A phase 1/2 safety and efficacy study of TAK-754 gene therapy: The challenge of achieving durable factor VIII expression in haemophilia A clinical trials.

IF 3 2区 医学 Q2 HEMATOLOGY Haemophilia Pub Date : 2025-01-01 Epub Date: 2024-12-23 DOI:10.1111/hae.15121
John Chapin, Maria Teresa Álvarez Román, Mila Ayash-Rashkovsky, Dorothee Diogo, Jon Kenniston, Francisco-Jose Lopez-Jaime, Caterina Maggiore, María-Eva Mingot-Castellano, Kavitha Rajavel, Antoine Rauch, Sophie Susen, Marcin von Grotthuss, Matt Wagoner, Qin Wang
{"title":"A phase 1/2 safety and efficacy study of TAK-754 gene therapy: The challenge of achieving durable factor VIII expression in haemophilia A clinical trials.","authors":"John Chapin, Maria Teresa Álvarez Román, Mila Ayash-Rashkovsky, Dorothee Diogo, Jon Kenniston, Francisco-Jose Lopez-Jaime, Caterina Maggiore, María-Eva Mingot-Castellano, Kavitha Rajavel, Antoine Rauch, Sophie Susen, Marcin von Grotthuss, Matt Wagoner, Qin Wang","doi":"10.1111/hae.15121","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Haemophilia A is an X-linked bleeding disorder resulting from a deficiency of factor VIII (FVIII). To date, multiple gene therapies have entered clinical trials with the goal of providing durable haemostatic protection from a single dose. TAK 754 (BAX 888) is an investigational AAV8-based gene therapy containing a FVIII transgene. Reduction in CpG motifs was performed to reduce immunogenicity based on prior observations. Here, we describe the results of the first two cohorts treated with TAK 754.</p><p><strong>Aim: </strong>To report clinical and translational results of the TAK-754 phase 1/2 AAV gene therapy study for the treatment of haemophilia A.</p><p><strong>Methods: </strong>A phase 1/2 single arm open-label dose escalation study of TAK-754 was performed in participants with severe haemophilia A (NCT03370172). Participants were monitored for safety events, endogenous FVIII activity and bleeding rates. Glucocorticoids were implemented to preserve transgene expression. A transcriptomics analysis was performed to evaluate immunogenicity along with additional post-hoc analyses.</p><p><strong>Results: </strong>Four participants were dosed in two cohorts. Infusion of TAK 754 was well-tolerated. All participants developed mild transient transaminase elevation and subsequent loss of FVIII expression within the first 12 months of treatment despite use of glucocorticoids. Transcriptomic analysis did not demonstrate significant changes in immunogenicity signals in peripheral blood. One serious adverse event of hypophosphatemia occurred in the second cohort without obvious risk factors.</p><p><strong>Conclusions: </strong>Sustained FVIII expression remains a challenge in haemophilia A AAV gene therapy trials. Mechanisms of transgene expression loss require further study as clinical studies enter long term follow-up periods.</p>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":" ","pages":"108-117"},"PeriodicalIF":3.0000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780198/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Haemophilia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/hae.15121","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/23 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Introduction: Haemophilia A is an X-linked bleeding disorder resulting from a deficiency of factor VIII (FVIII). To date, multiple gene therapies have entered clinical trials with the goal of providing durable haemostatic protection from a single dose. TAK 754 (BAX 888) is an investigational AAV8-based gene therapy containing a FVIII transgene. Reduction in CpG motifs was performed to reduce immunogenicity based on prior observations. Here, we describe the results of the first two cohorts treated with TAK 754.

Aim: To report clinical and translational results of the TAK-754 phase 1/2 AAV gene therapy study for the treatment of haemophilia A.

Methods: A phase 1/2 single arm open-label dose escalation study of TAK-754 was performed in participants with severe haemophilia A (NCT03370172). Participants were monitored for safety events, endogenous FVIII activity and bleeding rates. Glucocorticoids were implemented to preserve transgene expression. A transcriptomics analysis was performed to evaluate immunogenicity along with additional post-hoc analyses.

Results: Four participants were dosed in two cohorts. Infusion of TAK 754 was well-tolerated. All participants developed mild transient transaminase elevation and subsequent loss of FVIII expression within the first 12 months of treatment despite use of glucocorticoids. Transcriptomic analysis did not demonstrate significant changes in immunogenicity signals in peripheral blood. One serious adverse event of hypophosphatemia occurred in the second cohort without obvious risk factors.

Conclusions: Sustained FVIII expression remains a challenge in haemophilia A AAV gene therapy trials. Mechanisms of transgene expression loss require further study as clinical studies enter long term follow-up periods.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
TAK-754基因治疗的1/2期安全性和有效性研究:在血友病A临床试验中实现持久的因子VIII表达的挑战
A型血友病是一种由因子VIII (FVIII)缺乏引起的x连锁出血性疾病。迄今为止,多种基因疗法已进入临床试验,其目标是单次剂量提供持久的止血保护。TAK 754 (BAX 888)是一种基于aav8的试验性基因疗法,含有一种FVIII转基因。根据先前的观察,减少CpG基序以降低免疫原性。在这里,我们描述了使用TAK 754治疗的前两个队列的结果。目的:报告TAK-754治疗血友病A的1/2期AAV基因治疗研究的临床和转化结果。方法:在严重血友病A (NCT03370172)患者中进行TAK-754的1/2期单臂开放标签剂量增加研究。监测参与者的安全事件、内源性FVIII活性和出血率。使用糖皮质激素保存转基因表达。进行转录组学分析以评估免疫原性以及额外的事后分析。结果:四名参与者被分为两个队列。输注TAK 754耐受良好。尽管使用糖皮质激素,但所有参与者在治疗的前12个月内均出现轻度短暂转氨酶升高和随后FVIII表达丧失。转录组学分析未显示外周血中免疫原性信号的显著变化。在第二组中发生了一例严重的低磷血症不良事件,但无明显危险因素。结论:在血友病a AAV基因治疗试验中,持续的FVIII表达仍然是一个挑战。随着临床研究进入长期随访期,转基因表达缺失的机制有待进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Haemophilia
Haemophilia 医学-血液学
CiteScore
6.50
自引率
28.20%
发文量
226
审稿时长
3-6 weeks
期刊介绍: Haemophilia is an international journal dedicated to the exchange of information regarding the comprehensive care of haemophilia. The Journal contains review articles, original scientific papers and case reports related to haemophilia care, with frequent supplements. Subjects covered include: clotting factor deficiencies, both inherited and acquired: haemophilia A, B, von Willebrand''s disease, deficiencies of factor V, VII, X and XI replacement therapy for clotting factor deficiencies component therapy in the developing world transfusion transmitted disease haemophilia care and paediatrics, orthopaedics, gynaecology and obstetrics nursing laboratory diagnosis carrier detection psycho-social concerns economic issues audit inherited platelet disorders.
期刊最新文献
Tissue Transfer in the Management of Wound Complications in Patients With Haemophilia: Report of Two Cases. Comparison of Single Knee Arthroplasty and Bilateral Knee Arthroplasty in Haemophiliacs During a Single Operation: A Systematic Review and Meta-Analysis. Deceased Donor With Hemophilia A: To Consider or Not for Liver Donation. Haemophilia Infants Gross Motor Development: Comparisons With Full-Term and Preterm Infants of the Same Nationality. Operationalising a Haemophilia Gene Editing Lexicon for Practical Use.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1