A Phase 2 Study Evaluating the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Narsoplimab in Paediatric Patients (28 Days to 18 Y.O.) with High Risk Haematopoietic Stem Cell Transplant Thrombotic Microangiopathy - OMS721

开始日期2024-03-07

申办/合作机构

Omeros Corp.

NCT05855083 / Recruiting临床2期

A Phase 2 Study Evaluating the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Narsoplimab in Pediatric Patients (28 Days to ≤ 18 Years of Age.) With High-Risk Hematopoietic Stem Cell Transplant Thrombotic Microangiopathy

The purpose of this study is to evaluate the safety and efficacy of narsoplimab in pediatric patients with thrombotic microangiopathies (TMA) following hematopoietic stem cell transplant (HSCT).

开始日期2023-05-01

申办/合作机构

Omeros Corp.

NCT04488081 / Recruiting临床2期

I-SPY COVID TRIAL: An Adaptive Platform Trial to Reduce Mortality and Ventilator Requirements for Critically Ill Patients

The goal of this project is to rapidly screen promising agents, in the setting of an adaptive platform trial, for treatment of critically ill COVID-19 patients. In this phase 2 platform design, agents will be identified with a signal suggesting a big impact on reducing mortality and the need for, as well as duration, of mechanical ventilation.

开始日期2020-07-31

申办/合作机构

Quantumleap Healthcare Collaborative

[+23]

100 项与 Narsoplimab 相关的临床结果

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100 项与 Narsoplimab 相关的转化医学

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100 项与 Narsoplimab 相关的专利（医药）

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项与 Narsoplimab 相关的文献（医药）

2023-12-01·Clinical Rheumatology

A narrative review of potential drug treatments for nephritis in children with IgA vasculitis (HSP)

Review

作者: Lamond, Megan ; Chetwynd, Andrew J ; Marro, Julien ; Oni, Louise ; Williams, Chloe E C

Abstract:

Immunoglobulin A (IgA) vasculitis (IgAV, also known as Henoch-Schoenlein purpura, HSP) is the most common vasculitis of childhood. It usually presents with a simple, self-limiting disease course; however, a small subset of patients may develop kidney involvement (IgAV-N) which occurs 4–12 weeks after disease onset and is the biggest contributor to long-term morbidity. Treatment currently targets patients with established kidney involvement; however; there is a desire to work towards early prevention of inflammation during the window of opportunity between disease presentation and onset of significant nephritis. There are no clinical trials evaluating drugs which may prevent or halt the progression of nephritis in children with IgAV apart from the early use of corticosteroids which have no benefit. This article summarises the latest scientific evidence and clinical trials that support potential therapeutic targets for IgAV-N that are currently being developed based on the evolving understanding of the pathophysiology of IgAV-N. These span the mucosal immunity, B-cell and T-cell modulation, RAAS inhibition, and regulation of complement pathways, amongst others. Novel drugs that may be considered for use in early nephritis include TRF-budesonide; B-cell inhibiting agents including belimumab, telitacicept, blisibimod, VIS649, and BION-1301; B-cell depleting agents such as rituximab, ofatumumab, and bortezomib; sparsentan; angiotensin converting enzyme inhibitors (ACE-Is); and complement pathway inhibitors including avacopan, iptacopan, and narsoplimab. Further clinical trials, as well as pre-clinical scientific studies, are needed to identify mechanistic pathways as there may be an opportunity to prevent nephritis in this condition.Key Points• Kidney involvement is the main cause of long-term morbidity and mortality in IgA vasculitis despite the current treatment recommendations.• The evolving understanding of the pathophysiology of IgA vasculitis is allowing exploration of novel treatment options which target underlying immune pathways.• Novel treatments currently being trialled in IgA nephropathy may have benefit in IgA vasculitis due to the similarities in the underlying pathophysiology, such as TRF-budesonide, B-cell modulators, and complement inhibitors.• Further studies, including clinical trials of novel drugs, are urgently needed to improve the long-term outcomes for children with IgA vasculitis nephritis.

2024-03-01·Transplantation and Cellular Therapy

Compassionate Use Narsoplimab for Severe Refractory Transplantation-Associated Thrombotic Microangiopathy in Children

Article

作者: Bryson, Elyse ; Williams, Kirsten M ; Silvis, Katherine ; Fitch, Taylor ; Qayed, Muna ; Watkins, Benjamin ; Deeb, Laura ; Chandrakasan, Shanmuganathan ; Chonat, Satheesh ; Jones, Jayre ; Patel, Seema ; Schoettler, Michelle L

