The purpose of this study is to evaluate the efficacy of povetacicept in adult participants compared with placebo in reducing proteinuria and preserving renal function.

开始日期2024-08-30

申办/合作机构

Alpine Immune Sciences, Inc.

NCT05757570 / Recruiting临床1/2期

Open-Label Study to Assess the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Povetacicept in Subjects With Autoimmune Cytopenias (RUBY-4)

The goal of this clinical study is to evaluate povetacicept in adults with autoimmune cytopenias of immune thrombocytopenia, autoimmune hemolytic anemia, and cold agglutinin disease to determine if povetacicept is safe and potentially beneficial in treating these diseases. During the study treatment period participants will receive povetacicept approximately every 4 weeks for 6 months, with the possibility of participating in a 6-month study treatment extension period.

开始日期2023-07-03

申办/合作机构

Alpine Immune Sciences, Inc.

NCT05732402 / Recruiting临床1/2期

An Open-Label, Multiple-Ascending Dose Study to Assess the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Different Dose Levels of Povetacicept in Subjects With Autoantibody-Associated Glomerular Diseases (RUBY-3)

The goal of this clinical study is to evaluate multiple dose levels of povetacicept (ALPN-303) in adults with immunoglobulin A (IgA) nephropathy, membranous nephropathy, lupus-related kidney disease (lupus nephritis). or anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis to determine if povetacicept is safe and potentially beneficial in treating these diseases.
During the study treatment period, participants will receive povetacicept approximately every 4 weeks for 6 months, with the possibility of participating in a 6-month treatment extension period and an optional 52 week treatment extension period.

开始日期2023-03-15

申办/合作机构

Alpine Immune Sciences, Inc.

100 项与 Povetacicept 相关的临床结果

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100 项与 Povetacicept 相关的转化医学

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100 项与 Povetacicept 相关的专利（医药）

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项与 Povetacicept 相关的文献（医药）

2024-11-01·CTS-Clinical and Translational Science

A first‐in‐human, randomized study of the safety, pharmacokinetics and pharmacodynamics of povetacicept, an enhanced dual BAFF/APRIL antagonist, in healthy adults

Article

作者: Smith, Alina ; Davies, Rupert ; Peng, Stanford L. ; Thomas, Heather M. ; Blair, Tiffany ; Dillon, Stacey R. ; McLendon, Kristi ; Wang, NingXin ; Chunyk, Allison G. ; Enstrom, Amanda ; Lickliter, Jason ; Blanchfield, Lori

Abstract:

Therapeutic agents targeting the tumor necrosis factor (TNF) superfamily cytokines B‐cell activating factor (BAFF, BLyS) and/or A PRoliferation Inducing Ligand (APRIL) have demonstrated clinical effectiveness in multiple autoimmune diseases, such as systemic lupus erythematosus, lupus nephritis, and immunoglobulin A nephropathy (IgAN). However, their clinical utility can often be limited by incomplete and/or prolonged times to clinical response and inconvenient dosing regimens, which may be improved by more potent dual inhibition of both cytokines. Povetacicept (ALPN‐303; TACI vTD‐Fc) is a crystallizable fragment (Fc) fusion protein of an engineered transmembrane activator and CAML interactor (TACI) domain which mediates more potent inhibitory activity than wild‐type TACI‐Fc or BAFF‐ or APRIL‐specific antibodies and demonstrates superior pharmacokinetic and pharmacodynamic activity in multiple preclinical disease models. In this first‐in‐human study in healthy adults, povetacicept was well‐tolerated as single ascending doses of up to 960 mg administered intravenously or subcutaneously. Dose‐dependent pharmacokinetics were observed. Coverage of BAFF and APRIL was observed for 2–3 weeks and ≥4 weeks after doses of 80 mg and ≥240 mg, respectively. Maximal pharmacodynamic effects were observed at dose levels ≥80 mg for a single dose, associated with on‐target reductions in antibody‐secreting cells as well as in all circulating immunoglobulin isotypes, including the IgAN disease‐related biomarker galactose‐deficient‐immunoglobulin A1 (Gd‐IgA1), and were superior to results reported for wild‐type TACI‐Fc. These data strongly support further development of povetacicept for the treatment of B‐cell‐mediated automimmune diseases.

2023-12-02·Expert opinion on biological therapy

Antibody based therapeutics for autoimmune hemolytic anemia

Review

作者: Fattizzo, Bruno ; Cavallaro, Francesca ; Barcellini, Wilma

INTRODUCTION:

Autoimmune hemolytic anemia (AIHA) treatment has been revolutionized by the introduction of target therapies, mainly monoclonal antibodies (MoAbs).

