Long-term Follow-up of Subjects With Sickle Cell Disease Treated With Ex Vivo Gene Therapy Using Autologous Hematopoietic Stem Cells Transduced With a Lentiviral Vector

This is a multi-center, long-term safety and efficacy follow-up study for subjects with sickle cell disease who have been treated with ex vivo gene therapy drug product in bluebird bio-sponsored clinical studies. After completing the parent clinical study (approximately 2 years), eligible subjects will be followed for an additional 13 years for a total of 15 years post-drug product infusion. No investigational drug product will be administered in the study.

开始日期2020-10-21

申办/合作机构

bluebird bio, Inc.

NCT04293185 / Recruiting临床3期

A Phase 3 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With the BB305 Lentiviral Vector in Subjects With Sickle Cell Disease

This is a non-randomized, open-label, multi-site, single-dose, Phase 3 study in approximately 35 adults and pediatric subjects ≥2 and ≤50 years of age with sickle cell disease (SCD). The study will evaluate hematopoietic stem cell (HSC) transplantation (HSCT) using bb1111 (also known as LentiGlobin BB305 Drug Product for SCD).

开始日期2020-02-14

申办/合作机构

bluebird bio, Inc.

NCT02140554 / Completed临床1/2期

A Phase 1/2 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With the LentiGlobin BB305 Lentiviral Vector in Subjects With Severe Sickle Cell Disease

This is a non-randomized, open label, multi-site, single dose, Phase 1/2 study in approximately 50 adults and adolescents with severe SCD. The study will evaluate hematopoietic stem cell (HSC) transplantation (HSCT) using lovo-cel.

开始日期2015-02-02

申办/合作机构

bluebird bio, Inc.

100 项与 Lovotibeglogene autotemcel 相关的临床结果

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100 项与 Lovotibeglogene autotemcel 相关的转化医学

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100 项与 Lovotibeglogene autotemcel 相关的专利（医药）

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项与 Lovotibeglogene autotemcel 相关的文献（医药）

2024-10-01·JOURNAL OF PHARMACY TECHNOLOGY

Gene Therapies for Sickle Cell Disease

Review

作者: Singh, Divita ; Weaver, Salome Bwayo ; Wilson, Kierra M.

Background: Sickle cell disease (SCD) is a prevalent autosomal recessive hemoglobinopathy affecting millions worldwide, particularly individuals of African ancestry. Sickle cell disease is a lifelong condition associated with a negative impact on quality of life and mortality, causing complications such as painful vaso-occlusive episodes, acute chest syndrome, stroke, long-term anemia, and end-organ damage. Currently, there are 4 U.S. Food and Drug Administration (FDA)-approved drugs, including hydroxyurea, l-glutamine, voxelotor, and crizanlizumab, which work to alleviate symptoms and prevent complications associated with SCD, albeit without addressing the underlying cause of SCD. Allogeneic hematopoietic stem cell transplant (HSCT) has shown promise as a curative approach to SCD but is limited by donor availability and associated complications. This paper aims to review the efficacy and safety of exagamglogene autotemcel and lovotibeglogene autotemcel for managing patients with SCD, including their place in therapy, cost, and accessibility in clinical care. Data Sources: The authors searched PubMed and Medline from 2017 to 2024, for primary literature on both exagamglogene autotemcel and lovotibeglogene autotemcel. Results: The authors identified relevant studies and summarized the data on the two gene therapies. Conclusion: Exagamglogene autotemcel and lovotibeglogene autotemcel are two management strategies that address the underlying cause of SCD and provide curative potential for patients with SCD.