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common and potentially severe complication of hematopoietic cell transplantation. TA-TMA-directed therapy with eculizumab, a complement C5 inhibitor, has resulted in a survival benefit in some studies. However, children with TA-TMA refractory to C5 inhibition with eculizumab (rTA-TMA) have mortality rates exceeding 80%, and there are no other known therapies. Narsoplimab, an inhibitor of the MASP-2 effector enzyme of the lectin pathway, has been studied in adults with TA-TMA as first-line therapy with a response rate of 61%. Although there are limited data on narsoplimab use as a second-line agent in children, we hypothesized, that complement pathways proximal to C5 are activated in rTA-TMA, and that narsoplimab may ameliorate rTA-TMA in children. In this single-center study, children were enrolled on single-patient, Institutional Review Board-approved compassionate use protocols for narsoplimab treatment. Clinical complement lab tests were obtained at the discretion of the treating physician, although all patients were also offered participation in a companion biomarker study. Research blood samples were obtained at the time of TA-TMA diagnosis, prior to eculizumab treatment, at the time of refractory TA-TMA diagnosis prior to the first narsoplimab dose, and 2 weeks after the first narsoplimab dose. Single ELISA kits were used to measure markers of complement activation according to the manufacture's instructions. Five children with rTA-TMA received narsoplimab; 3 were in multiorgan failure and 2 had worsening multiorgan dysfunction at the time of treatment. Additional comorbidities at the time of treatment included sinusoidal obstructive syndrome (SOS; n = 3), viral infection (n = 3), and steroid-refractory stage 4 lower gut grade IV acute graft-versus-host disease (aGVHD, n = 3). Two infants with concurrent SOS and no aGVHD had resolution of organ dysfunction; 1 also developed transfusion-independence (complete response), and the other's hematologic response was not assessable in the setting of leukemia and chemotherapy (partial response). One additional patient achieved transfusion independence but had no improvement in organ manifestations (partial response), and 2 patients treated late in the course of disease had no response. Narsoplimab was well tolerated without any attributed adverse effects. Three patients consented to provide additional research blood samples. One patient with resolution of organ failure demonstrated evidence of proximal pathway activation prior to narsoplimab treatment with subsequent declines in Ba, Bb, C3a, and C5a and increases in C3 in both clinical and research lab tests. Otherwise, there was no clear pattern of other complement markers, including MASP-2 levels, after therapy. In this cohort of ill children with rTA-TMA and multiple comorbidities, 3 patients benefited from narsoplimab. Notably, the 2 patients with resolution of organ involvement did not have steroid-refractory aGVHD, which is thought to be a critical driver of TA-TMA. Additional studies are needed to determine which patients are most likely to benefit from narsoplimab and which markers may be most helpful for monitoring lectin pathway activation and inhibition.

2023-07-21·Clinical and Experimental Immunology

MASP2 inhibition by narsoplimab suppresses endotheliopathies characteristic of transplant-associated thrombotic microangiopathy:in vitroandex vivoevidence

Article

作者: Tan, Adrian ; Elhadad, Sonia ; Huang, Jenny ; Laurence, Jeffrey ; Redmond, David

Abstract:

Transplant-associated thrombotic microangiopathy (TA-TMA) is an endotheliopathy complicating up to 30% of allogeneic hematopoietic stem cell transplants (alloHSCT). Positive feedback loops among complement, pro-inflammatory, pro-apoptotic, and coagulation cascade likely assume dominant roles at different disease stages. We hypothesized that mannose-binding lectin-associated serine protease 2 (MASP2), principal activator of the lectin complement system, is involved in the microvascular endothelial cell (MVEC) injury characteristic of TA-TMA through pathways that are susceptible to suppression by anti-MASP2 monoclonal antibody narsoplimab. Pre-treatment plasmas from 8 of 9 TA-TMA patients achieving a complete TMA response in a narsoplimab clinical trial activated caspase 8, the initial step in apoptotic injury, in human MVEC. This was reduced to control levels following narsoplimab treatment in 7 of the 8 subjects. Plasmas from 8 individuals in an observational TA-TMA study, but not 8 alloHSCT subjects without TMA, similarly activated caspase 8, which was blocked in vitro by narsoplimab. mRNA sequencing of MVEC exposed to TA-TMA or control plasmas with and without narsoplimab suggested potential mechanisms of action. The top 40 narsoplimab-affected transcripts included upregulation of SerpinB2, which blocks apoptosis by inactivating procaspase 3; CHAC1, which inhibits apoptosis in association with mitigation of oxidative stress responses; and pro-angiogenesis proteins TM4SF18, ASPM, and ESM1. Narsoplimab also suppressed transcripts encoding pro-apoptotic and pro-inflammatory proteins ZNF521, IL1R1, Fibulin-5, aggrecan, SLC14A1, and LOX1, and TMEM204, which disrupts vascular integrity. Our data suggest benefits to narsoplimab use in high-risk TA-TMA and provide a potential mechanistic basis for the clinical efficacy of narsoplimab in this disorder.