AREAS COVERED:

The anti-CD20 rituximab, which targets Ab production by B-cells, induces 80% of response in warm-type AIHA (wAIHA) and 50-60% in cold agglutinin disease (CAD). Other B-cell targeting MoAbs including ianalumab, povetacicept, and obexelimab are under active study. The anti-CD38 MoAb daratumumab has been used in several reports to target long-lived plasma-cells responsible for AIHA relapse, being effective even in multi-refractory cases. Anti-complement MoAbs will soon change the treatment paradigm in CAD; the anti-C1s sutimlimab rapidly increased Hb in more than 80% of the cases. Finally, MoAbs inhibiting the neonatal Fc receptor (FcRn), such as nipocalimab, can reduce the half-life of the pathogenic autoAbs, representing a promising treatment for wAIHA.

EXPERT OPINION:

MoAbs offer the potential to improve efficacy by reducing toxicity. However, there is a huge need for clinical trials exploring response duration rather than short-term efficacy. Complement inhibitors and anti-FcRns do not abrogate autoAb production and are being developed as long-term therapies. Thus, the combination of B-cell/plasma cell targeting drugs deserves to be explored. On the other hand, their rapid efficacy should be exploited for the acute AIHA phase.

2023-07-01·Arthritis & rheumatology (Hoboken, N.J.)

Povetacicept, an Enhanced DualAPRIL/BAFFAntagonist That Modulates B Lymphocytes and Pathogenic Autoantibodies for the Treatment of Lupus and Other B Cell–Related Autoimmune Diseases

Article

作者: Evans, Lawrence S. ; Mudri, Sherri ; Bhandari, Janhavi G. ; Maria, Zahra ; Kuijper, Joseph L. ; Rixon, Mark W. ; Dillon, Stacey R. ; Wang, NingXin ; Griffin, Luana L. ; DeMonte, Daniel ; Lewis, Katherine E. ; Wolfson, Martin F. ; Hong, Youji ; Messenheimer, David J. ; Holland, Pamela M. ; Yang, Jing ; Peng, Stanford L. ; Garrett, Logan B. ; Hebb, LuAnne ; Seaberg, Michelle ; Kleist, Kayla ; Debrot, Susan ; Ardourel, Daniel ; Sanderson, Russell J. ; Chunyk, Allison G.

Objective:

Dysregulated APRIL/BAFF signaling is implicated in the pathogenesis of multiple autoimmune diseases, including systemic lupus erythematosus and lupus nephritis. We undertook this study to develop and evaluate a high‐affinity APRIL/BAFF antagonist to overcome the clinical limitations of existing B cell inhibitors.

Methods:

A variant of TACI‐Fc generated by directed evolution showed enhanced binding for both APRIL and BAFF and was designated povetacicept (ALPN‐303). Povetacicept was compared to wild‐type (WT) TACI‐Fc and related molecules in vitro and in vivo.

Results:

Povetacicept inhibited APRIL and BAFF more effectively than all evaluated forms of WT TACI‐Fc and selective APRIL and BAFF inhibitors in cell‐based reporter assays and primary human B cell assays, mediating potent suppression of B cell proliferation, differentiation, and immunoglobulin (Ig) secretion. In mouse immunization models, povetacicept significantly reduced serum immunoglobulin titers and antibody‐secreting cells more effectively than anti‐CD20 monoclonal antibodies, WT TACI‐Fc, or APRIL and BAFF inhibitors. In the NZB × NZW mouse lupus nephritis model, povetacicept significantly enhanced survival and suppressed proteinuria, anti–double‐stranded DNA antibody titers, blood urea nitrogen, glomerulonephritis, and renal immunoglobulin deposition. In the bm12 mouse lupus model, povetacicept significantly reduced splenic plasmablasts, follicular helper T cells, and germinal center B cells. In non‐human primates, povetacicept was well tolerated, exhibited high serum exposure, and significantly decreased serum IgM, IgA, and IgG levels after a single dose.

Conclusion:

Enhanced APRIL and BAFF inhibition by povetacicept led to greater inhibition of B cell populations critical for autoantibody production compared to WT TACI‐Fc and CD20‐, APRIL‐, or BAFF‐selective inhibitors. Potent, dual inhibition by povetacicept has the potential to significantly improve clinical outcomes in autoantibody‐related autoimmune diseases.image

109

项与 Povetacicept 相关的新闻（医药）

2024-12-03

·PRNewswire

Lupus Nephritis Clinical Trial Pipeline Experiences Momentum: DelveInsight Estimates a Diverse Pipeline Comprising 30+ Companies Working in the Domain

