Yang Liu

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Casgevy 拆解——第一个获批 CRISPR 疗法改了什么、贵在哪、疗效多久 Casgevy, Anatomized: What the First Approved CRISPR Therapy Actually Changes, What It Costs, and How Long It Lasts

2026-07-31 · Casgevy, CRISPR基因编辑, BCL11A, 镰状细胞病, β-地中海贫血基因疗法

2023 年 11 月 16 日,英国药品与保健品管理局(MHRA)在一份公告里写下了一个第一次:全世界第一款获批上市的 CRISPR/Cas9 基因编辑疗法。三周后的 12 月 8 日,美国 FDA 跟进批准,这款药有了一个正式的名字——Casgevy,通用名 exagamglogene autotemcel,简称 exa-cel。它要卖 220 万美元一次。围绕它的争论此后两年没停过:这笔钱买到的到底是什么,值不值,又能撑多久。

从一段 enhancer 到一款药

Casgevy 改的不是镰状细胞病或 β-地中海贫血本身的致病基因。它绕开了病因,去动一个开关——这个开关叫 BCL11A,是它在出生后把胎儿血红蛋白(HbF)的生产线关掉、换上成人版血红蛋白。2013 年,Bauer 等人在 Science 上发现,只要精确破坏 BCL11A 里一段红系特异的 enhancer,就能在红细胞谱系里把这个开关调暗,同时不影响它在造血干细胞和淋巴细胞里的本职工作(这条从统计信号到可编辑靶点的完整链条,见本连载第 41 篇)。Casgevy 是第一款把这个发现真正做成药、送进人体的产品,由 Vertex Pharmaceuticals 与 CRISPR Therapeutics 联合开发。

它编辑的具体位置,落在 BCL11A 第二内含子里那段 enhancer 上一个 GATA1 转录因子结合基序附近。CRISPR-Cas9 在此处切开双链,细胞用非同源末端连接修复,留下的插入缺失突变破坏了这个基序,GATA1 无法再稳定结合,BCL11A 在红系里的表达随之下调,原本被锁住的 HbF 重新被写进红细胞。整个操作在体外完成:从患者自身采集 CD34⁺ 造血干细胞,用电穿孔把 Cas9 蛋白和向导 RNA 以核糖核蛋白复合物的形式送入细胞,不使用任何病毒载体——这一点后来成为它和同一天获批的另一款疗法 Lyfgenia(慢病毒基因添加路线)之间最根本的技术分野,留到下一篇细讲。

数字从哪来

支撑获批的是两项独立的 3 期单臂开放试验,统称 CLIMB。镰状细胞病一侧(CLIMB SCD-121,NCT03745287)招募了 12 到 35 岁、过去两年里每年至少发生两次严重血管闭塞危象(VOC)的患者,44 人接受了治疗。Frangoul 等人 2024 年在《新英格兰医学杂志》上报告的最终结果里,30 名有足够随访数据的患者中,29 人在连续至少 12 个月里没有再发生任何 VOC,达标率 97%(95% 置信区间 83%–100%);同一批患者里,100% 在这段时间里没有因病住院。中位随访 19.3 个月。β-地中海贫血一侧(CLIMB-111,NCT03655678)则招募了输血依赖型患者,52 人接受治疗,35 人有足够随访数据评估,其中 32 人此后不再需要输血,达标率 91%(95% 置信区间 77%–98%),中位随访 20.4 个月。这两篇论文与 2021 年 Frangoul 等人报告的首批两名患者的早期数据(见第 41 篇)一脉相承,只是把样本量和随访时间都拉长了一大截。

安全性上,两项试验里没有患者出现与治疗相关的恶性肿瘤,不良事件谱系与常规的清髓性自体干细胞移植大体相当——这是判断这类疗法是否”划算”时绕不开的参照系,因为 Casgevy 本质上仍是一次完整的移植,而不是打一针那么简单。脱靶风险方面,团队先用计算同源性搜索加 GUIDE-seq 方法在健康供者细胞里锁定了 223 个非重叠候选区域,再把每位患者样本里各自新增检出的位点并入复核,FDA 审评团队据此确认,不同患者样本中实际核查的候选位点总数在 237 到 249 个之间;发现的几个与 BCL11A 序列相似的区域落在 3 号染色体着丝粒附近的基因间区,不带 CRISPR/Cas9 编辑留下的典型印记,研究者据此判断这些位点并未真正被编辑到——这组数据发表在 2024 年 NEJM 的一篇通讯文章里,是目前对这款药脱靶风险最直接的一手证据。