2024-06-01·PHARMACOECONOMICS

Cost-Effectiveness of Lovotibeglogene Autotemcel (Lovo-Cel) Gene Therapy for Patients with Sickle Cell Disease and Recurrent Vaso-Occlusive Events in the United States

Article

作者: Shah, Nirmish ; Gallagher, Meghan E ; Andemariam, Biree ; Herring, William L ; Paramore, Clark ; Mladsi, Deirdre ; Zhang, Lixin ; Dong, Olivia M ; Leiding, Jennifer W ; Chawla, Anjulika ; Morse, K C

BACKGROUND AND OBJECTIVE:

Gene therapies for sickle cell disease (SCD) may offer meaningful benefits for patients and society. This study evaluated the cost-effectiveness of lovotibeglogene autotemcel (lovo-cel), a one-time gene therapy administered via autologous hematopoietic stem cell transplantation, compared with common care for patients in the United States (US) with SCD aged ≥ 12 years with ≥ 4 vaso-occlusive events (VOEs) in the past 24 months.

METHODS:

We developed a patient-level simulation model accounting for lovo-cel and SCD-related events, complications, and mortality over a lifetime time horizon. The pivotal phase 1/2 HGB-206 clinical trial (NCT02140554) served as the basis for lovo-cel efficacy and safety. Cost, quality-of-life, and other clinical data were sourced from HGB-206 data and the literature. Analyses were conducted from US societal and third-party payer perspectives. Uncertainty was assessed through probabilistic sensitivity analysis and extensive scenario analyses.

RESULTS:

Patients treated with lovo-cel were predicted to survive 23.84 years longer on average (standard deviation [SD], 12.80) versus common care (life expectancy, 62.24 versus 38.40 years), with associated discounted patient quality-adjusted life-year (QALY) gains of 10.20 (SD, 4.10) and direct costs avoided of $1,329,201 (SD, $1,346,446) per patient. Predicted societal benefits included discounted caregiver QALY losses avoided of 1.19 (SD, 1.38) and indirect costs avoided of $540,416 (SD, $262,353) per patient. Including lovo-cel costs ($3,282,009 [SD, $29,690] per patient) resulted in incremental cost-effectiveness ratios of $191,519 and $124,051 per QALY gained from third-party payer and societal perspectives, respectively. In scenario analyses, the predicted cost-effectiveness of lovo-cel also was sensitive to baseline age and VOE frequency and to the proportion of patients achieving and maintaining complete resolution of VOEs.

CONCLUSIONS:

Our analysis of lovo-cel gene therapy compared with common care for patients in the US with SCD with recurrent VOEs estimated meaningful improvements in survival, quality of life, and other clinical outcomes accompanied by increased overall costs for the health care system and for broader society. The predicted economic value of lovo-cel gene therapy was influenced by uncertainty in long-term clinical effects and by positive spillover effects on patient productivity and caregiver burden.

2024-01-01·CELL TRANSPLANTATION

Hematopoietic Stem Cell Transplantation in Sickle Cell Disease: A Multidimentional Review

Review

作者: Mirhosseini, Seied Amirhossein ; Alemi, Hediyeh ; Rad, Soroush ; Kasaeian, Amir ; Kiumarsi, Azadeh ; Janbabai, Ghasem ; Rostami, Mohammad Reza ; Khavandgar, Naghmeh ; Mousavi, Seied Asadollah ; Rostami, Tahereh

While exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) have been approved by the US Food and Drug Administration (FDA) as the first cell-based gene therapies for the treatment of patients 12 years of age and older with sickle cell disease (SCD), this treatment is not universally accessible. Allogeneic hematopoietic stem cell transplant (HSCT) has the potential to eradicate the symptoms of patients with SCD, but a significant obstacle in HSCT for SCD is the availability of suitable donors, particularly human leukocyte antigen (HLA)-matched related donors. Furthermore, individuals with SCD face an elevated risk of complications during stem cell transplantation due to SCD-related tissue damage, endothelial activation, and inflammation. Therefore, it is imperative to consider optimal conditioning regimens and investigate HSCT from alternative donors. This review encompasses information on the use of HSCT in patients with SCD, including the indications for HSCT, conditioning regimens, alternative donors, and posttransplant outcomes.