The lupus nephritis market is poised for growth, driven by rising disease prevalence, advancements in therapeutics such as biologics and targeted therapies, and increased investment in R&D. Heightened awareness and robust support from governments and key industry players further create a dynamic environment for innovation and better patient outcomes. LAS VEGAS, Dec. 3, 2024 /PRNewswire/ -- DelveInsight's ' Lupus Nephritis Pipeline Insight 2024 ' report provides comprehensive global coverage of pipeline lupus nephritis therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the lupus nephritis pipeline domain. Key Takeaways from the Lupus Nephritis Pipeline Report DelveInsight's lupus nephritis pipeline report depicts a robust space with 30+ active players working to develop 35+ pipeline therapies for lupus nephritis treatment. Key lupus nephritis companies such as AstraZeneca, Hoffmann-La Roche, Novartis, Qilu Pharmaceutical, Vera Therapeutics, Conduit Pharmaceuticals, Amgen, Johnson & Johnson, BeiGene, RemeGen, Argenx, Kyverna Therapeutics, Cabaletta Bio, ImmPACT Bio, Alpine Immune Sciences, AlloSite Therapeutics, iCell Gene Therapeutics, Caribou Biosciences, Adicet Bio, Shenzhen Pregene Biopharma Co., Ltd., Resolve Therapeutics, BioAegis Therapeutics, Lepton Pharmaceuticals, Transcenta Holding, and others are evaluating new lupus nephritis drugs to improve the treatment landscape. Promising lupus nephritis pipeline therapies such as Anifrolumab, Obinutuzumab, Ianalumab, QLG1074, Atacicept, AZD1656, Daxdilimab, Nipocalimab, Zanubrutinib, Telitacicept, Efgartigimod alfa, KYV-101, CABA-201, IMPT-514, Povetacicept, ONT01, BCMA-CD19 cCAR T cells, CB-010, ADI-001, PRG-2311, RSLV-621, Recombinant human plasma gelsolin, LN-008, TST 008, and others are under different phases of lupus nephritis clinical trials. In November 2024, Adicet Bio announced that the first LN patient had been dosed in the Phase I clinical trial evaluating ADI-001 in autoimmune diseases. In November 2024, Kyverna Therapeutics announced that it would present updated clinical data from LN patients treated with KYV-101 in ongoing Kyverna-sponsored KYSA-1 and KYSA-3 Phase I/II studies and named patient treatments. In October 2024, Kezar Life Sciences suspended subject enrolment and patient dosing in the Phase II PALIZADE trial of zetomipzomib for active lupus nephritis. In June 2024, Nkarta announced the initiation of Ntrust-I, a multi-center clinical trial of NKX019 in lupus nephritis, with the first patient in screening. The company also announced the clearance by the U.S. Food and Drug Administration (FDA) of its second Investigational New Drug (IND) application for NKX019 in autoimmune disease. In June 2024, Adicet Bio announced that the US Food and Drug Administration (FDA) had granted Fast Track Designation to ADI-001 for the potential treatment of relapsed/refractory class III or class IV lupus nephritis. In April 2024, Caribou Biosciences announced that it had received clearance of its Investigational New Drug (IND) application from the U.S. Food and Drug Administration (FDA) for CB-010, an allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knockout (KO), for the treatment of lupus nephritis (LN) and extrarenal lupus (ERL). The Phase 1, multicenter, open label GALLOP clinical trial of CB-010 in patients with LN and ERL is expected to initiate by year-end 2024. In March 2024, Artiva Therapeutics is looking to dose the first patient in a Phase I/II trial assessing its cell therapy AlloNK in lupus nephritis (LN). Request a sample and discover the recent advances in lupus nephritis treatment drugs @ Lupus Nephritis Pipeline Report The lupus nephritis pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage lupus nephritis drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the lupus nephritis clinical trial landscape. Lupus Nephritis Overview Lupus nephritis is a serious complication of systemic lupus erythematosus (SLE), an autoimmune disease that can affect multiple organ systems. In lupus nephritis, the immune system mistakenly attacks the kidneys, leading to inflammation and damage. The exact cause is not fully understood, but it is believed to involve a combination of genetic, hormonal, and environmental factors, including infections and exposure to certain drugs or UV light. Symptoms of lupus nephritis can vary but often include swelling in the legs and feet, high blood pressure, foamy urine, and in severe cases, hematuria. Patients may also experience fatigue, joint pain, and skin rashes, typical of lupus. Diagnosis usually involves