项与 Narsoplimab 相关的新闻（医药）

2024-04-17

·同写意

诺华FIC新药，即将赢下第二战场

大会由扬州市人民政府主办，同写意专业策划，以“打造生物医药新质生产力”为主题，邀请众多行业领袖和先锋人物一起取势明道，就如何打造中国医药新质生产力，面向未来创新药如何立项，资本寒冬下的创新药BD与出海，GLP-1&小核酸药物以及抗体药的质量与生产四大主题展开深度研讨，为行业发展提供方向性指引。在“转型三部曲”的终章，去年正式剥离仿制药业务的诺华，开始加速在创新产品上的跑马圈地。核药Pluvicto撑起抗肿瘤的大旗之后，这家药企的故事，也眼看在肾病领域延续。4月15日，在世界肾脏病学大会上，诺华公布了Fabhalta（iptacopan）治疗IgAN患者的III期研究的中期分析结果。数据显示，iptacopan能有效降低患者的尿蛋白水平，有望成为首个针对替代补体途径的IgAN治疗药物。近来，IgAN赛道新药获批、高额并购吸引着制药界的关注，并显示出逐渐火热的苗头。但不明确的发病机制，以及并不能说“卖”得很好的首款新药，给这片潜在蓝海蒙上了一层雾霾。诺华有意要带领行业跨进一步。去年，IgAN药物开发明星公司Chinook被浑水做空不到一个月，诺华便宣布以高达35亿美元的价格将其收购。1月，随着关联Biotech信瑞诺医药的卖身，诺华完整拥有了一系列IgAN在研管线。基于这些底气，眼下，诺华正发起对IgAN市场的抢滩。它透露，已经成功获批过一次的首创新药iptacopan，第二项适应症剑指IgAN。这是一个不断扩大的蓝海市场。不过，置身其中的不只有成为纯粹创新药企的诺华。一出好戏，呼之欲出。1“自带管线的药物”此次公布的III期APPLAUSE-IgAN研究，旨在评估iptacopan治疗原发性IgAN成人患者的疗效和安全性。研究的主要终点，是第9个月时通过尿蛋白/肌酐比值评估的蛋白尿水平变化，以及24个月内的年化总肾小球滤过率斜率。结果显示，与安慰剂组相比，iptacopan组患者的蛋白尿水平减少了38.3%。诺华表示，蛋白尿的减少是一个“越来越被认可的”替代指标，与患者的肾衰竭进展相关，并已被用作支持IgAN药物加速批准的临床试验终点。通过此替代终点，FDA已经加速批准了Calliditas Therapeutics的Tarpeyo和Travere Therapeutics的Filspari在IgAN中的应用。基于中期分析的积极结果，诺华已向FDA申请加速批准iptacopan用于治疗IgAN患者的补充新药申请（sNDA），且已获FDA优先审评。若获批准，该药物将成为第一款专门针对替代补体通路的IgAN疗法。在去年10月披露的数据中，iptacopan就展现出了优越性，ODDO BHF的分析师更是用“完美无瑕”盛赞该药物在研究中的表现。当时，分析师们表示，由于iptacopan在IgAN和其他肾脏、血液疾病方面中的前景，其具有成为“自带管线药物（pipeline in a pill，PiP）”的潜力。Iptacopan是诺华开发的一款针对替代补体通路的补体因子B（CFB）抑制剂，于2023年12月获FDA批准上市，用于治疗阵发性睡眠性血红蛋白尿症（PNH）成人患者，成为该领域首个口服单药疗法。今年3月，EMA人用药品委员会（CHMP）也建议授予iptacopan的上市许可，用于患有溶血性贫血的成人PNH。与阿斯利康的补体抑制剂Soliris（eculizumab）和Ultomiris（ravulizumab）相比，iptacopan的口服疗法在给药方式上具有优势，阿斯利康的药物则是通过注射或输液方式进行给药。Iptacopan简介，图源：诺华官网Iptacopan曾被Evaluate列为10款值得关注的潜在重磅疗法之一，部分原因就在于该疗法具有治疗多种适应症的潜力。上述适应症之外，Iptacopan目前也在临床阶段探索其他领域的治疗可能，包括C3肾小球疾病（C3G）、免疫复合物膜增殖性肾小球肾炎（IC-MPGN）和非典型溶血性尿毒症综合征（aHUS）等补体介导疾病。去年12月，诺华公布该疗法用以治疗C3G患者的APPEAR-C3G临床III期研究数据。与安慰剂相比，接受iptacopan治疗6个月的C3G患者蛋白尿显著减轻。目前尚未有疗法获批用以治疗C3G。至于IgAN，APPLAUSE-IgAN仍在进行中，以检验iptacopan延缓疾病进展的能力。为此，研究者将考量24个月内的年化总肾小球滤过率（eGFR）斜率。这些结果预计将于明年公布。Jefferies的分析师估计，该药的峰值销售额可能达到36亿美元。iptacopan在研，图源：诺华官网240余年“肾病”史诺华与肾病的渊源可追溯到40年前。1983年，FDA批准环孢素（也称环孢素A或环孢多肽A等）用于临床肾移植。这款开创了免疫抑制治疗新时代的产品，最初发现于山德士（诺华公司前身之一）的实验室，如今已被广泛应用于肾脏疾病、器官移植和自身免疫性疾病等治疗中。尽管上市已久，且面临众多仿制药的竞争，根据诺华的财报，环孢素在2022年仍带来3.1亿美元的营收。诺华在肾病领域管线布局但平心而论，环孢素之后的很长一段时间内，诺华管线中并未见到有关肾病研究的身影。