一次治疗,一整年的流程

“一次性治愈”这个说法容易让人误以为治疗是瞬间发生的。实际过程漫长得多。患者先要经历动员和采血(单采),这一步通常需要连续几天,部分患者还要间隔至少两周再采一轮才能凑够足够的细胞数;随后细胞被送往制造工厂进行编辑、扩增与放行检验,这个环节可能耗时数月;等制造完成,患者要住院接受清髓性预处理(通常用白消安),再在预处理后的窗口期内回输编辑好的细胞。从第一次采血到细胞回输,整个流程往往横跨数月乃至接近一年,期间患者大部分时间处于免疫抑制或住院观察状态。这也是为什么两家公司在定价时,拿来做参照的不是”一针多少钱”,而是镰状细胞病患者一生的医疗支出——按 Vertex 和 bluebird bio(Lyfgenia 的开发方)各自估算,一名反复发作的重症患者终生医疗成本在 400 万到 600 万美元之间。2023 年 12 月,Casgevy 在美国的批发采购价定为 220 万美元,同日获批的 Lyfgenia 定价 310 万美元。

三张批文

Casgevy 的监管路径本身值得单独记一笔,因为它是全球第一款走完这条路的 CRISPR 药物:英国 MHRA 于 2023 年 11 月 16 日率先批准,用于治疗 12 岁以上的镰状细胞病与输血依赖型 β-地中海贫血,拿下”世界第一”;美国 FDA 于同年 12 月 8 日批准其用于镰状细胞病适应症(限有反复 VOC 病史的 12 岁以上患者),又在 2024 年 1 月 16 日追加批准了 β-地中海贫血适应症,比原定审批时限提前了两个多月;欧盟方面,欧洲药品管理局的人用药品委员会在 2023 年底给出正面意见,欧盟委员会于 2024 年 2 月正式授予有条件上市许可。三地监管机构在不到三个月内相继放行,这在基因治疗史上前所未有的速度背后,是长达十余年的 BCL11A 机制研究和两项独立 3 期试验积累下来的证据密度。这三张批文最初都把适用人群限定在 12 岁以上;随着儿童队列数据陆续补齐,FDA 已于 2026 年 7 月 1 日把美国的年龄下限降到 2 岁以上,是这款药第一次被批准用于如此年幼的患者。

两年过去,谁真的用上了

获批之后,真正的瓶颈从”能不能治”变成了”能不能被用上”。这类疗法要求患者所在地必须有具备清髓移植能力、且经过厂商认证的”授权治疗中心”(ATC),两家公司花了近两年时间在全球铺设这张网络,到 2025 年才把目标里的 75 家中心陆续激活。商业放量因此起步缓慢:2024 年 Casgevy 全年收入约 1000 万美元,而 2025 年内全球新增 147 人完成首次细胞采集、启动治疗流程,较 2024 年增长近三倍;当年新增回输患者 64 人(其中第四季度 30 人),全年收入升至约 1.16 亿美元,美国约九成患者已能获得医保报销覆盖。这个爬坡曲线说明,限制这款药物影响力的,已经不再是分子层面的问题,而是一整条从采集中心、制造产能到报销体系的基础设施要重新搭建一遍——这条基础设施在多数镰状细胞病负担最重的地区根本不存在,这个议题留到本连载讨论可及性时再展开。

Casgevy 留下的,与其说是一种药,不如说是一次示范:一个由人类遗传学发现的调控开关,经过十余年打磨,真正被编辑进了病人的细胞,并且拿到了三大监管机构的批准。它没有解决基因治疗最古老的两个难题——为什么必须先摧毁病人自己的骨髓才能腾出位置,以及为什么这一切必须贵到只有极少数人负担得起。这两个问题,连同它与同日获批的 Lyfgenia 之间那条更深的技术分野,是接下来几篇要继续拆解的部分。