项与 Lovotibeglogene autotemcel 相关的新闻（医药）

2024-10-28

·EndPoints

Bipartisan letter questions FDA's 'narrow' interpretation for priority review vouchers

Sen. Tim Scott (R-SC) and Rep. Danny Davis (D-IL) are questioning the FDA’s “narrow” interpretation of “active ingredient” when it comes to awarding the potentially lucrative priority review vouchers. The letter , dated last Thursday and addressed to FDA Commissioner Rob Califf, focuses on the two FDA approvals of sickle cell gene therapies in late 2023. It explains how FDA’s recent administration of the PRV program — granting a PRV to one of the sickle cell gene therapies but not the other — “may not be fulfilling the program’s promise, original vision, and intent.” Scott and Davis question FDA on why it “made an initial decision to narrowly interpret the definition of ‘active ingredient’ in the PRV statute, resulting in the unexpected denial of at least one pediatric PRV.” But they also note that FDA “may be in the process of reconsidering its interpretation” so they want to make their thoughts clear. Bluebird bio had initially expected to win a PRV for its sickle cell gene therapy, approved in December 2023, and Novartis even drew up plans to purchase the PRV for $103 million. Ultimately, the FDA did not grant the PRV to bluebird, but Vertex Pharmaceuticals won a PRV for its gene therapy for sickle cell, approved on the same day as bluebird’s. A spokesperson told Endpoints News, “We believe that both the science and the congressional intent of the Rare Pediatric Disease Priority Review Voucher Program clearly support the issuance of a PRV associated with the approval of LYFGENIA and have continued to pursue a resolution with the FDA.” The FDA previously said that Lyfgenia contains the same active ingredient as bluebird’s gene therapy Zynteglo, approved for beta thalassemia. Scott and Davis explain how Congress did not define the term “active ingredient” in the law governing PRVs, but sought to prevent potential manufacturers from receiving PRVs for “simply making small tweaks to old drugs.” “The development of these complex gene therapies to treat an entirely new disease affecting thousands of patients can hardly be considered a ‘small tweak’ to an ‘old drug,'” the letter says, noting that Congress did not specify how FDA should determine if two active ingredients in an ex vivo gene therapy are the same or different. Scott and Davis add that FDA’s decision to interpret the law “in a narrower way than the statute requires – and one that flies directly against Congressional intent” risks disrupting “this delicate ecosystem, jeopardizing not only the availability of SCD treatments today, but also investments in complex and life-saving innovation for the future.” Editor’s note: Article updated with bluebird bio comment.