a combination of blood tests, urinalysis, and imaging studies. A kidney biopsy may be necessary to evaluate the extent of kidney damage and guide treatment. Treatment for lupus nephritis aims to reduce inflammation and prevent kidney damage. It often involves corticosteroids and immunosuppressive medications such as mycophenolate mofetil or azathioprine. In severe cases, more aggressive treatments, including cyclophosphamide or biologic therapies like belimumab, may be utilized. Regular monitoring of kidney function and overall health is crucial for managing the disease effectively. Find out more about lupus nephritis treatment drugs @ Drugs for Lupus Nephritis Treatment A snapshot of the Lupus Nephritis Pipeline Drugs mentioned in the report: Learn more about the emerging lupus nephritis pipeline therapies @ Lupus Nephritis Clinical Trials Lupus Nephritis Therapeutics Assessment The lupus nephritis pipeline report proffers an integral view of the lupus nephritis emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Lupus Nephritis Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Oral, Intravenous, Subcutaneous, Parenteral, Topical Therapeutics Assessment By Molecule Type: Recombinant fusion proteins, Small molecule, Monoclonal antibody, Peptide, Polymer, Gene therapy Therapeutics Assessment By Mechanism of Action: Interferon alpha-beta receptor antagonists, Cell death inhibitors, Cell death stimulants, Antibody-dependent cell cytotoxicity, B-cell activation factor receptor antagonists, Glucokinase stimulants, Dendritic cell inhibitors, Complement factor D inhibitors, Complement C3 inhibitors, Proteasome inhibitors, Natural killer cell replacements, Immunologic cytotoxicity; T lymphocyte replacements Key Lupus Nephritis Companies: AstraZeneca, Hoffmann-La Roche, Novartis, Qilu Pharmaceutical, Vera Therapeutics, Conduit Pharmaceuticals, Amgen, Johnson & Johnson, BeiGene, RemeGen, Argenx, Kyverna Therapeutics, Cabaletta Bio, ImmPACT Bio, Alpine Immune Sciences, AlloSite Therapeutics, iCell Gene Therapeutics, Caribou Biosciences, Adicet Bio, Shenzhen Pregene Biopharma Co., Ltd., Resolve Therapeutics, BioAegis Therapeutics, Lepton Pharmaceuticals, Transcenta Holding, and others. Key Lupus Nephritis Pipeline Therapies: Anifrolumab, Obinutuzumab, Ianalumab, QLG1074, Atacicept, AZD1656, Daxdilimab, Nipocalimab, Zanubrutinib, Telitacicept, Efgartigimod alfa, KYV-101, CABA-201, IMPT-514, Povetacicept, ONT01, BCMA-CD19 cCAR T cells, CB-010, ADI-001, PRG-2311, RSLV-621, Recombinant human plasma gelsolin, LN-008, TST 008, and others. Dive deep into rich insights for new drugs for lupus nephritis treatment, visit @ Lupus Nephritis Drugs Table of Contents For further information on the lupus nephritis pipeline therapeutics, reach out @ Lupus Nephritis Treatment Drugs Related Reports Lupus Nephritis Epidemiology Lupus Nephritis Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical, and forecasted lupus nephritis epidemiology in the 7MM. Lupus Nephritis Market Lupus Nephritis 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 lupus nephritis companies, including NOVARTIS, MORPHOSYS, ASTRAZENECA, ROCHE, KEZAR LIFE SCIENCES, ALEXION PHARMACEUTICALS, CABALETTA BIO, among others. Systemic Lupus Erythematosus Market Systemic Lupus Erythematosus 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 SLE companies, including Biogen, Novartis, MorphoSys, Idorsia Pharmaceuticals, Viatris, RemeGen, UCB Pharma, Genentech, Bristol Myers Squibb, AbbVie, among others. Systemic Lupus Erythematosus Pipeline Systemic Lupus Erythematosus Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key myasthenia gravis companies, including Yake Biotechnology, UCB, Sorrento Therapeutics, SinoMab Bioscience Ltd, Shanghai Junshi Biosciences, Sareum, Sanofi, Roche, Rheos Medicine, Resolve, Provention Bio, Pfizer, Novartis, Neovacs, Merck, Medsenic, Landos Biopharma, Kezar Life Sciences, Kangpu Biopharmaceuticals, Janssen Research & Development, Janssen, InnoCare, ImmuPharma, I-MAB Biopharma, ILTOO, Idorsia Pharmaceuticals, Horizon Therapeutics, Genovax, Exinda Thearapeutics, Equillium, Eli Lilly and Company, Eisai, Daiichi Sankyo Company, Corestem, Corbus Pharmaceuticals, Citryll BV, Chipscreen Biosciences, Carna Bioscience, Bristol-Myers Squibb, Brickell Biotech, Boston Pharmaceuticals, Biogen, Athos Therapeutics, Asahi Kasei Pharma, Aria Pharmaceuticals, Antengene Therapeutics, Amgen, Alpine Immune Sciences, Akeso Biopharma, AbbVie, 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 WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床申请