参考文献

  1. Bauer DE, et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science. 2013;342(6155):253-7. DOI
  2. Frangoul H, et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. N Engl J Med. 2021;384(3):252-260. DOI
  3. Frangoul H, et al. Exagamglogene Autotemcel for Severe Sickle Cell Disease. N Engl J Med. 2024;390(18):1649-1662. DOI
  4. Locatelli F, et al. Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia. N Engl J Med. 2024;390(18):1663-1676. DOI
  5. Specificity of CRISPR-Cas9 Editing in Exagamglogene Autotemcel. N Engl J Med. 2024;390(18):1723-1725 (correspondence; published online 2024-04-24). DOI
  6. FDA. CASGEVY Approval Letter, December 8, 2023. FDA.gov
  7. FDA. FDA Approves First Gene Therapy for Young Children with Sickle Cell Disease (Casgevy label expansion). FDA.gov
  8. Vertex Pharmaceuticals / CRISPR Therapeutics. Vertex and CRISPR Therapeutics Announce US FDA Approval of CASGEVY for Sickle Cell Disease, December 8, 2023. news.vrtx.com
  9. Vertex Pharmaceuticals. Vertex Announces US FDA Approval of CASGEVY for Transfusion-Dependent Beta Thalassemia, January 16, 2024. investors.vrtx.com
  10. Vertex and CRISPR Therapeutics. Authorization of CASGEVY by the United Kingdom MHRA, November 16, 2023. news.vrtx.com
  11. European Commission Approves First CRISPR/Cas9 Gene-Edited Therapy, CASGEVY, February 2024. news.vrtx.com
  12. BioPharma Dive. CRISPR therapy for sickle cell approved by FDA in gene editing milestone (pricing at $2.2 million). biopharmadive.com
  13. CRISPR Therapeutics. CRISPR Therapeutics Provides Business Update and Reports Fourth Quarter and Full Year 2025 Financial Results, February 12, 2026. ir.crisprtx.com
  14. Vertex Pharmaceuticals. Vertex Reports Fourth Quarter and Full Year 2025 Financial Results, February 12, 2026. news.vrtx.com
  15. FDA. CBER Bioinformatics BLA Review Memorandum, BLA 125787 (CASGEVY) — Approval History, Letters, Reviews, and Related Documents. FDA.gov

On November 16, 2023, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) announced a first: the world’s first approved CRISPR/Cas9 gene-editing therapy. Three weeks later, on December 8, the US FDA followed with its own approval, giving the drug an official name — Casgevy, generic name exagamglogene autotemcel, or exa-cel for short. It costs $2.2 million for a single treatment. The debate around it hasn’t let up in the two years since: what exactly that money buys, whether it’s worth it, and how long it lasts.

From an Enhancer to a Drug

Casgevy doesn’t touch the disease-causing gene behind sickle cell disease or β-thalassemia itself. It bypasses the cause and instead disables a switch — BCL11A, the gene that, after birth, shuts down production of fetal hemoglobin (HbF) and hands the job over to the adult form. In 2013, Bauer and colleagues reported in Science that precisely disrupting an erythroid-specific enhancer within BCL11A could dial down that switch specifically in the red blood cell lineage, without disturbing the gene’s normal job in hematopoietic stem cells and lymphocytes (the full chain from statistical signal to editable target is covered in article #41 of this series). Casgevy is the first product to actually turn that discovery into a drug and put it into patients, developed jointly by Vertex Pharmaceuticals and CRISPR Therapeutics.

The specific site it edits sits within that enhancer, in BCL11A’s second intron, near a binding motif for the transcription factor GATA1. CRISPR-Cas9 cuts the double strand there; the cell repairs it through non-homologous end joining, and the resulting insertions/deletions disrupt the motif so that GATA1 can no longer bind stably. BCL11A expression drops in the erythroid lineage, and the fetal hemoglobin that had been locked away gets written back into red blood cells. The whole procedure happens outside the body: CD34+ hematopoietic stem cells are collected from the patient, and electroporation delivers Cas9 protein and guide RNA as a ribonucleoprotein complex into the cells — no viral vector involved. That distinction later became the deepest technical divide between Casgevy and Lyfgenia, the lentiviral gene-addition therapy approved on the very same day — a comparison this series will get into in the next piece.