近年来，诺华有意扩大对肾病的投入，“心血管、肾脏及代谢疾病”也跃至该公司现阶段聚焦的四大核心领域之一（其他的是免疫学、神经疾病与肿瘤学）。除了紧锣密鼓的筹备iptacopan的相关研究，与其他MNC一样，诺华也在重金买资产。今年伊始，诺华宣布全资收购信瑞诺医药，后者拥有2个处于III期临床的IgAN管线：atrasentan和zigakibart。其中，atrasentan正在全球开展III期试验，中期分析结果积极。Atrasentan是一种强效高选择性内皮素A（ETA）受体拮抗剂，拟用于治疗IgAN患者。36周中期分析显示，研究达到了主要疗效终点，即与安慰剂相比，IgAN患者中的蛋白尿具有统计学意义的显著减少；安全性与先前报告的II期AFFINITY研究IgAN队列的数据一致。根据中期蛋白尿终点分析的结果，诺华计划于今年向FDA提交申请，以期atrasentan在美国得到加速批准。Zigakibart（BION-1301）也已启动III期MRCT研究。这些进展意味着，诺华已手握多款临近商业化的IgAN新药，未来将有望改变IgAN药物的市场格局。2023年财报显示，诺华全年实现营收454亿美元，同比增长10%。其中，在美国和欧洲上市不久的放射配体疗法创新药物Pluvicto，2023年销售额达到9.8亿美元，同比暴涨约261%。某种程度上，诺华已成为潜力无限的“核药”代名词，但大厂头顶的“专利悬崖”乌云也很难挥去。刚成为创新“完全体”的诺华表现不错，同时，因分拆完山德士后利润率骤跌也是不争的事实。到2026年，失去多款药物的独家专利的诺华，还可能损失近百亿美元。在果断舍弃ADC大盘后，诺华确实需要寻找更多潜在的可能性。以IgAN为代表的肾病领域，无疑成为这家药企的掘金之地。3隐秘蓝海的角逐者前几天，福泰制药和Alpine一笔49亿美元的收购，在IgAN这条隐秘的蓝海赛道的水面砸出巨大声响。这笔交易的重点产品，是一款自免药物povetacicept (ALPN-303)，在II期针对IgAN试验中，显示出了同类最佳的潜在疗效，有望在2024年下半年进入III期临床。IgAN是最为常见的一种原发性肾小球疾病，每年全球每百万成年人中，约有25人被新诊断为IgAN。援引弗若斯特沙利文的数据，全球IgAN治疗药物市场预计从2020年的5.67亿美元，增至2025年的11.96亿美元，2020年至2025年复合年增长率达16.1%，2025年全球IgAN患者总数将达到近1000万人。从市场格局看，全球仅Nefecon、Sparsentan以及盐酸地拉卓（日本）获批治疗IgAN。Sparsentan由Travere开发，2023年2月获得FDA加速批准，成为首个IgAN非免疫抑制疗法。Nefecon则是全球首个IgAN靶向治疗药物，于2021年12月获得FDA批准，现已成为首个同时被FDA、EMA、NMPA三大药监机构批准用于治疗IgAN的创新药物。Nefecon在上市首年销售额达3680万美元，2023年销售额破1亿美元。可能是由于IgAN在美国属于罕见病，Nefecon的商业化成绩算不上亮眼。不过相较于仅有13至15万名患者的美国，国内IgAN患者规模则要大得多。目前，我国预计有260到430万左右潜在IgAN患者。照此说，Nefecon或将在我国获得新的增长点。参赛选手逐渐集聚。与Calliditas签订独家授权许可协议的云顶新耀，自然是跑在第一名的选手，拥有在大中华地区、新加坡、韩国开发以及商业化Nefecon的权利。由荣昌生物开发，曾在红斑狼疮治疗的临床研究中取得成功的泰它西普，去年在IgAN中的II期临床研究中也取得了阳性结果，用药24周后，患者尿蛋白水平较基线下降了49%。作为国内首个进入临床阶段的MASP-2单抗，康诺亚的CM338也显示出对肾组织C3、C4、IgA沉积有良好的抑制作用。另外，恒瑞医药、创胜集团、麦济生物等药企也有相关产品处于临床在研阶段。逐渐繁荣之余，IgAN药物研发市场也受到了不少负面消息的冲击。去年8月，刚获得FDA批准仅半年的Sparsentan，在跟厄贝沙坦（Irbesartan）“头对头”的较量中，错过了III期研究的次要终点；10月，另一家明星公司Omeros披露，靶向补体系统MASP-2的单抗Narsoplimab（OMS721）治疗晚期IgAN的III期临床（ARTEMIS-IGAN）失败，并终止这一产品在IgAN适应症的开发。这片蓝海之所以“隐秘”，自然是因为存在着不少未知。不过，探索的过程中总会经历各种挑战，比如安全性、有效性、可生产性甚至药物经济学等的疑问或困难，技术总会在这个过程中得到进一步的迭代，成功会为勇敢者加冕。期待越来越多新靶点、新技术的探索，揭开IgAN的神秘面纱。参考文章：1、Novartis touts surrogate endpoint win, nabs priority review for Fabhalta in IgAN；fiercepharma2、355亿巨额并购，IgA肾病赛道起风了；氨基财经3、对话韩照中博士：不意外的IgA肾病III期失败，我们从中学到什么？；同写意更多优质内容，欢迎关注↓↓↓