2024-11-25

·思齐俱乐部

“医药一哥”恒瑞正在酝酿一款大药？

近期，恒瑞医药公布了CFB抑制剂HRS-5965治疗阵发性睡眠性血红蛋白尿（PNH）患者的II期研究结果，早期数据表明略优于诺华的Iptacopan（伊普可泮）。而据Evaluate预测，伊普可泮2028年销售额将达到11亿美元（约合人民币80亿元）。瞄准80亿大药一年一度的美国血液学会（ASH）年会，即将于12月盛大开启。恒瑞医药将在本次会议上公布HRS-5965治疗阵发性睡眠性血红蛋白尿（PNH）的II期研究结果。 HRS-5965是新型口服CFB抑制剂，在研适应症包括PNH（III期）、IgA肾病（II期）、补体参与介导的原发性/继发性肾小球疾病（Ⅰ期）、补体参与介导的溶血性贫血（Ⅰ期）。其中，PNH是一种罕见的危及生命的补体诱导的溶血性疾病。根据已公布的摘要显示，在未接受补体抑制剂治疗的PNH患者中，HRS-5965单药治疗（50 mg或75 mg）可降低LDH水平并且快速、持久、无需输血的改善血红蛋白水平，而且两种剂量均耐受良好，表明其有望为PNH患者群体提供一种新的治疗选择。同类竞品中，全球仅有诺华的Iptacopan（伊普可泮）于去年12月获批上市，目前已相继拿下PNH和IgA肾病两个适应症，Evaluate预测该药2028年销售额将达到11亿美元（约合人民币80亿元）。伊普可泮的市场前景，体现在头对头击败了阿斯利康两大补体C5抑制剂——Soliris（依库珠单抗）和Ultomiris（瑞利珠单抗），而这两款产品2023年销售额分别高达31.45亿美元、29.65亿美元。2020年，阿斯利康豪掷390亿美元收购亚力兄（Alexion），将这两款产品纳入囊中。图片来源：平安证券研报事实上，C5抑制剂并非完美无缺。作为针对补体蛋白C5进行抑制的药物，由于它不能完全阻断补体系统，尤其是C3介导的血管外溶血途径，导致一些PNH患者在治疗后出现残留贫血。相比之下，CFB抑制剂通过作用于补体因子B（即C3激活剂前体），能够更有效地减少血管内和血管外溶血，从而帮助患者改善血红蛋白水平，甚至可能无需输血。此外，CFB抑制剂是口服给药，相比抗C5疗法的静脉注射方式更具依从性，能满足患者对于便捷、灵活治疗方式的需求。目前，恒瑞医药HRS-5965已经启动了头对头依库珠单抗用于PNH的III期研究。值得一提的是，HRS-5965在治疗PNH的II期研究中，显示出了略优于伊普可泮的早期数据。据II期研究结果显示（主要终点是血红蛋白从基线到第12周的变化），在第12周，HRS-5965的50 mg BID组和75 mg BID组的血红蛋白水平均较基线明显升高（LSM分别为37.6 g/L和37.7 g/L），且LDH水平平均下降87%和85%。而伊普可泮首次人体研究的中期结果数据显示，两种给药组（25 mg/100 mg、50 mg/200 mg组）血红蛋白水平平均改善+26.7 g/L、+32.1 g/L，LDH水平在第12周均下降了86%。当然，目前还无法确定HRS-5965的最终疗效是否能超过伊普可泮，需要更多的临床数据和长期观察来验证。但HRS-5965不是恒瑞医药唯一布局的补体系统靶向疗法。肾病赛道迎大变革？无论CFB抑制剂还是补体C5抑制剂，都属于补体系统靶向疗法的范畴。补体系统是参与机体免疫反应和炎症反应的重要系统之一，当补体系统发生异常激活时，会攻击自身细胞，导致免疫性疾病。目前，针对补体系统异常激活的补体活化途径，包括经典途径、凝集素途径和替代途径（又称旁路途径），由此也诞生了多种药物类别，包括补体C5aR抑制剂、C3补体抑制剂、MASP2抑制剂等。有研究表明，IgA肾病的病情进展与凝集素途径和旁路途径有关。恒瑞医药另一款针对IgA肾病的补体系统靶向疗法SHR-2010，就是基于凝集素途径研发的MASP2抑制剂，目前已处于Ⅱ期临床。在肾病治疗领域，恒瑞还布局了针对IgA肾病的SHR-2173、布地奈德缓释胶囊，针对慢性肾脏病的HRS-1780（盐皮质激素），以及处于Ⅲ期临床的SHR6508（拟钙剂），一种作用于钙敏感受体（CaSR）的变构调节剂，适应症为慢性肾脏病维持性血液透析患者的继发性甲状旁腺功能亢进。恒瑞医药肾病治疗领域的管线图片来源：恒瑞医药2024年半年报特别是IgA肾病，由于患者数量庞大且缺少治疗手段，现已成为制药巨头的必争之地。例如，诺华不仅拥有CFB抑制剂Iptacopan（伊普可泮），还在2023年以35亿美元收购Chinook，拿下了ETA拮抗剂Atrasentan（阿曲生坦）和APRIL单抗Zigakibart；今年4月，Vertex（福泰制药）也宣布斥资49亿美元收购Alpine，拿下后者核心管线Povetacicept（APRIL/BAFF双重拮抗剂）。当然，IgA肾病只是补体系统靶向疗法的其中一个应用。例如，罗氏与ASO领头羊Ionis公司合作开发的CFB反义疗法IONIS-FB-LRx，除了正在开展治疗lgA肾病的Ⅲ期临床，也曾探索用于地理萎缩（GA）。安斯泰来也在2023年5月豪掷59亿美元收购Iveric Bio，押注后者的补体C5抑制剂Izervay（Avacincaptad pegol），该药于去年8月获FDA批准用于治疗年龄相关性黄斑变性（AMD）继发地图样萎缩（GA）。据统计，2020年全球约有2亿AMD患者。阿斯利康的长效补体C5抑制剂瑞利珠单抗，除已获批治疗PNH，还斩获了非典型溶血性尿毒症综合征（aHUS）、重症肌无力、视神经脊髓炎等多种自免疾病。今年前9个月，瑞利珠单抗收入同比大增35%至28.35亿美元，超过了上一代产品依库珠单抗（同比增长11%至20.45亿美元）。此外，阿斯利康还布局了第三代C5抑制剂Gefurulimab，目前正在国内开展治疗重症肌无力的III期临床，有望成为一款可居家用药的每周1次的皮下注射疗法。新风口来临补体系统靶向疗法展现出的市场前景，也吸引了其他中国药企下场布局，包括再鼎医药、康诺亚、科越医药、天辰生物等。今年5月，再鼎医药与合作伙伴再生元在中国启动了C5抗体Pozelimab与C5靶向siRNA疗法Cemdisiran联合治疗阵发性夜间血红蛋白尿（PNH）的Ⅲ期试验。此外，该联合疗法还在开发用于重症肌无力症。目前，Pozelimab已于2023年获FDA批准上市，成为FDA批准的首款治疗成人和1岁以上儿童CD55缺乏型蛋白丢失性肠病（CHAPLE）药物。康诺亚研发了MASP-2单抗CM338，现已进入临床研究阶段；科越医药开发了全球首创的双功能抗C5抗体和因子H融合蛋白KP104，并在2024 EHA会议上公布了II期研究结果，显示出可作为PNH新型单药疗法但同时靶向补体旁路途径和末端途径的同类最佳治疗（BIC）的潜力。另外，天辰生物开发的全球首创补体双功能抗体LP-005，是一款靶向C5/C3的双特异性抗体，预计2024年内启动II期临床试验，在研适应症包括PNH、IgA肾病等，特点在于可同时抑制三条补体信号通路，并具备一个月给药一次的便利性优势。值得一提的是，朗来科技全资子公司美悦生物的CFB抑制剂MY008211A片，是中国企业自主研发的首个进入PNH临床试验的小分子药物，目前已进入III期阶段。综上可见，补体系统靶向疗法的风口正在来临。令人欣慰的是，中国药企的管线中不乏创新药物，无疑值得期待。来源：药智网作者：粽哥2025 商务合作 130 6172 3098 zakk.cui@siqibest.com 点击阅读原文了解更多