Where the Numbers Come From

The approval rested on two independent, single-arm, open-label phase 3 trials, together called CLIMB. The sickle cell side, CLIMB SCD-121 (NCT03745287), enrolled patients aged 12 to 35 who had experienced at least two severe vaso-occlusive crises (VOCs) per year over the preceding two years; 44 patients were treated. In the final results Frangoul and colleagues reported in the New England Journal of Medicine in 2024, 29 of the 30 patients with sufficient follow-up data went at least 12 consecutive months without a single VOC — a 97% success rate (95% CI, 83–100%); all 30 (100%) had no disease-related hospitalizations over that period. Median follow-up was 19.3 months. The β-thalassemia side, CLIMB-111 (NCT03655678), enrolled transfusion-dependent patients; 52 were treated, 35 had sufficient follow-up to evaluate, and 32 of them no longer needed transfusions — a 91% success rate (95% CI, 77–98%), with median follow-up of 20.4 months. Both papers build directly on the early data from the first two patients that Frangoul and colleagues reported in 2021 (see article #41); the later results simply extend the sample size and follow-up considerably.

On safety, neither trial reported any treatment-related malignancy, and the adverse-event profile was broadly consistent with a standard myeloablative autologous stem-cell transplant — the reference point that matters most when judging whether this kind of therapy is “worth it,” since Casgevy is, at its core, still a full transplant procedure, not a simple injection. On off-target risk, the team first used a computational homology search combined with GUIDE-seq to identify 223 non-overlapping candidate regions in healthy donor cells, then folded in any additional sites newly detected in each patient’s own sample; the FDA review team confirmed that the actual number of candidate sites checked per patient sample ranged from 237 to 249. A handful of regions with sequence similarity to BCL11A turned up near the centromere of chromosome 3, in intergenic regions, but showed none of the signature marks of CRISPR/Cas9 editing — leading the researchers to conclude these sites were not actually edited. That data, published in a 2024 NEJM correspondence, is currently the most direct primary evidence available on this drug’s off-target risk.

One Treatment, Nearly a Year of Process

The phrase “one-time cure” makes it easy to assume the treatment happens in an instant. The real process is far longer. Patients first go through mobilization and apheresis (cell collection), typically over several consecutive days; some need a second round at least two weeks later to collect enough cells. The cells are then shipped to a manufacturing facility for editing, expansion, and release testing, a step that can take months. Once manufacturing is complete, the patient is hospitalized for myeloablative conditioning (typically with busulfan), and the edited cells are infused back within the post-conditioning window. From the first blood draw to the cell infusion, the whole process often spans several months to nearly a year, during which patients spend most of their time immunosuppressed or under inpatient observation. That’s also why, in setting the price, the two companies didn’t benchmark against “cost per injection” but against the lifetime medical costs of a sickle cell patient — by Vertex’s and bluebird bio’s (developer of Lyfgenia) respective estimates, a patient with recurrent severe disease incurs $4 million to $6 million in lifetime medical costs. In December 2023, Casgevy’s US wholesale acquisition cost was set at $2.2 million; Lyfgenia, approved the same day, was priced at $3.1 million.

Three Approvals

Casgevy’s regulatory path is worth recording on its own, since it’s the first CRISPR drug to travel this route anywhere in the world: the UK’s MHRA approved it first, on November 16, 2023, for sickle cell disease and transfusion-dependent β-thalassemia in patients 12 and older, claiming the “world first”; the US FDA approved it for the sickle cell indication (limited to patients 12 and older with a history of recurrent VOCs) on December 8 of the same year, then added the β-thalassemia indication on January 16, 2024 — more than two months ahead of its original review deadline; in the EU, the European Medicines Agency’s Committee for Medicinal Products for Human Use issued a positive opinion in late 2023, and the European Commission formally granted conditional marketing authorization in February 2024. Three regulatory bodies clearing the drug within less than three months of each other is an unprecedented pace in the history of gene therapy, built on top of more than a decade of BCL11A mechanistic research and the accumulated evidence density of two independent phase 3 trials. All three approvals initially restricted the eligible population to patients 12 and older; as pediatric cohort data has gradually come in, the FDA lowered the US age floor to 2 and older on July 1, 2026 — the first time this drug has been approved for patients this young.

