Outcome of Emicizumab Prophylaxis in Patients of Haemophilia A with or without Inhibitor An Early Experience from A Tertiary Care Hospital From Eastern India - NIL

开始日期2024-08-15

申办/合作机构-

NCT04563520 / Recruiting临床3期IIT

aPCC and Emicizumab Safety Study in Congenital Hemophilia A Patients With Inhibitors (SAFE Study: Safety of aPCC Following Emicizumab Prophylaxis)

The purpose of the aPCC-emicizumab safety study is to prospectively investigate the safety and hemostatic efficacy of a personalized dose of aPCC in children and adults with hemophilia A and inhibitors on emicizumab prophylaxis during acute bleeding events or prior to procedures.

开始日期2024-08-01

申办/合作机构

Emory University

[+1]

NCT05248594 / RecruitingN/AIIT

Real World Use of Emicizumab in Infants and Children Ages 0-3 Years With Hemophilia A

We have developed a questionnaire to elucidate the dosing, frequency and indication for the use of emicizumab in patients with Hemophilia A (mild, moderate or severe) ages 0-3 years. We are also collecting data on any pre-, peri and post surgical practices while on emicizumab. More importantly, we are asking if pediatricians are planning to introduce factor 8 to children who are already on emicizumab for primary prophylaxis as well as how and when they are planning to do so. We hope that this data will help inform understanding of current use of emicizumab in infants and young children as a form of primary prophylaxis, especially when venous access has historically been a limiting factor.

开始日期2024-08-01

申办/合作机构

Montefiore Medical Center

[+1]

100 项与 factor IX 相关的临床结果

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100 项与 factor IX 相关的转化医学

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0 项与 factor IX 相关的专利（医药）

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6,143

项与 factor IX 相关的文献（医药）

2025-01-01·CLINICA CHIMICA ACTA

Coagulation factors VIII and factors IX testing practices in China: Results of the 5-year external quality assessment program

Article

作者: Xu, Chengshan ; Hu, Gaofeng ; Li, Chenbin ; Du, Zhongli ; Ma, Yating

BACKGROUND AND AIMS:

Testing for coagulation factors VIII (FVIII) and IX (FIX) plays significant importance in the diagnostic and treatment of hemophilia A and B. External quality assessment (EQA) scheme aimed to assess the participants' performance of testing for coagulation factors and identify shortcomings in clinical practice. This study aimed to investigate the performance trends of the participating laboratories in China national external quality assessment Scheme (China NEQAS) for FVIII and FIX over a five-year period (2019-2023).

MATERIALS AND METHODS:

A total of ten external quality assessment (EQA) rounds were conducted from 2019 to 2023 in the China NEQAS for FVIII and FIX. The distribution of method, reagent and instrument were calculated. The trends of method- specific inter-laboratory coefficient of variation (CV) and pass rates were analyzed over 5 years. The dilutions for coagulation factor testing were also investigated.

RESULTS:

All laboratories use one-stage assays to detect FVIII and FIX activity. The inter-laboratory overall CV decreased year by year (10.9 % to 9.3 % for FVIII and 13.5 % to 10.2 % for FIX), and the laboratory pass rate steadily increased (88.0 % to 93.4 % for FVIII and 81.3 % to 92.7 % for FIX). The majority of laboratories employed a single dilution methodology for the assessment of FVIII and FIX activity. The interlaboratory CV was elevated for the Siemens reagent (Actin FSL) during analysis of moderately abnormal FIX concentrations of EQA samples in most batches.

CONCLUSIONS:

The implementation of the external quality assessment has contributed to facilitate the enhancement of testing quality. Chromogenic assay is a supplement to accurate determination when necessary. Laboratories may choose to perform dilution tests or direct assays to identify the presence of inhibitors, particularly when they are suspected.

2024-12-31·JOURNAL OF MEDICAL ECONOMICS

Analysis of long-term clinical and cost impact of etranacogene dezaparvovec for the treatment of hemophilia B population in the United States

Article

作者: Sivamurthy, Krupa ; McDade, Cheryl ; Rouse, Robert ; Thiruvillakkat, Kris ; Yan, Songkai ; Wilson, Michele

INTRODUCTION:

Etranacogene dezaparvovec (EDZ), Hemgenix, is a gene therapy recently approved for people with hemophilia B (PwHB).

OBJECTIVE:

To estimate long-term clinical impact and cost of EDZ in the United States (US).