临床2期临床3期并购

2024-11-25

·求实药社

80亿！医药一哥在酝酿一款大药！

近期，恒瑞医药公布了CFB抑制剂HRS-5965治疗阵发性睡眠性血红蛋白尿（PNH）患者的II期研究结果，早期数据表明略优于诺华的Iptacopan（伊普可泮）。而据Evaluate预测，伊普可泮2028年销售额将达到11亿美元（约合人民币80亿元）。 “医药一哥”恒瑞正在酝酿一款大药？ <01> 瞄准80亿大药一年一度的美国血液学会（ASH）年会，即将于12月盛大开启。恒瑞医药将在本次会议上公布HRS-5965治疗阵发性睡眠性血红蛋白尿（PNH）的II期研究结果。 HRS-5965是新型口服CFB抑制剂，在研适应症包括PNH（III期）、IgA肾病（II期）、补体参与介导的原发性/继发性肾小球疾病（Ⅰ期）、补体参与介导的溶血性贫血（Ⅰ期）。其中，PNH是一种罕见的危及生命的补体诱导的溶血性疾病。根据已公布的摘要显示，在未接受补体抑制剂治疗的PNH患者中，HRS-5965单药治疗（50 mg或75 mg）可降低LDH水平并且快速、持久、无需输血的改善血红蛋白水平，而且两种剂量均耐受良好，表明其有望为PNH患者群体提供一种新的治疗选择。同类竞品中，全球仅有诺华的Iptacopan（伊普可泮）于去年12月获批上市，目前已相继拿下PNH和IgA肾病两个适应症，Evaluate预测该药2028年销售额将达到11亿美元（约合人民币80亿元）。伊普可泮的市场前景，体现在头对头击败了阿斯利康两大补体C5抑制剂——Soliris（依库珠单抗）和Ultomiris（瑞利珠单抗），而这两款产品2023年销售额分别高达31.45亿美元、29.65亿美元。2020年，阿斯利康豪掷390亿美元收购亚力兄（Alexion），将这两款产品纳入囊中。图片来源：平安证券研报事实上，C5抑制剂并非完美无缺。作为针对补体蛋白C5进行抑制的药物，由于它不能完全阻断补体系统，尤其是C3介导的血管外溶血途径，导致一些PNH患者在治疗后出现残留贫血。相比之下，CFB抑制剂通过作用于补体因子B（即C3激活剂前体），能够更有效地减少血管内和血管外溶血，从而帮助患者改善血红蛋白水平，甚至可能无需输血。此外，CFB抑制剂是口服给药，相比抗C5疗法的静脉注射方式更具依从性，能满足患者对于便捷、灵活治疗方式的需求。目前，恒瑞医药HRS-5965已经启动了头对头依库珠单抗用于PNH的III期研究。值得一提的是，HRS-5965在治疗PNH的II期研究中，显示出了略优于伊普可泮的早期数据。据II期研究结果显示（主要终点是血红蛋白从基线到第12周的变化），在第12周，HRS-5965的50 mg BID组和75 mg BID组的血红蛋白水平均较基线明显升高（LSM分别为37.6 g/L和37.7 g/L），且LDH水平平均下降87%和85%。而伊普可泮首次人体研究的中期结果数据显示，两种给药组（25 mg/100 mg、50 mg/200 mg组）血红蛋白水平平均改善+26.7 g/L、+32.1 g/L，LDH水平在第12周均下降了86%。当然，目前还无法确定HRS-5965的最终疗效是否能超过伊普可泮，需要更多的临床数据和长期观察来验证。但HRS-5965不是恒瑞医药唯一布局的补体系统靶向疗法。 <02> 肾病赛道迎大变革？无论CFB抑制剂还是补体C5抑制剂，都属于补体系统靶向疗法的范畴。补体系统是参与机体免疫反应和炎症反应的重要系统之一，当补体系统发生异常激活时，会攻击自身细胞，导致免疫性疾病。目前，针对补体系统异常激活的补体活化途径，包括经典途径、凝集素途径和替代途径（又称旁路途径），由此也诞生了多种药物类别，包括补体C5aR抑制剂、C3补体抑制剂、MASP2抑制剂等。有研究表明，IgA肾病的病情进展与凝集素途径和旁路途径有关。恒瑞医药另一款针对IgA肾病的补体系统靶向疗法SHR-2010，就是基于凝集素途径研发的MASP2抑制剂，目前已处于Ⅱ期临床。