临床3期申请上市并购优先审批临床2期

2024-04-15

·PRNewswire

Pre-clinical result of LP-005, a novel bi-functional complement antibody-fusion protein was unveiled by LongBio at WCN2024

BUENOS AIRES, Argentina, April 15, 2024 /PRNewswire/ -- LongBio Pharma (Suzhou) Co., Ltd. (referred to as "LongBio"), a leading biotech company dedicated to developing innovative protein treatments for nephrology, allergy, respiratory, hematology, ophthalmology, and other autoimmune and rare diseases, proudly announced the release of pre-clinical data of LP-005, a novel bi-functional complement antibody-fusion protein, at the 2024 World Congress of Nephrology (WCN24) held by International Society of Nephrology (ISN). The poster titled "Bi-functional C5 antibody-fusion protein (LP-005) with potential best-in-class bioactivity for complement inhibition" was presented by LongBio during the conference. Date and Time: April 15, 2024, at 17:45 pm (UTC -3) Location : Exhibition Hall and Main Foyer Poster Number: MON-100 Methods: Eculizumab, POT-4 (also known as APL-1) was purchased from vendors. The sequences of Ravulizumab, Crovalimab, Pozelimab, Narsoplimab and Ab-fH were obtained from INN and made in-house with LP-005, LP-005C. CP, AP, LP and C3b deposition assays with head-to-head comparison were conducted. Monkey PK/PD assay of LP-005C and Ab-fH was also conducted. Results: LP-005 shows the most potent inhibition in CP, AP and LP compared to Eculizumab, Ravulizumab, Crovalimab, Pozelimab and Narsoplimab. In addition, it also has the most efficient inhibition in C3b assay compared to Antibody-fH fusion and POT-4 (APL-1). The monkey PK/PD study indicates that when fusing to the same C5 antibody, LongBio's unique inhibitor (inCibitorTM) shows a better PK/PD profile compared to the natural fH 1-5 fragment. LP-005 is a novel bifunctional complement antibody fusion protein targeting both C3 and C5, with better bioactivity in CP, AP, LP and C3b deposition assays. Meanwhile, LP-005 is engineered to optimize surface charge (PI) and FcRn binding, making it first Q4W bi-functional complement inhibitor all over the world. With all these advantages above, LP-005 has the potential to be a best-in-class drug candidate with excellent and full complement inhibitory activity and will be explored in complement mediated disorders. LP-005's phase I study in healthy volunteers will be completed in 2024Q2 in China. At present, LP-005 showed expected PK/PD profile and well tolerated safety profile. More clinical data will be unveiled at 2024 European Meeting on Complement in Human Diseases in September. The phase II studies with indication of IgAN (IgA Nephropathy) and PNH (Paroxysmal nocturnal hemoglobinuria, rare disease) will initial in 2024Q2. Other indications in neurology and ophthalmology are also scheduled to develop. About InCibitor™ InCibitorTM is a new generation of complement inhibitor platform developed by LongBio. The bi-functional complement inhibitor LP-005 developed based on this platform is going to start Phase II study of IgAN and PNH. LongBio is also exploring the development of new drugs related to hematology, nephrology, neurology, ophthalmology, oncology, and gene therapy based on this platform. About LongBio LongBio Pharma is a biotech company located in Shanghai/Changshu, China. The company, which was founded in 2018, focuses on autoimmune and rare diseases, serving patients and society. LongBio Pharma aims to bring our drugs to both domestic and international markets with our partners, especially to bring patients with more affordable and high-quality bio-medicines. Our leading pipeline is a next generation of anti-IgE antibody (LP-003), which is about to start Phase III study in 2024Q2, and prepare for BLA in 2025H1. The second leading pipeline is a bi-functional complement antibody fusion-protein (LP-005) , which is in Phase I at present, intending to start Phase II/III in 2024Q2. For more information, please visit: or please contact: [email protected]. SOURCE LongBio