优先审批基因疗法并购

2024-10-24

·佰傲谷BioValley

兜售唯一临床管线，张锋公司的再次转向

日前，Editas Medicine发布了一则战略更新，将重心再次转向体内CRISPR基因编辑。同时，寻求其目前唯一的临床管线reni-cel（之前名为EDIT-301）的对外许可或合作伙伴。在Editas过去的研发中，其实可以看到其重心在体内或体外疗法的不断摇摆，小编研究了一下，发现还是蛮有意思的——从AAV体内-到HSPC体外-再到LNP体内。被兜售的reni-cel reni-cel是一款用于治疗镰状细胞病（SCD）和β-地中海贫血的CRISPR-Cas12a基因编辑药物。EDIT-301由来自患者的CD34+造血干细胞和祖细胞（HSPC）构成，这些细胞经过CRISPR-Cas12a编辑γ珠蛋白基因（HBG1和HBG2）启动子，能够持续产生的胎儿血红蛋白（HbF）。 reni-cel是Editas公司管线内唯一一款临床管线，忍痛放弃reni-cel的原因可能是过长的开发时间、潜在的市场挑战、公司资金短缺等。根据报告，reni-cel尽管展示出积极的早期临床试验结果，所有镰状细胞贫血病（SCD）患者均未发生血管闭塞事件VOE；所有β地中海贫血患者的总血红蛋白均早期稳步升高，高于输血非依赖性阈值9g/dL。但是距离推进上市，还需要几年的时间。而在目前的SCD和β-地贫治疗市场上，包括美国FDA在内的几个监管机构已经批准了另一种CRISPR疗法Casgevy，另外还有蓝鸟的Lyfgenia（SCD）和Zynteglo（β-地贫）。值得注意的是，Casgevy的开发商Vertex与Editas达成了协议，Vertex获得了CRISPR-Cas9基因编辑技术的非独家授权，用于包括Casgevy在内的SCD和β-地贫体外基因编辑药物。为此，Editas将获得来自Vertex的5000万美元预付款+外加5000万美元的或有付款和年度许可费。不过，前些时候，Editas为了提前变现，将Vertex许诺的年度许可费交易给了DRI Healthcare，换取5700万美元的现金。延伸阅读：张锋公司现金流告急，提前变现许可权益几年后的未来，SCD和β-地贫的市场竞争可能更为激烈，reni-cel的竞争力很难讲。以及长达数年的CRISPR产品临床开发，对于公司资金压力也更大。 Editas的总裁兼首席执行官在一份声明中表示：“我们相信，对于患者和我们股东来说，最好的选择是寻求代替方案，例如全球合作伙伴或者对外许可，这件允许我们与另一方或由另一方进一步开发或最终商业化reni-cel，并将使Editas在2025年的支出大幅度减少。” 目前，Editas公司已聘请投资银行Moelis & Company来领导寻找reni-cel的合作伙伴或收购者的工作。不过，reni-cel的临床工作还未完全停摆。Editas报告将会对针对SCD的1/2/3期试验RUBY中和针对β-地贫的试验EdiTHAL中已经完成招募的患者给药并持续随访；预计将在2024年年末报告更多的临床数据。自此，由Editas对CRISPR体外项目的开发告一段落，转而面向CRISPR的LNP体内项目。新的重心 Editas推出了未来的重点——针对SCD和β-地贫的LNP体内编辑项目。是的，在放弃已经进入到临床阶段并显示较为积极的数据的SCD和β-地贫项目reni-cel后，Editas瞄准的适应症居然还是SCD和β-地贫，可能是新的LNP体内项目的竞争优势更大吧，毕竟体内LNP是通用型疗法，成本和价格会更低。 