在肾病治疗领域，恒瑞还布局了针对IgA肾病的SHR-2173、布地奈德缓释胶囊，针对慢性肾脏病的HRS-1780（盐皮质激素），以及处于Ⅲ期临床的SHR6508（拟钙剂），一种作用于钙敏感受体（CaSR）的变构调节剂，适应症为慢性肾脏病维持性血液透析患者的继发性甲状旁腺功能亢进。恒瑞医药肾病治疗领域的管线图片来源：恒瑞医药2024年半年报特别是IgA肾病，由于患者数量庞大且缺少治疗手段，现已成为制药巨头的必争之地。例如，诺华不仅拥有CFB抑制剂Iptacopan（伊普可泮），还在2023年以35亿美元收购Chinook，拿下了ETA拮抗剂Atrasentan（阿曲生坦）和APRIL单抗Zigakibart；今年4月，Vertex（福泰制药）也宣布斥资49亿美元收购Alpine，拿下后者核心管线Povetacicept（APRIL/BAFF双重拮抗剂）。当然，IgA肾病只是补体系统靶向疗法的其中一个应用。例如，罗氏与ASO领头羊Ionis公司合作开发的CFB反义疗法IONIS-FB-LRx，除了正在开展治疗lgA肾病的Ⅲ期临床，也曾探索用于地理萎缩（GA）。安斯泰来也在2023年5月豪掷59亿美元收购Iveric Bio，押注后者的补体C5抑制剂Izervay（Avacincaptad pegol），该药于去年8月获FDA批准用于治疗年龄相关性黄斑变性（AMD）继发地图样萎缩（GA）。据统计，2020年全球约有2亿AMD患者。阿斯利康的长效补体C5抑制剂瑞利珠单抗，除已获批治疗PNH，还斩获了非典型溶血性尿毒症综合征（aHUS）、重症肌无力、视神经脊髓炎等多种自免疾病。今年前9个月，瑞利珠单抗收入同比大增35%至28.35亿美元，超过了上一代产品依库珠单抗（同比增长11%至20.45亿美元）。此外，阿斯利康还布局了第三代C5抑制剂Gefurulimab，目前正在国内开展治疗重症肌无力的III期临床，有望成为一款可居家用药的每周1次的皮下注射疗法。 <03> 新风口来临补体系统靶向疗法展现出的市场前景，也吸引了其他中国药企下场布局，包括再鼎医药、康诺亚、科越医药、天辰生物等。今年5月，再鼎医药与合作伙伴再生元在中国启动了C5抗体Pozelimab与C5靶向siRNA疗法Cemdisiran联合治疗阵发性夜间血红蛋白尿（PNH）的Ⅲ期试验。此外，该联合疗法还在开发用于重症肌无力症。目前，Pozelimab已于2023年获FDA批准上市，成为FDA批准的首款治疗成人和1岁以上儿童CD55缺乏型蛋白丢失性肠病（CHAPLE）药物。康诺亚研发了MASP-2单抗CM338，现已进入临床研究阶段；科越医药开发了全球首创的双功能抗C5抗体和因子H融合蛋白KP104，并在2024 EHA会议上公布了II期研究结果，显示出可作为PNH新型单药疗法但同时靶向补体旁路途径和末端途径的同类最佳治疗（BIC）的潜力。另外，天辰生物开发的全球首创补体双功能抗体LP-005，是一款靶向C5/C3的双特异性抗体，预计2024年内启动II期临床试验，在研适应症包括PNH、IgA肾病等，特点在于可同时抑制三条补体信号通路，并具备一个月给药一次的便利性优势。值得一提的是，朗来科技全资子公司美悦生物的CFB抑制剂MY008211A片，是中国企业自主研发的首个进入PNH临床试验的小分子药物，目前已进入III期阶段。综上可见，补体系统靶向疗法的风口正在来临。令人欣慰的是，中国药企的管线中不乏创新药物，无疑值得期待。免责声明：文章内容仅供参考，不构成投资建议。投资者据此操作，风险自担, 关于对文中陈述、观点判断保持中立，不对所包含内容的准确性、可靠性或完整性提供任何明示或暗示的保证。请读者仅作参考，并请自行承担全部责任。本公众号发布的各类文章重在分享，如有侵权请联系我们，我们将会删除。联系我们 I-RNA 2025 展位火热预定中！扫码立即咨询电话：13816031174 （同微信）赞助形式包括但不仅限于演讲席位、会场展位、会刊彩页、晚宴赞助、会议用品宣传等。点击此处“阅读全文”咨询更多！