Two Years Later: Who Actually Got It

After approval, the real bottleneck shifted from “can it treat” to “can it actually reach patients.” This kind of therapy requires that wherever a patient lives, there must be a manufacturer-certified “Authorized Treatment Center” (ATC) with myeloablative transplant capability, and the two companies spent nearly two years building out that network worldwide, only getting their target of 75 centers activated by 2025. Commercial uptake was correspondingly slow to start: Casgevy brought in roughly $10 million in revenue for all of 2024. In 2025, 147 patients worldwide newly initiated treatment by completing their first cell collection — nearly triple the growth seen in 2024 — with 64 new patients infused that year (30 of them in the fourth quarter alone), pushing full-year revenue to roughly $116 million; about 90% of US patients now have access to insurance coverage. That ramp-up curve shows that what limits this drug’s reach is no longer a molecular-level problem, but an entire infrastructure — from collection centers to manufacturing capacity to reimbursement systems — that has to be built essentially from scratch. That infrastructure simply doesn’t exist yet in most of the regions carrying the heaviest sickle cell disease burden, a subject this series will return to when it turns to access.

What Casgevy leaves behind is less a drug than a demonstration: a regulatory switch discovered through human genetics, refined over more than a decade, actually edited into patients’ cells, and cleared by three major regulatory authorities. It hasn’t solved gene therapy’s two oldest problems — why a patient’s own bone marrow still has to be destroyed to make room for the new cells, and why all of this has to cost so much that only a very small number of people can afford it. Those two questions, along with the deeper technical divide between Casgevy and Lyfgenia, approved the same day, are what the next few pieces in this series will keep unpacking.

References

  1. Bauer DE, et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science. 2013;342(6155):253-7. DOI
  2. Frangoul H, et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. N Engl J Med. 2021;384(3):252-260. DOI
  3. Frangoul H, et al. Exagamglogene Autotemcel for Severe Sickle Cell Disease. N Engl J Med. 2024;390(18):1649-1662. DOI
  4. Locatelli F, et al. Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia. N Engl J Med. 2024;390(18):1663-1676. DOI
  5. Specificity of CRISPR-Cas9 Editing in Exagamglogene Autotemcel. N Engl J Med. 2024;390(18):1723-1725 (correspondence; published online 2024-04-24). DOI
  6. FDA. CASGEVY Approval Letter, December 8, 2023. FDA.gov
  7. FDA. FDA Approves First Gene Therapy for Young Children with Sickle Cell Disease (Casgevy label expansion). FDA.gov
  8. Vertex Pharmaceuticals / CRISPR Therapeutics. Vertex and CRISPR Therapeutics Announce US FDA Approval of CASGEVY for Sickle Cell Disease, December 8, 2023. news.vrtx.com
  9. Vertex Pharmaceuticals. Vertex Announces US FDA Approval of CASGEVY for Transfusion-Dependent Beta Thalassemia, January 16, 2024. investors.vrtx.com
  10. Vertex and CRISPR Therapeutics. Authorization of CASGEVY by the United Kingdom MHRA, November 16, 2023. news.vrtx.com
  11. European Commission Approves First CRISPR/Cas9 Gene-Edited Therapy, CASGEVY, February 2024. news.vrtx.com
  12. BioPharma Dive. CRISPR therapy for sickle cell approved by FDA in gene editing milestone (pricing at $2.2 million). biopharmadive.com
  13. CRISPR Therapeutics. CRISPR Therapeutics Provides Business Update and Reports Fourth Quarter and Full Year 2025 Financial Results, February 12, 2026. ir.crisprtx.com
  14. Vertex Pharmaceuticals. Vertex Reports Fourth Quarter and Full Year 2025 Financial Results, February 12, 2026. news.vrtx.com
  15. FDA. CBER Bioinformatics BLA Review Memorandum, BLA 125787 (CASGEVY) — Approval History, Letters, Reviews, and Related Documents. FDA.gov