临床1期临床2期临床结果基因疗法

2024-04-12

·药智网

IgA肾病赛道起风了

一直以来，自免领域愈发受到大小药厂的关注。而在众多细分赛道中，免疫球蛋白A肾病（IgA肾病）的热度尤为凸显。继去年诺华斥资35亿美元收购Chinook，如今，Vertex决定49亿美元（人民币355亿元）收购Alpine，以扩大其在肾脏和免疫系统疾病领域的布局。曾经，IgA肾病领域的发展不温不火，但随着海内外biotech陆续展示出令人期待的研究成果，跨国大药厂开始蠢蠢欲动。这也意味着，主打IgA肾病药物研发的biotech，潜力和价值正在被市场重新评估和认识。相比诺华收购Chinook，Vertex对Alpine的估值更为慷慨，较Alpine前收盘价溢价约67%。这不仅体现了其对Alpine未来价值的高度认可，也有可能成为未来同类药企和药物估值的一个重要参考。在充满希望与挑战的创新药研发领域，每一次投资和并购都可能成为推动科学前进的一股新风，为患者带来福音，为行业注入活力。眼下，IgA肾病赛道的大风已起，期待新的变革与突破早日到来。01值得押注的IgA肾病赛道免疫球蛋白A（IgA）肾病是全球最常见的原发性肾小球肾炎，最早于1968年在法国报道。那时，人们认为这是一个良性病，不会有肾功能损害。但后来的一些研究发现，并不是所有IgA肾病都是良性状态。一项回顾性研究显示，每隔10年会有20%的IgA肾病患者进展为尿毒症；跟踪20年以上，尿毒症比例会达到甚至超过50%，对患者的生活有相当大的影响。国内一项关于IgAN患者预后的报告同样发现，虽然正在接受治疗，但超过1/3的患者发病20年后进展至终末期肾脏病，近一半的患者在30年内发展为终末期肾脏病，高达20%-40%的IgA患者，在诊断后10-20年内发生肾功能衰竭，也是引起我国青年人肾衰竭的常见病因。从流行病数据来看，IgA肾病具有显著的人种差异。在美国，IgA肾病属于罕见病，美国仅有13-15万名患者；亚洲国家发病率明显高于欧洲、美洲及非洲等国家，而在亚洲国家中，中国和日本的发病率又是最高的。根据最新数据，在中国，2022年IgA肾病的新确诊人数在10万左右，存量患者的规模超过100万人。如果算上未明确诊断IgA肾病的患者，这一数字可能会超过400万。而按照弗若斯特沙利文报告，到2030年，全球IgA肾病患者可达1016.52万人。尽管患者群体规模庞大，但多年来，针对该疾病公认的首选治疗为强化降压治疗。直到2021年，SGLT2抑制剂治疗才首次写入中国IgA肾病临床指南。以达格列净为代表的列净类降糖药成为20年来，照进这一疾病领域的第一道微光。除此之外，对于症状较为严重的患者，加用糖皮质激素可以说是目前最普遍的治疗手段。不过，该类药物难以避免地会带来诸多副作用，以及出现耐药情况，患者整体预后改善非常有限。总体来说，IgA肾病患者对于安全便捷的新疗法，有着极为急切的治疗需求。大规模的患者群体、有待新疗法面世的临床需求，IgA肾病自然成了大药企的掘金之地。02被寄予厚望的B细胞因子与大多数自身免疫性疾病类似，IgA肾病的发病机制并不单一，至今也未完全清楚。关于IgAN的发病机制，目前比较公认的是的“四重打击”学说：第一重打击为遗传或环境因素导致Gd-IgA1(半乳糖缺陷型IgA1)产生，这种异常的抗体其实对机体而言也是一种抗原物质；第一重打击后，针对Gd-IgA1的特异性抗体的产生(大多为IgG，少数为IgA1)，而随着含Gd-IgA1的致病性免疫复合物的不断形成（第三重打击），免疫复合物最终沉积膜区，诱发免疫反应，引起肾小球损伤，也就是第四重打击。可以看到，没有免疫异常就没有IgA肾病。基于相关发病机制，眼下全球多个针对IgA肾病的在研新药正蓄势待发，以期填补现有治疗手段的匮乏。全球范围内，关于IgA肾病的新药研发方向可分为四大类：糖质激素类、靶向血管内皮素系统类、靶向B细胞免疫通路类和靶向补体系统类，涉及了较多的信号通路以及相关靶点。其中，诺华、Vertex通过并购，不约而同地布局了B细胞及其因子。去年6月，诺华在自有产品Iptacopan（LNP-023）的II期临床已取得积极结果并接近完成III期临床的情况下，仍以35亿美元的价格收购手握两款IgA肾病候选产品的Chinook。Chinook核心管线之一Atrasentan，是一种强效高选择性内皮素A（ETA）受体拮抗剂，可选择性阻断ETA受体；另一核心管线是BION-1301，则是APRIL（一种增殖诱导配体）抗体，可阻断APRIL与其受体结合，降低Gd-IgA1循环水平来治疗IgA肾病。今年4月10日，Vertex则宣布计划以49亿美元收购Alpine，后者核心管线Povetacicept，是BAFF（B细胞因子）和APRIL的双重抑制剂。BAFF和APRIL是维持B细胞水平和体液免疫的关键因子，参与了多种自身介导的免疫疾病，如IgA肾病和系统性红斑狼疮。BAFF可以维持细胞水平，而APRIL可以调节B细胞的功能。在IgA肾病患者中，BAFF和APRIL水平较高，且与Gd-IgA1水平和疾病严重程度呈正相关。与健康人群相比，IgA肾病患者体内APRIL可刺激淋巴细胞，并生成更多的Gd-IgA1。