METHODS:

A decision-analytic model was developed to evaluate the long-term impact of introducing EDZ for PwHB over a 20-year time horizon. Factor IX (FIX) prophylaxis comparator was a weighted average of different FIX prophylaxis regimens based on US market share data. We compared a scenario in which EDZ is introduced in the US versus a scenario without EDZ. Clinical inputs (annualized FIX-treated bleed rate; adverse event rates) were obtained from HOPE-B phase 3 trial. EDZ durability input was sourced from an analysis predicting long-term FIX activity with EDZ. EDZ one-time price was assumed at $3.5 million. Other medical costs, including FIX prophylaxis, disease monitoring, bleed management, and adverse events were from literature. The model estimated annual and cumulative costs, treated bleeds, and joint procedures over 20 years from EDZ introduction.

RESULTS:

Approximately 596 PwHB were eligible for EDZ. EDZ uptake was estimated to avert 11,282 bleeds and 64 joint procedures over 20 years. Although adopting EDZ resulted in an annual excess cost over years 1-5 (mean: $53 million annually, total $265 million), annual cost savings were achieved beginning in year 6 (mean: $172 million annually; total $2.58 billion in years 6-20). The total cumulative 20-year cost savings was $2.32 billion, with cumulative cost savings beginning in year 8.

CONCLUSION:

Introducing EDZ to treat PwHB is expected to result in cost savings and patient benefit over 20 years. Initiating PwHB on EDZ sooner can produce greater and earlier savings and additional bleeds avoided. These results may be a conservative estimate of the full value of EDZ, as PwHB would continue to accrue savings beyond 20 years.

2024-10-01·Seminars in thrombosis and hemostasis

Substrates, Cofactors, and Cellular Targets of Coagulation Factor XIa

Review

作者: Shatzel, Joseph J ; Lira, André L ; Moellmer, Samantha A ; McCarty, Owen J T ; Kohs, Tia C L ; Puy, Cristina

Abstract:

Coagulation factor XI (FXI) has increasingly been shown to play an integral role in several physiologic and pathological processes. FXI is among several zymogens within the blood coagulation cascade that are activated by proteolytic cleavage, with FXI converting to the active serine protease form (FXIa). The evolutionary origins of FXI trace back to duplication of the gene that transcribes plasma prekallikrein, a key factor in the plasma kallikrein–kinin system, before further genetic divergence led to FXI playing a unique role in blood coagulation. While FXIa is canonically known for activating the intrinsic pathway of coagulation by catalyzing the conversion of FIX into FIXa, it is promiscuous in nature and has been shown to contribute to thrombin generation independent of FIX. In addition to its role in the intrinsic pathway of coagulation, FXI also interacts with platelets, endothelial cells, and mediates the inflammatory response through activation of FXII and cleavage of high-molecular-weight kininogen to generate bradykinin. In this manuscript, we critically review the current body of knowledge surrounding how FXI navigates the interplay of hemostasis, inflammatory processes, and the immune response and highlight future avenues for research. As FXI continues to be clinically explored as a druggable therapeutic target, understanding how this coagulation factor fits into physiological and disease mechanisms becomes increasingly important.

