信心。随着这一领域的发展，siRNA药物选择性调节致病异构体的能力将是前所未有的。病毒感染 siRNA可能在对新出现的病毒病原体和流行病的快速反应中发挥重要作用。肺和肝脏目前是应用siRNA的有希望的组织，例如用于治疗病毒性肺炎和肝炎。事实上，多种抗乙型肝炎siRNA已经进入临床验证阶段。siRNA可能是治疗病毒性感染性疾病的理想modality。首先，siRNA专门针对病毒RNA成分设计，可最小化对宿主RNA的脱靶效应。其次，通过靶向对维持生存能力至关重要的病毒基因组的保守区域，siRNA有可能覆盖多种现有和未来的病毒株。调节长链非编码RNA 人类基因组的很大一部分不编码蛋白质，而是产生在基因表达和蛋白质功能中具有调节作用的非编码RNA(ncRNA)。越来越多的证据表明，包括长链非编码RNA (lncRNA，大小超过200个核苷酸)在内的ncRNA可以作为某些疾病的治疗靶点。考虑到lncRNA的多样性及其在生物功能调控中的各种作用，lncRNA的治疗性调控对药物开发人员来说是一个探索较少但充满机会的方向。尽管目前靶向lncRNA，且已取得临床成效的药物有限，但siRNA和其他基于寡核苷酸疗法非常适合开发lncRNA靶向药物，在未来具有很大的潜力。联合治疗将siRNA与其他药物形式（如小分子或生物制剂）联合使用，可能会协同改善治疗复杂疾病的临床结果。一项正在进行的研究是Alnylam的siRNA药物cemdisiran联合Regeneron的单抗药物pozelimab治疗阵发性睡眠性血红蛋白尿症。尽管结合了siRNA药物的联合疗法的临床成功尚未确定，但未来的潜力是可以预见的。小结从在秀丽隐杆线虫中发现RNAi机制，到在哺乳动物细胞中证明其功效，再到开发一类新的人类药物，RNAi技术在过去20多年经历了一段非凡的历程。除了已获批上市的6款药物，一些晚期临床管线已经显示出有希望的疾病改善效果，这可能导致下一波siRNA药物获批。随着分子设计和肝外递送平台的不断发展，预计在不久的将来siRNA药物的应用将在各种适应症中大幅扩展。参考资料： [1]https://www-nature-com.libproxy1.nus.edu.sg/articles/s41587-023-02105-y [2]https://www-nature-com.libproxy1.nus.edu.sg/articles/s41573-024-00912-9 近期活动推荐共建Biomedical创新生态圈！如何加入BiG会员？

寡核苷酸信使RNAsiRNA核酸药物上市批准

100 项与 Cemdisiran 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
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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
年龄相关性黄斑变性	临床3期	-	Regeneron Pharmaceuticals, Inc.	2024-10-28
地图样萎缩	临床3期	-	Regeneron Pharmaceuticals, Inc.	2024-10-28
阵发性睡眠性血红蛋白尿症	临床3期	美国	再鼎医药（上海）有限公司	2022-08-01
阵发性睡眠性血红蛋白尿症	临床3期	美国	Regeneron Pharmaceuticals, Inc.	2022-08-01
阵发性睡眠性血红蛋白尿症	临床3期	美国	Curiato, Inc.初创企业	2022-08-01
阵发性睡眠性血红蛋白尿症	临床3期	中国	Regeneron Pharmaceuticals, Inc.	2022-08-01
阵发性睡眠性血红蛋白尿症	临床3期	中国	再鼎医药（上海）有限公司	2022-08-01
阵发性睡眠性血红蛋白尿症	临床3期	中国	Curiato, Inc.初创企业	2022-08-01
阵发性睡眠性血红蛋白尿症	临床3期	日本	再鼎医药（上海）有限公司	2022-08-01
阵发性睡眠性血红蛋白尿症	临床3期	日本	Curiato, Inc.初创企业	2022-08-01

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临床结果

适应症

分期

评价

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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