一项纳入了44例IgA肾病患者、22例非IgA肾病的肾病患者、23例健康人群的研究表明，与健康人群和非IgA肾病的肾病患者相比，IgA肾病患者的BAFF和APRIL水平较高，同时循环中的B细胞水平也较高。总之，这些研究证实，BAFF、APRIL参与了IgA肾病的发生。通过抑制BAFF和APRIL可以阻断它们与相应受体结合，并阻止下游信号通路的后续激活，从而减少对肾脏的损害。这也在临床中得到了证实。2022年阿塞西普在IgA肾病中进行的II期临床研究（JANUS研究）取得了阳性结果。阿塞西普是首个针对BAFF和APRIL的抑制剂，原本想用于治疗红斑狼疮，但临床失败，而后其在IgA肾病患者临床试验达到主要终点，高剂量组的蛋白尿与基线相比平均减少33%，与安慰剂相比具有统计学意义。但这一结果并未达到市场预期。2023年，泰它西普在IgA肾病中的II期临床研究取得了阳性结果。泰它西普是针对BAFF和APRIL的第一个国内原研抑制剂。之前曾在红斑狼疮治疗的临床研究中取得成功，获批上市，现如今在IgA肾病中的表现同样喜人，用药24周后，患者尿蛋白水平较基线下降了49%。被Vertex看中的Alpine，也是一号种子选手。最新临床数据显示，在用药36周时，患者尿蛋白水平较基线降低64.1%，100%患者血尿消退，Gd-IgA1显著减少，且安全性良好。Povetacicept进展最快的适应症为IgA肾病，今年下半年将启动三期关键临床，后续探索的适应症还有系统性红斑狼疮、膜性肾病、血球减少症。去年11月2日，Alpine发布一期阳性数据后，Alpine股价应声暴涨39.92，自11月至Vertex宣布溢价收购前，其股价涨幅达280%。此次收购事件宣布后，Alpine股价大涨20.82%，盘后再次暴涨36.1%。无论是诺华的入局，还是Vertex的溢价收购，均证实了肾科尤其是IgA肾病赛道的巨大潜力。03战局愈演愈烈目前，补体抑制剂也是IgA肾病领域的研发热点。所谓补体，是补足免疫系统对病原体及异常细胞杀伤能力的一套系统。这套系统可根据不同的级联活化途径，分为三类，分别为补体经典途径、补体替代途径和补体凝集素途径。正常情况下，补体是参与破坏或清除病原微生物及异常细胞的重要机制，但过度激活也会作用于机体自身导致政策器官及组织的损伤。既往研究表明，在IgA肾病患者体内，补体系统攻击肾脏是源于补体替代途径和补体凝集素途径激活。目前，在研的IgA肾病适应症相关补体抑制剂包括因子B抑制剂（Iptacopan）、抗MASP-2单抗（Narsoplimab）、靶向C5蛋白RNAi疗法（Cemdisiram）、抗C5单克隆抗体（依库珠单抗）等。其中，进展最快的是诺华的Iptacopan，通过抑制B因子阻断旁路途径放大循环，减少蛋白尿，III期临床已达到主要终点，用药24周患者蛋白尿水平较安慰剂组减少40%。当然，鉴于IgA肾病病理机制的复杂性，这一领域也充斥着负面消息。去年10月16日，另一倍受关注的补体抑制剂便宣布临床失败。根据Omeros的新闻稿，对III期试验进行中期分析表明，与安慰剂相比，在主要终点上，Narsoplimab并未取得统计学意义上的显著改善。Omeros决定终止这一产品在IgA肾病适应症的开发。随后，其股价暴跌超过30%。不过，Omeros并没有放弃征战IgA肾病，反而决定继续推进补体靶向药物治疗IgA肾病的研究。随着此次受挫，原本用于IgA肾病商业化和继续推进相关临床试验的资金，将被转用于Omeros的其他后期项目，包括IgA肾病旁路途径抑制剂OMS906正在进行的II期和即将进行的III期项目。回到国内来说，当前已有不少药企入局IgA肾病赛道。其中，云顶新耀的布地奈德口服缓释制剂Nefecon（耐赋康）已经杀出重围。该药是全球首个IgA肾病靶向治疗药物，已在美国、欧盟和国内获批上市。全球III期临床数据显示，给药9月时，服用Nefecon患者蛋白尿水平与基线相比减少34%;给药12月时，患者蛋白尿水平与基线相比减少52%。基于国内患者群体规模及耐赋康的先发优势，后续商业化表现或许可以期待。更多的入局者则在探索激素以外的治疗方案。除了上文提及的荣昌生物在研的泰它西普，康诺亚的CM338是国内首个进入临床阶段的MASP-2单抗，根据公司披露，CM338活性是Narsoplimab的10-50倍，并对肾组织C3、C4、IgA沉积有良好的抑制作用。恒瑞医药、创胜集团、麦济生物等药企的同类靶点产品，也已处于临床在研阶段。对于药企来说，这场以满足临床需求出发点的探索仍将继续。而随着越来越多新靶点、新技术的探索，IgA肾病缺乏有效治疗手段的局面，有望得到显著转变。当然，这也意味着IgA肾病战局愈演愈烈，入局者不仅需要尽快在临床试验中取得成功，而且数据也要有竞争力。谁将最终成为王者，就看各家的临床研究数据以及商业化能力。注：以上图片来源氨基观察来源 | 氨基观察（药智网获取授权转载）撰稿 | 武月责任编辑 | 八角声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。商务合作 | 王存星 19922864877（同微信）阅读原文，是受欢迎的文章哦