290

项与 factor IX 相关的新闻（医药）

2024-08-30

·微信

文献解读 | 悉尼大学开发rAAV+睡美人转座子基因递送系统，可用于治疗新生儿遗传性肝病

腺相关病毒（rAAV）载体已经成为体内基因治疗的首选工具，尤其在成人肝脏等分裂不活跃的细胞中，rAAV基因治疗药物的疗效显著。然而，在快速增殖的细胞（如新生儿肝脏）中，传统rAAV载体的疗效非常有限，主要原因是rAAV载体携带的外源基因组处于游离状态，容易在细胞复制时发生丢失或稀释，这一局限性也使得一些需要早期干预的遗传性肝脏疾病的治疗成功率较低。为了应对这一挑战，悉尼大学儿童医学研究所研究人员开发了一种rAAV/ Sleeping Beauty（SB）转座子系统，它结合了rAAV的高效肝脏靶向能力和SB系统的基因组整合能力，可用于新生小鼠肝脏的稳定基因转导，相关研究结果发表在The Journal of Gene Medicine杂志上。该研究采用了两种不同催化活性的SB转座酶（SB11和SB100X），并与之前的rAAV/ piggyBac（PB）系统进行了对比，目的是评估rAAV/SB系统在新生小鼠肝脏中实现稳定和高效基因递送的能力，并验证其在治疗遗传性肝脏疾病中的潜力。稳定基因转导的实现研究团队将SB11或SB100X转座酶编码序列包装到AAV8载体中，通过腹腔注射将这些载体导入到新生C57Bl/6小鼠体内。组织学分析表明，SB100X和PB系统在稳定基因修饰细胞的比例上显著优于SB11，尤其是在SB100X组中，稳定转基因细胞比例比无转座酶组高出6倍。长效基因表达的稳定性进一步的实验表明，rAAV/SB系统介导的转基因表达在成年后依然稳定，特别是在使用SB100X时，基因表达水平显著增强且稳定。相比之下，SB11组表现较弱。SB100X与PB系统在基因表达水平和稳定性上表现出相似的效果。治疗相关的基因表达为了验证该系统的临床应用潜力，研究团队用表达人凝血因子IX（FIX）的SB转座子载体，对新生小鼠进行了治疗。结果显示，使用SB100X的FIX活性显著高于SB11组，且FIX蛋白水平在血浆中大幅提升，表明rAAV/SB混合系统在快速增殖的肝脏细胞中可以实现高效的治疗性基因表达。图1 rAAV/SB系统向新生小鼠递送人凝血因子IX (hFIX) 的治疗效果 OTC严重缺陷小鼠模型中的表型校正在OTC缺陷的小鼠模型中，rAAV/SB100X系统显著延长了小鼠的生存期，并降低了尿液中的鸟氨酸水平。相比于单独使用OTC表达载体，rAAV/SB系统在增加OTC阳性细胞比例和OTC mRNA表达水平方面具有显著优势，进一步验证了其在治疗遗传性肝病中的潜力。图2 OTC缺陷Spfash小鼠的表型矫正。总之，这项研究首次展示了rAAV+Sleeping Beauty转座子系统在新生小鼠肝脏中的有效性和长期稳定性，特别是在治疗新生儿发病的遗传性肝病中有良好的应用前景。尽管PB系统在某些方面表现更佳，但SB系统在基因整合的随机性和潜在的安全性方面具有一定的优势。未来的研究可进一步探索SB系统在临床应用中的潜力，特别是通过短暂表达转座酶来优化治疗效果。小派贴士派真生物CRO & CDMO一站式服务平台，可提供从基因合成、载体构建到病毒包装的整体解决方案，产线涵盖AAV、慢病毒和mRNA服务含定制服务，可全面支持您的基因编辑研究。我们还提供多种mRNA、AAV现货产品，欢迎后台留言或点击文末“阅读原文”了解详情。参考资料： https://doi.org/10.1002/jgm.3726 关于派真生物