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适应症	最高研发状态	国家/地区	公司	日期
免疫球蛋白a肾病	临床3期	美国	Alpine Immune Sciences, Inc.	2024-08-30
免疫球蛋白a肾病	临床3期	中国香港	Alpine Immune Sciences, Inc.	2024-08-30
免疫球蛋白a肾病	临床3期	英国	Alpine Immune Sciences, Inc.	2024-08-30
自身免疫性血细胞减少症	临床2期	美国	Alpine Immune Sciences, Inc.	2023-07-03
自身免疫性血细胞减少症	临床2期	澳大利亚	Alpine Immune Sciences, Inc.	2023-07-03
自身免疫性血细胞减少症	临床2期	奥地利	Alpine Immune Sciences, Inc.	2023-07-03
自身免疫性血细胞减少症	临床2期	加拿大	Alpine Immune Sciences, Inc.	2023-07-03
自身免疫性血细胞减少症	临床2期	德国	Alpine Immune Sciences, Inc.	2023-07-03
自身免疫性血细胞减少症	临床2期	意大利	Alpine Immune Sciences, Inc.	2023-07-03
自身免疫性血细胞减少症	临床2期	挪威	Alpine Immune Sciences, Inc.	2023-07-03

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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


NCT05732402 (RUBY-3, ISN WCN2024) 人工标引	临床1/2期	免疫球蛋白a肾病 galactose-deficient IgA1 (Gd-IgA1)	12	Povetacicept 80 mg	積網窪鬱鹹繭網遞顧衊(醖壓範遞觸觸蓋顧觸構) = Povetacicept has been well tolerated, with the majority of treatment-emergent adverse events being of low grade and none leading to treatment discontinuation or dose reduction/interruption. 夢鏇遞衊淵膚糧選鹹遞 (鏇獵簾範蓋願鑰鑰獵願 )	积极	2024-04-01
NCT05732402 (RUBY-3, ASN2023) 人工标引	临床1/2期	肾小球肾炎	13	povetacicept 80 mg	積鹽鏇遞範鬱構齋鏇鏇(憲鏇艱鏇衊範積蓋顧衊) = 襯鹹積鹽鬱鏇艱遞築夢遞範壓網憲鹽築鹽襯壓 (選鹹築夢製憲製範簾範 )	积极	2023-11-02
NCT05732402 (RUBY-3, BusinessWire) 人工标引	临床1/2期	免疫球蛋白a肾病	-	povetacicept	鏇鹽膚衊夢齋夢壓蓋鹹(範襯壓觸範鬱簾鏇窪鬱) = in the first IgAN dose cohort (80 mg subcutaneously once every 4 weeks) has been safe and well-tolerated to date, with no serious or severe adverse events, no events of hypogammaglobulinemia (IgG < 3g/L), and no instances of hypersensitivity or administration-related reactions. 築廠壓窪鑰鹹觸憲醖窪 (艱衊鑰糧鹹餘築壓範夢 )	积极	2023-08-30