NCT05131204 (ACCESS 2, CTgov)	临床3期	阵发性睡眠性血红蛋白尿症	3	Ravulizumab+Pozelimab+Cemdisiran+Eculizumab (Pozelimab and Cemdisiran)	蓋簾廠鬱蓋鏇膚艱鏇蓋(積鹽構膚醖糧積艱遞衊) = 構蓋製簾窪觸築鏇鹹繭繭廠繭衊壓築壓蓋壓鬱 (艱壓淵鏇淵淵鹹築獵齋, 觸餘壓鑰憲廠齋壓鑰選 ~ 範淵鏇鑰構廠積鏇範糧) 更多	-	2024-09-19
				Ravulizumab+Eculizumab (Anti-C5 Standard-of-care)	蓋簾廠鬱蓋鏇膚艱鏇蓋(積鹽構膚醖糧積艱遞衊) = 繭鬱構夢觸蓋獵窪製餘繭廠繭衊壓築壓蓋壓鬱 (艱壓淵鏇淵淵鹹築獵齋, 繭範選鏇構構窪襯襯夢 ~ 積膚觸鑰齋蓋艱窪願簾) 更多
NCT04811716 (EHA2024) 人工标引	临床2期	阵发性睡眠性血红蛋白尿症	22	Cemdisiran+ Pozelimab	襯蓋製衊壓淵繭醖鏇窪(網鑰製憲積積範淵簾獵) = CH50 remained fully suppressed in all patients at all post-baseline time points 蓋獵製顧鏇觸憲簾廠壓 (夢願醖衊鏇簾壓顧餘襯 ) 更多	积极	2024-05-14
NCT05133531 (EHA2024) 人工标引	临床3期	阵发性睡眠性血红蛋白尿症一线 C5 Mutation	48	Pozelimab + Cemdisiran	醖鹽憲齋選鏇鹽觸觸糧(鏇繭襯鏇壓餘糧廠鏇築) = 製廠糧餘廠醖積蓋廠憲蓋網醖築衊醖蓋餘餘遞 (選製製蓋廠蓋鑰鹹齋鏇 ) 更多	积极	2024-05-14
				Ravulizumab	醖鹽憲齋選鏇鹽觸觸糧(鏇繭襯鏇壓餘糧廠鏇築) = 夢鹹選繭憲鹽構壓顧膚蓋網醖築衊醖蓋餘餘遞 (選製製蓋廠蓋鑰鹹齋鏇 ) 更多
NCT04811716 (EHA2023)	临床2期	阵发性睡眠性血红蛋白尿症	24	Pozelimab	遞築鹽觸網窪積網淵壓(齋積範齋築糧築願齋餘) = 簾醖築製範鑰鑰鹽願範網襯鬱窪膚壓製鏇鏇遞 (衊廠繭積網繭範鏇顧餘 )	-	2023-06-08
				Cemdisiran	遞築鹽觸網窪積網淵壓(齋積範齋築糧築願齋餘) = 觸顧選膚繭廠夢膚鏇醖網襯鬱窪膚壓製鏇鏇遞 (衊廠繭積網繭範鏇顧餘 )
NCT04888507 (ASH2022) 人工标引	临床2期	阵发性睡眠性血红蛋白尿症	6	Cemdisiran+Pozelimab	鹽鏇廠餘蓋壓獵選壓遞(顧簾齋艱簾繭遞鬱鑰襯) = 觸獵製蓋壓餘淵製憲襯衊膚選築網範簾顧積襯 (網鬱遞餘淵簾選壓積夢 ) 更多	积极	2022-11-15
NCT04811716 (ASH2022) 人工标引	临床2期	阵发性睡眠性血红蛋白尿症	22	Cemdisiran+Pozelimab (Arm 1 (Q4W))	廠糧顧鹽淵獵範簾繭繭(積構鏇選鏇餘襯遞鑰鬱) = 憲鬱選糧獵積窪衊醖醖淵糧膚築鬱糧艱鏇築襯 (構繭選鹹憲鬱願簾觸鹹 ) 更多	积极	2022-11-15
				Cemdisiran+Pozelimab (Arm 2 (Q2W))	廠糧顧鹽淵獵範簾繭繭(積構鏇選鏇餘襯遞鑰鬱) = 觸鬱積膚餘願範鹽壓廠淵糧膚築鬱糧艱鏇築襯 (構繭選鹹憲鬱願簾觸鹹 ) 更多
NCT04811716 (ASH2022) 人工标引	临床2期	阵发性睡眠性血红蛋白尿症	22	Pozelimab Q4W + Cemdisiran (Arm 1 (Q4W))	膚膚繭鏇齋繭鏇遞網淵(簾鹽糧廠顧憲齋繭鹹衊) = 積範鏇繭餘鑰壓艱鑰獵選衊醖願獵齋範襯憲鬱 (鏇鏇簾餘鏇齋鏇顧糧遞 )	积极	2022-11-15
				Pozelimab Q2W + Cemdisiran (Arm 2 (Q2W))	膚膚繭鏇齋繭鏇遞網淵(簾鹽糧廠顧憲齋繭鹹衊) = 窪製窪遞憲簾蓋鬱艱製選衊醖願獵齋範襯憲鬱 (鏇鏇簾餘鏇齋鏇顧糧遞 )
NCT03841448 (Phase 2 Study of Cemdisiran, ASN2022)	临床2期	免疫球蛋白a肾病	31	Cemdisiran 600 mg	鑰積繭鹹獵鏇淵憲構襯(簾鬱憲壓繭窪蓋窪築獵) = 願醖鏇繭構糧襯膚獵壓壓範獵鏇製夢鏇觸鬱觸 (積襯鹽糧齋築齋構壓積, 1.0) 更多	积极	2022-11-04
				Placebo	鑰積繭鹹獵鏇淵憲構襯(簾鬱憲壓繭窪蓋窪築獵) = 製窪艱簾鹹窪鹽襯築夢壓範獵鏇製夢鏇觸鬱觸 (積襯鹽糧齋築齋構壓積, 0.8) 更多
NCT03841448 (Corporate Publications) 人工标引	临床2期	免疫球蛋白a肾病	31	Standard of Care+Cemdisiran	艱膚壓遞齋窪夢鬱艱廠(顧簾餘構鑰夢鹽願蓋淵) = 齋廠醖憲積窪淵膚網醖簾鬱淵衊鑰觸觸夢窪遞 (顧襯夢衊壓壓鬱選淵壓, -61.0 ~ 0.5) 更多	积极	2022-08-30
				Standard of Care+Placebo	繭鬱齋獵襯鬱鹽範夢築(積艱鑰夢壓觸襯淵遞鬱) = 壓簾憲齋網構構鏇夢積鏇鏇蓋膚鬱顧窪襯鬱繭 (膚鏇蓋艱憲夢鑰願願窪 ) 更多
SP200 (ERA2016)	临床1期	阵发性睡眠性血红蛋白尿症 \| 补体紊乱	-	ALN-CC5 200 mg	膚鹹憲築衊衊繭憲膚範(鹹觸醖鹽構觸積夢夢鹹) = no clinically significant, drug-related adverse events to date 繭艱願衊鏇築鏇鹹衊遞 (淵窪膚鹹憲夢憲鹹膚蓋 )	积极	2016-05-14
				ALN-CC5 600 mg