基因疗法临床研究临床结果

2024-08-26

·生物制品圈

3800页PDF分享|全球创新型双抗药物资料汇编

本文档由闫加庆老师花费很多心血整理，全文3800多页，完整文档获取可关注公众号后回复 “双抗药物技术审评”，即可获取下载方式！双特异性抗体 (bispecific antibody，BsAb)，又称双功能性抗体，原本指一种可以与相同或不同抗原上的不同表位结合的抗体结构。由于科学技术的发展，其定义扩展到具有两种功能抗体，抗体片段或者蛋白质融合而成的分子；具有多功能抗体，抗体片段或者蛋白质融合而成的分子成为多功能分子。自1960年Nisonoff首次提出双抗的概念，并非常幸运地在结合两个不同的抗原结合位点的蛋白筛选到一个具有双重特异性的F(ab’)2分子。双抗就成了科学家们追逐的一个梦想，随着单克隆抗体技术，基因工程技术以及各类双抗平台的出现，呈现出一个明显的井喷趋势，被誉为“下一代的抗体药物”。双抗市场规模无论是在国内还是国外都呈现飞速发展的趋势，2015年全球双抗市场规模仅约1亿美元，至2019年该市场规模高速增至17亿美元，随着双抗药物获批上市进程持续加快，全球双抗市场规模将快速上升，预计2030年全球双抗市场规模将达807亿美元，2022～2030年平均复合增长率达39.6%。中国市场增速更甚，虽然截至目前国内仅有罗氏、百济神州/安进、康方三家企业获批，罗氏的Glofitamab和Faricimab上市申请已受理，但市场规模高速扩张，增速已超全球水平，2030年市场规模预计将达108亿美元，2022～2030年复合增长率高达81.7%。截至2023年04月，全球共有10款双特异性抗体获批上市（包含1款已退市），其中中国获批上市的有3种，日本单独上市1种。全球获批上市品种来看，罗氏（含基因泰克）和强生分别被批准3款和2款，占全部被批准的50%比例；中国获批上市的有3种，包括安进靶向CD3和CD19的Blincyto、罗氏靶向FIX和FX的Hemlibra、康方生物的卡度尼利单抗（唯一双免疫检查点的双抗）。根据分子结构分析，抗CD3抗体（@CD3）有5款，占比50%；从战略定位层面值得粉碎性骨折性学习的有4款：分别是①罗氏靶点Hemlibra，深扎根于机理研究；②Immucore的Kimmtrak和Ablynx的Ozoralizumab，从自己擅长且具有技术优势开发；③ 罗氏的Faricimab和Ablynx的Ozoralizumab，定位于肿瘤外领域。 1.发展阶段随着抗体工程和抗体生物学领域里程碑式的进步，产生双特异性抗体的概念和技术创新不断发展，目前已知的双特异性抗体构型有100多种。其中大约四分之一已经发展成为技术平台，并正在被生物技术和制药公司商业化，用于产生创新型以及差异化的治疗方法。下图罗列了双特异性抗体领域的进展时间线： 2.作用机理双特异性抗体是一类具有双功能的人工抗体分子，能同时特异性结合两种不同的抗原，因此双特异性抗体就是依赖这种衔接器的功能生成了不同的作用。介导免疫细胞杀伤：双特异性抗体可以介导T细胞、NK细胞及巨噬细胞等免疫细胞杀伤。如抗CD3的双特异性抗体能够分别结合T细胞表面CD3分子和癌细胞表面抗原，从而拉近细胞毒性T细胞与癌细胞的距离，引导T细胞直接杀伤癌细胞，而不再依赖于T细胞的双重激活信号。再比如将靶向CD16a的抗体与靶向TAA的抗体进行配对组合获得的BsAb可以在一定程度上重新定向NK细胞，发挥抗肿瘤效应。双靶点信号阻断：同时结合双靶点，阻断双信号通路是双特异性抗体的另一个重要作用机制。单一信号通路阻断往往不能完全抑制疾病的进程，反而还容易导致其他补偿通路的激活。BsAb可以特异性阻断多条信号通路，达到更好的抑制疾病的效应。双免疫细胞靶点强化协同机制：例如康宁杰瑞KN046、康方生物AK104和齐鲁制药PSB205的2个免疫检查点的候选药物；再比如科望生物引进的ES101和信达生物的IBI319 是1个免疫检查点和1个免疫活化靶点的药物。促进蛋白形成功能性复合体：双特异性抗体的两臂可分别结合两种抗原，形成功能性复合体。针对该复合体的抗体药物，可减少体内排斥反应，提供更好的治疗方案。例如2017年上市的靶向凝血因子IXa和X的双特异性抗体Emicizumab，是一种人源化双特异性IgG4抗体，作用机制是同时桥联结合因子IXa和因子X，从而仿真FVⅢ的生理功能，促进凝血酶的产生。 3.研发平台业内一直流传一句话：单抗研发看靶点，双抗研发看平台。原因在于双抗能产生的1+1>2的疗效使得成熟靶点重新“焕发活力”，双抗研发存在链错配的难点，解决关键则在于平台。目前已知的双特异性抗体构型有100多种。其中大约四分之一已经发展成为技术平台，并正在被生物技术和制药公司商业化，用于产生创新型以及差异化的治疗方法。本文档由闫加庆老师花费很多心血整理，全文3800多页，完整文档获取可关注公众号后回复 “双抗药物技术审评”，即可获取下载方式！参考文献 [1]. A.F, Labrjin, et al. Bispecific antibodies: a mechanistic review of the pipeline. Drug discovery (2019) [2].S.M.Lim, K.H Pyo, R. Soo et al. The promise of bispecific antibodies: Clinical applications and challenges . Cancer Treatment Reviews 99 (2021) : 1~14 [3]. Ma et al. Bispecific antibodies: from research to clinical application. Frontiers in immunology 12 (2021) : 1~19. 识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

上市批准免疫疗法

2024-08-16

·Armstrong生物药资讯

晟斯生物：重组凝血因子VIII二次申报上市仍未获批准

2024年8月14日，晟斯生物重组凝血因子VIII的上市申请收到通知件，意味着未获得批准。此前的2021年，晟斯生物首次递交重组凝血因子VIII的上市申请，2022年收到通知件。2023年，晟斯生物再次递交重组凝血因子VIII的上市申请，此次仍未获得批准。除了FRSW107外（每周注射2次），晟斯生物每周一针的FRSW117已经启动三期临床。赛诺菲的ALTUVIIIO为全球首款每周一次的超长效重组凝血因子VIII，美国上市后快速放量，2024年上半年销售额2.8亿欧元，同比增长近14倍。 ALTUVIIIO采用Fc融合、XTEN两种长效技术来延长半衰期。晟斯生物的FRSW117则采用Fc、PEG修饰两种技术来延长半衰期。神州细胞的重组八因子为国产首款，2023年公司18.87亿元年营收主要来自该产品。2023年，正大天晴、国药集团蓉生药业的重组八因子也陆续上市。晟斯生物FRSW107两度折戟，已经失去先机，只能寄望于每周一针的FRSW117。不过，新技术已经陆续取得突破，罗氏FIX/FX双抗为全球最畅销的血友病药物，赛诺菲的AT siRNA已经申报上市，血友病基因疗法也陆续进入商业化阶段。内容来源于网络，如有侵权，请联系删除。