并购临床结果免疫疗法

100 项与 Narsoplimab 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11531	-	-	DB16418

研发状态

适应症	最高研发状态	国家/地区	公司
血栓性微血管病	临床2期	荷兰更多	Omeros Corp. 更多
造血干细胞移植	临床2期	德国更多	Omeros Corp. 更多
免疫球蛋白a肾病	终止	-	Omeros Corp. 更多
狼疮性肾炎	无进展	中国香港更多	Omeros Corp. 更多
溶血性尿毒症综合征	无进展	立陶宛更多	Omeros Corp. 更多

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临床结果

适应症

分期

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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


ASH2023	N/A	血栓性微血管病	-	Narsoplimab	獵醖繭夢鑰獵觸選構構(膚鹽鑰範鏇淵膚網鏇鏇) = 鏇鏇鹹願積齋壓蓋製製衊廠襯襯獵構壓鏇餘鑰 (鏇淵壓築衊顧壓觸範觸 ) 更多	积极	2023-12-10
NCT03608033 (ARTEMIS - IGAN, NEWS) 人工标引	临床3期	免疫球蛋白a肾病	180	Narsoplimab	膚夢繭製齋顧願衊觸餘(壓膚構願鹹憲鬱糧鹽壓) = The ARTEMIS-IGAN trial did not reach statistical significance on the primary endpoint of reduction in proteinuria from baseline compared to placebo. Proteinuria reduction in the placebo group was substantially greater than reported in other IgA nephropathy clinical trials. 鏇鏇網觸繭鏇衊觸糧廠 (衊夢蓋糧憲廠願廠夢鹽 )	不佳	2023-10-16
P561 (EBMT2023)	N/A	造血干细胞移植	1	Narsoplimab	鹽憲顧觸願淵獵窪觸顧(鏇顧淵積願艱製鏇艱淵) = Narsoplimab was well tolerated with no adverse events 選齋憲鬱醖範壓鏇願廠 (積廠鏇醖壓範鹹憲齋鏇 )	积极	2023-04-23
NCT02222545 (Pubmed \| J Urol)	临床2期	造血干细胞移植	28	Narsoplimab	膚鬱醖願窪範簾鏇獵鹽(鏇築獵獵鹹餘觸鏇淵鑰) = 構範願鹹觸餘鏇構觸築鹽積繭鬱顧願網窪製艱 (願廠艱蓋積艱鏇獵鹽獵 ) 更多	积极	2022-04-19
NCT02222545 (P462, EBMT2022)	临床2期	血栓性微血管病 KMT2A-MLL	1	Narsoplimab 4mg/kg IV	艱窪襯淵鹹鏇廠餘衊鹽(製鑰願艱鬱獵襯鏇膚繭) = 築窪鹹構願簾壓遞鑰窪築獵壓選窪繭範衊繭糧 (淵壓鹹積淵願醖餘鏇鬱 )	积极	2022-03-19
NCT02222545 (EHA2021) 人工标引	临床2期	血栓性微血管病	51	Narsoplimab (full analysis set [FAS])	衊願選簾鬱齋獵衊衊鑰(觸獵積醖遞繭鑰壓衊願) = 餘餘簾鹹顧憲艱積選遞糧積觸憲窪選鬱衊膚憲 (獵衊鑰齋鏇顧繭廠夢襯 ) 更多	积极	2021-06-09
NCT02222545 (EHA2021) 人工标引	临床2期	血栓性微血管病	51	Narsoplimab (per-protocol [PP])	衊願選簾鬱齋獵衊衊鑰(觸獵積醖遞繭鑰壓衊願) = 選齋夢鑰願廠艱鬱願夢糧積觸憲窪選鬱衊膚憲 (獵衊鑰齋鏇顧繭廠夢襯 ) 更多	积极	2021-06-09
NCT02222545 (not available, EBMT2021)	临床2期	血栓性微血管病	28	Narsoplimab	窪艱窪構鬱艱蓋鏇廠鹽(齋夢願鏇淵製遞鹽積鹽) = 積艱遞鏇糧衊淵窪範艱積壓餘選齋鬱獵艱網糧 (壓憲顧壓膚醖範積糧鹹 )	积极	2021-03-14
NCT02682407 (Pubmed \| Kidney Int Rep) 人工标引	临床2期	免疫球蛋白a肾病	12	Narsoplimab	憲顧築鹽獵選網製顧鬱(齋糧繭鹹選繭觸選夢夢) = The most commonly reported adverse events (AEs) included headache, upper respiratory infection, and fatigue. 夢鹽醖積選遞艱鏇積糧 (淵製襯獵選製鬱鏇夢遞 ) 更多	积极	2020-08-13
NCT02682407 (Pubmed \| Kidney Int Rep) 人工标引	临床2期	免疫球蛋白a肾病	12	vehicle+narsoplimab		积极	2020-08-13