Editas利用专有的新型靶向脂质纳米颗粒（t-LNP）开发了下一代SCD和β-地贫体内疗法，并在小鼠模型中完成了临床前概念验证。在人源化小鼠模型（植入人类造血干细胞且缺乏自身造血细胞的小鼠）中，体内疗法实现了造血干细胞和祖细胞（HSPC）的编辑诱导胎儿血红蛋白（HbF）产生。通过利用造血干细胞靶向策略和t-LNP制剂优化，单次给药后，HSPC的编辑水平达到29%。进一步证明，使用t-LNP配方进行的编辑可导致HbF诱导的功能结果，表现为存在表达HbF的人红细胞（平均20%），这些经编辑的红细胞在体内生存一个月。根据Editas报告，截止2024年第三季度，公司拥有约2.65亿美元的现金、现金等价物和有价证券，或在收到DRI的预付款后约为3.2亿美元。体内or体外？摇摆的Editas Editas在业内大名鼎鼎，是张锋创办的第一家公司，是第一家上市的CRISPR基因编辑公司，也是最早将CRISPR技术转化为临床药物的公司。在Editas过去的研发中，其实可以看到其重点在体内或体外疗法的不断摇摆，从AAV体内—到HSPC体外—再到LNP体内。被放弃的AAV体内项目最早先，Editas更多押注在AAV体内项目上，包括其最先推进临床的眼科项目EDIT-101。 EDIT-101是首个获批临床的体内CRISPR基因编辑药物，于2018年获得美国FDA批准IND。但是后来，因为商业潜力堪忧，投入和产出成本不匹配，Editas于2022年宣布为EDIT-101寻求合作机会但无果。延伸阅读：商业潜力堪忧，Editas领先的体内CRISPR疗法停止临床开发 2023年1月，Editas在正式宣布停止对EDIT-101内部投资的同时，又停止了一项AAV体内CRISPR项目EDIT-103。EDIT-103是一款视紫红质相关的常染色体显性视网膜色素变性 (RHO-adRP)疗法，同样临床数据还算积极。另外，被挺停止的还包括一款iNK细胞疗法EDIT-202。转战HSPC体外项目在放弃AAV体内之后，2023-2024年中的Editas将资源集中在HSPC体外项目reni-cel上。经历为时一年半的努力，reni-cel也被放弃。新目标LNP载体在Editas于10月22日发布的向体内CRISPR的战略更新前，Editas于21日宣布与Genevant Sciences达成合作协议。根据协议，双方将Editas的CRISPR Cas12a基因组编辑系统，及Genevant的专有脂质纳米颗粒（LNP）递送技术，共同开发针对特定领域两个未公开靶点的mRNA-CRISPR Cas12a-LNP产品。参考资料： 1.https://ir.editasmedicine.com/news-releases/news-release-details/editas-medicine-announces-progress-towards-2024-goals-including 2.https://ir.editasmedicine.com/news-releases/news-release-details/editas-medicine-and-genevant-sciences-collaborate-develop-novel 3.https://ir.editasmedicine.com/news-releases/news-release-details/editas-medicine-announces-strategic-updates-and-portfolio 本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·

基因疗法并购

2024-10-19

·Insight数据库

一针超 2000 万，曾刷新全球最贵药物记录，却让 7 人患上了血癌

本文作者：今心 67 名患者用药，7 名患上血癌。最新 Ⅲ 期临床长期随访结果一经发布，将这款 2 年前上市，曾居世界最贵药榜榜首，一针要 2000 万的基因疗法，再次被推上风口浪尖…… 一支超 2000 万，曾刷新全球最贵药物记录 SKYSONA，一种基因治疗药物，由 Bluebird Bio（蓝鸟）公司开发，用于减缓 4～17 岁早期活动性肾上腺脑白质营养不良（CALD）患者的疾病进展。 CALD 是一种罕见的遗传性脂质代谢疾病，通常在儿童早期阶段出现，可迅速导致进行性、不可逆转的神经功能丧失和死亡，主要症状包括认知行为异常、尿失禁、行动障碍等。[1] 2022 年 9 月，SKYSONA 的获批让 CALD 患者终于摆脱了无药可用的绝境——此前，唯一可能有效的治疗方案，是在疾病早期进行同种异体造血干细胞移植。然而移植就必须要匹配到合适的来源，据估计，超过 80% 患者根本无法匹配到合适的骨髓。如果没有 SKYSONA，患者要么无药可治，近半数在 5 年内死亡；有幸可以移植，出现严重并发症和死亡的风险依然很大。[2] 于是，SKYSONA 基因疗法就被寄予了厚望，据两项 Ⅲ 期临床研究结果显示接受此疗法的患儿，有 94% 没有出现神经功能下降，超过 80% 四年内没有出现重大功能障碍和血癌。[3] 截至 2024 年 4 月 25 日，CALD患者无事件生存率，图源：NEJM 根据当时美国媒体的报道，SKYSONA 上市后价格为 300 万美元，按照当时最新汇率，折合人民币约 2095 万元，一跃成为全球最贵的治疗药物。[4] 虽然与其他基因治疗一样，SKYSONA 也非常昂贵，但凭借缓解疾病发展上的优势，它仍然为时刻面临瘫痪、死亡风险的 CALD 患儿带来了新的希望。但，这个希望，是否值得冒着血癌的风险？ 7 人患血癌，获批前就有 3 例由于 CALD 致病机理是 ABCD1 基因突变，导致饱和极长链脂肪酸在血、脑白质、肾上腺皮质等器官和组织内大量聚积，引起中枢神经系统脱髓鞘和肾上腺皮质萎缩或发育不良。[4] 因此 SKYSONA 疗法是利用 Lenti-D 慢病毒载体（LVV）进行体外转导，将 ABCD1 基因的功能拷贝添加到患者自身的造血干细胞（HSC）中，这样可以稳定 CALD 患者的病情进展，从而尽可能地保留神经功能。[3] 这种疗法虽疗效可观，但是 10 月 9 日 NEJM 报道的两项 Ⅲ 期研究的长期随访显示，8 年随访中共有 7 人罹患血癌，其中 6 名出现骨髓增生异常综合症，1 名出现急性髓系白血病。[3] 图源：NEJM 通过分析该研究推测，发生血癌可能是因为基因治疗的克隆载体插入了靶点之外的癌症相关基因位点，或导致了某些位点的体细胞突变累积。同时，基因疗法的预处理方案选择也可能与血癌发生有关，使用白消安-氟达拉滨组比使用白消安-环磷酰胺组，血癌发生率更高。 10% 左右的血癌发生率乍看触目惊心，但其实在获批上市前，蓝鸟进行的 Ⅲ 期临床试验中，就有 3 名受试者患上了血癌。[5] 虽然有研究人员认为这些血癌可能与基因治疗有关，但具体的关系并不明确。同时，考虑到由于当时接受 SKYSONA 治疗的有症状患者的无主要功能障碍（MFD）生存率显著高于未接受治疗患者，FDA 还是加速批准了这个疗法。非恶性血液学、神经学和其他疾病适应证加速审批，图源：FDA 官网开绿灯，「安全第一」还是「先批再说」 SKYSONA 并不是个例，因考量「风险收益比」而开绿灯的情况，并不罕见。比如蓝鸟的另一个基因疗法 lyfgenia，主要是针对 12 岁以上患有镰状细胞贫血（SCD）的患者。对于 SCD 患者来说，体内异常的红细胞黏附在一起，严重的会导致血管闭塞危象。而一旦出现血管闭塞危象，患者往往忍受着极端疼痛。目前 SCD 的治疗方法主要是对症治疗，患者只能终身输血。[6] 因此， lyfgenia 疗法为 SCD 患着缓解血管闭塞危象带来了希望。在一项为期 24 个月的多中心研究结果表明，在 32 名接受 lyfgenia 患者中，有 88% 的患者血管闭塞危象获得了完全缓解。[7] 虽然有患者在接受该疗法时患血癌，但监管机构还是基于该疗法的有效性予以批准上市。同样，也是因为 SCD 患者迫切需要这一治疗选择。而且如果是唯一的治疗选项，III 期临床未完成，也可能加速获批。最近，托夫生（Tofersen），作为针对渐冻症的全球首款对因治疗药物，申报提交不到一个月就正式获批。[8] 图源：FDA 官网但事实上，直到获批，该药 III 期临床试验并未完成，只是得到了「可显著降低渐冻症基因损伤标志物」的试验结果。但考虑到「药物被证明对替代终点有影响，该终点很可能预测患者临床获益」，托夫生终获加速审批。[9] 而在我国，今年 3 月 21 日，托夫生首先在瑞金海南医院应用于临床；不到 7 个月，托夫生也正式获批。图源：国家药监局越来越多的加速审批表明，面对特殊情况，全世界的监管机构在评估疗效和安全性时，也在更多考虑患者的治疗需求。「唯一的治疗方法」，不应放弃据统计，FDA 在 2023 年共批准了 55 款创新药，创过去 30 年来第二高数量。[8] 分析其背后原因，可以看到，为了加速针对治疗危及生命或严重疾病的药物进入市场，FDA 制定了四个加速审查通道：优先审查、快速通道、突破性疗法和加速批准。中国 2020 年颁布的《药品注册管理办法》，在原优先审评程序的基础上，也增加了突破性治疗药物程序、附条件批准程序和特别审批程序。[10] 图源：政府官网其中指出，为了鼓励以临床需求为导向的新药研发，加快具有临床急需药品上市，申请人可基于替代终点、中间临床终点或早期临床试验数据等申请附条件批准上市。虽然加速审查是为了治疗的需求，但安全性的评估仍然不容忽视。在给药物制定加速审查通道的同时，各监管机构也在为安全性的评估持续努力。今年 7 月 FDA 发布了关于药物、生物制剂及其组合产品使用相关风险分析草案（URRA），为药品的整个生命周期识别、分析和减轻药品使用相关潜在危害提供了详细的建议。[11] 中国《药品注册管理办法》规定，附条件批准的药品，需要在在规定期限内按照要求完成药物临床试验等相关研究，以补充申请方式申报。图源：国家药监局回到对 SKYSONA 可能导致血癌这件事情上，分析这 7 名血癌患者可能致病原因的第一作者，神经内科脑白质营养不良诊所主任表示：「我之前遇到的患者，有 80% 在来医院时已经奄奄一息，现在这个比例已经发生了逆转。虽然有些接受治疗的患者会患血癌，但基因疗法能让一部分患者看到希望，我们不应该放弃。」[1] 本文特别邀请免疫与炎症全国重点实验室副教授虞淦军，遗传学博士、药企研发科学家周叶斌，天津大学泰达医院神经内科主任医师赵伟对这一事件进行解读，并讨论现阶段该如何看待基因疗法。免疫与炎症全国重点实验室副教授虞淦军：以慢病毒为基础的细胞和基因治疗产品的远期安全性问题越来越受到重视。虽说目前认为慢病毒将目的基因整合入基因组是「随机的」，但是其具体的整合机制仍不清楚。阐明其整合机制，也许有助于将来进行更好的改造和优化。另外，7/67 的血癌发生率虽说不算高，但对于血癌这种严重的不良后果，也不算低。这种不良后果的发生是否可能与患者自身的遗传背景有关，也值得深入研究。遗传学博士、药企研发科学家周叶斌： SKYSONA 更新的数据显示有患者出现血液肿瘤，其实这个问题是该疗法经过 FDA 外部专家审核时时重点讨论的安全性风险之一。这些讨论中提到如果能够有机会获得配型好的骨髓移植治疗，综合有效性安全性，这种传统治疗方案其实可能优于 SKYSONA。这也是为什么我们不应回避而是需要争取全面了解药物的不良反应，因为这可以促使我们为患者提供最好的治疗选择。天津大学泰达医院神经内科主任医师赵伟：绝大多数罕见病患者面临「无药可医」的困境。随着科学技术的不断进步，涌现出越来越多的针对罕见病的基因疗法。但基因疗法仍面临一些挑战，如基因传递的安全性和有效性。所以，在药物研发和审批过程中，确保受试者的安全至关重要。加快新药的上市，有助于确保患者能够及时获得有效的治疗。我们也注意到，国家药监局正在努力优化罕见病治疗药物的临床审批流程，更多地关注药物对患者的实际益处。致谢：本文经免疫与炎症全国重点实验室副教授虞淦军，遗传学博士、药企研发科学家周叶斌，天津大学泰达医院神经内科主任医师赵伟专业审核策划：今心 | 监制：云也、carollero 题图来源：视觉中国参考资料： [1]https://www.sciencedaily.com/releases/2024/10/241009183352.htm [2]https://www.drugs.com/newdrugs/fda-approves-skysona-elivaldogene-autotemcel-gene-therapy-early-active-cerebral-5899.html [3]https://www.nejm.org/doi/full/10.1056/NEJMoa2405541 [4]https://www.nejm.org/doi/10.1056/NEJMoa1700554 [5]https://www.fda.gov/media/180440/download [6]https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61029-X/abstract [7]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11374260/ [8]https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene [9]https://www.nature.com/articles/d41573-024-00001-x [10] https://www.gov.cn/zhengce/zhengceku/2020-04/01/content_5498012.htm Evaluate Aducanumab in Patients With Early Alzheimer’s Disease [11]https://www.fda.gov/media/170948/download 丁香园是面向医疗从业者的专业平台，以「助力中国医生」为己任。在丁香园，可以和同行讨论病例，在线学习公开课，使用用药助手等临床决策工具，在丁香人才找可靠医疗岗位。

基因疗法临床3期临床结果

100 项与 Lovotibeglogene autotemcel 相关的药物交易

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适应症	国家/地区	公司	日期
镰状细胞血症	美国	bluebird bio, Inc.	2023-12-08

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适应症	最高研发状态	国家/地区	公司	日期
β地中海贫血	临床2期	法国	bluebird bio, Inc.	2013-06-07
输血依赖性β地中海贫血	临床2期	法国	bluebird bio, Inc.	2013-06-07

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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


NCT02140554 (HGB-210, Tandem Meetings ASTCT and CIBMTR2024) 人工标引	临床1/2期	镰状细胞血症	47	Lovotibeglogene Autotemcel	獵衊鹹築壓鹽鏇築蓋選(繭簾鏇簾鬱壓鹹鏇選獵) = 鑰衊繭構壓衊獵願壓醖壓齋鬱製繭製醖鑰鏇蓋 (餘鬱齋餘醖艱鏇餘衊網 ) 更多	积极	2024-02-01
NCT02140554 (HGB-206, Tandem Meetings ASTCT and CIBMTR2023)	临床1/2期	镰状细胞血症 HbA T87Q \| neutropenia \| trisomy 8 ... 更多	35	Lovo-cel infusion	艱蓋觸鬱鑰齋築鹽夢願(獵糧願鏇壓艱鬱鑰襯獵) = Two patients with findings that initially raised suspicion of myelodysplastic syndrome (MDS) underwent further assessments in March 2022. Presentation included neutropenia in one patient, and persistent anemia despite adequate HbA T87Q production, bone marrow morphology showing erythroid-specific dysplasia consistent with dyserythropoiesis seen in other hemoglobinopathies, and low levels of trisomy 8 (≤7.7%) only observed by fluorescence in situ hybridization analysis in both patients. There were no clinical symptoms suggestive of hematologic malignancies (no driver mutations or clonal process [vector related or otherwise] as shown by integration site analysis and next-generation sequencing, and no chromosomal abnormalities on karyotyping). One patient maintained total Hb of 9.8 g/dL at Month 18 without transfusion; the other required chronic transfusions to maintain 10.3 g/dL at Month 18 with otherwise normal complete blood counts. These were the only patients with two α-globin deletions (− α 3.7/− α 3.7). We propose that α-globin trait may contribute to anemia and dyserythropoiesis after lovo-cel infusion. 顧窪築襯淵餘膚鹹憲餘 (網鹽醖衊網淵齋壓淵繭 ) 更多	积极	2023-02-01
NCT02151526 (CTgov)	临床1/2期	β地中海贫血 \| 输血依赖性β地中海贫血 \| 镰状细胞血症	7	LentiGlobin BB305 (LentiGlobin BB305 Drug Product for SCD)	鑰簾壓鹽壓鬱網鏇鑰淵(獵觸繭淵淵襯蓋窪遞蓋) = 願製構壓壓艱窪鹹繭願製網鑰鏇鹽壓遞鏇餘襯 (築艱壓膚願選願鏇簾膚, 壓醖窪醖憲願觸鹹蓋鹽 ~ 簾鑰襯鑰獵艱顧鏇鹹糧) 更多	-	2020-03-10
NCT02151526 (CTgov)	临床1/2期	β地中海贫血 \| 输血依赖性β地中海贫血 \| 镰状细胞血症	7	LentiGlobin BB305 (LentiGlobin BB305 Drug Product for TDT)	鑰簾壓鹽壓鬱網鏇鑰淵(獵觸繭淵淵襯蓋窪遞蓋) = 淵鏇窪膚窪夢窪憲鏇鹽製網鑰鏇鹽壓遞鏇餘襯 (築艱壓膚願選願鏇簾膚, 鏇艱窪鑰憲餘齋齋築憲 ~ 製淵構鬱積築鹽鏇襯夢) 更多	-	2020-03-10