Groundbreaking? Game-changing? Transformational? Historic?

开创性的？改变游戏规则？变革？历史？

None of the buzzwords sound adequate to describe Friday’s FDA approval of Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy (exa-cel) to treat sickle cell disease (SCD).

这些流行语听起来都不足以描述周五FDA批准Vertex Pharmaceuticals和CRISPR Therapeutics的Casgevy（exa cel）治疗镰状细胞病（SCD）。

The therapy is a long-awaited potential cure for the debilitating and life-threatening disease which affects more than 100,000 in the United States, most of them Black. It’s also the first medicine using the revolutionary CRISPR gene-editing system, which earned its inventors a Nobel Prize in 2020 and holds tantalizing potential to cure diseases for which there is no treatment..

这种疗法是人们期待已久的治疗这种衰弱和危及生命的疾病的潜在方法，这种疾病在美国影响了10多万人，其中大多数是黑人。它也是第一种使用革命性CRISPR基因编辑系统的药物，该系统的发明者于2020年获得诺贝尔奖，并具有治愈无法治疗的疾病的诱人潜力。。

On Friday, in surprising timing, the FDA approved a second gene therapy for SCD, bluebird bio’s Lyfgenia (lovo-cel), which was due for a decision on Dec. 20. Both approvals are for people 12 and older.

周五，令人惊讶的是，FDA批准了针对SCD的第二种基因疗法，即蓝鸟生物的Lyfgenia（lovo cel），该疗法将于12月20日做出决定。这两种批准都适用于12岁及以上的人。

The FDA has signed off on roughly two dozen cell or gene therapies, beginning with Novartis’ Kymriah in 2017. But none have the potential impact of Casgevy and Lyfgenia.

从2017年诺华的Kymriah开始，FDA已经签署了大约20多种细胞或基因疗法。但没有一个能像卡西维和利夫吉尼亚那样产生潜在的影响。

“(Sickle cell) is not a rare genetic disease that no one’s ever heard of,” Julie Gerberding, president and CEO of the Foundation for the National Institutes of Health, said in an interview on Monday. “The applicability to a larger population is really, I think, part of what makes this so exciting. Although it’s also sort of the 0.5 version of where we can go in terms of really having a population-level impact.”.

美国国立卫生研究院基金会主席兼首席执行官朱莉·格伯丁（JulieGerberding）周一在接受采访时表示：“镰状细胞并不是一种罕见的遗传病，没有人听说过。”。“我认为，对更大人口的适用性确实是这一点如此令人兴奋的部分原因。尽管这也是我们可以达到的0.5版本，因为它确实对人口水平产生了影响。”。

In October, an FDA advisory committee signed off on the safety of exa-cel, quelling concerns about off-target effects of CRISPR editing and clearing its path to approval. Then, three weeks ago, experts in the U.K. authorized Casgevy for SCD and another similar blood disorder, transfusion-dependent beta thalassemia (TDT)..

10月，FDA咨询委员会签署了exa-cel的安全性协议，平息了对CRISPR编辑脱靶效应的担忧，并为其获得批准扫清了道路。然后，三周前，英国专家授权卡西维治疗SCD和另一种类似的血液疾病，输血依赖性β地中海贫血（TDT）。。

While Vertex and CRISPR will charge $2.2 million for Casgevy, bluebird has priced Lyfgenia at $3.1 million, raising questions about coverage and accessability. Most gene therapies are priced at more than $1 million and the treatments can run all the way up to $3.5 million for the world’s costliest drug—CSL Behring and uniQure’s hemophilia B treatment Hemgenix..

Vertex和CRISPR将为Casgevy收取220万美元，而bluebird将Lyfgenia定价为310万美元，这引发了人们对覆盖率和可访问性的质疑。大多数基因疗法的价格都在100多万美元以上，对于世界上最昂贵的药物CSL Behring和uniQure的血友病B治疗药物Hemgenix，这些疗法的价格可能高达350万美元。。

Earlier this year, the Institute for Clinical and Economic Review (ICER) assessed that both Vertex and bluebird’s therapies would meet cost-effectiveness thresholds if priced between $1.35 million and $2.05 million.

今年早些时候，临床与经济评论研究所（ICER）评估，如果价格在135万美元至205万美元之间，Vertex和bluebird的疗法都将达到成本效益阈值。

SCD causes blood cells to fold into crescent shapes, which makes them more likely to collect in blood vessels, depriving the muscles of oxygen. Patients undergo blood transfusions but still live with the constant threat of strokes and episodes of searing pain. The disorder also leaves patients susceptible to a host of other complications such as anemia, jaundice, infections, gallstones and organ damage..

SCD导致血细胞折叠成新月形，这使得它们更有可能聚集在血管中，从而剥夺肌肉的氧气。患者接受输血治疗，但仍面临中风和灼痛发作的持续威胁。这种疾病还使患者易患贫血、黄疸、感染、胆结石和器官损伤等一系列其他并发症。。

Some patients can undergo bone marrow transplants that can cure the disease, but that requires a donor—a full brother or sister—and a variety of medicines to ensure that the body adapts to the new cells.

一些患者可以进行骨髓移植，以治愈疾病，但这需要捐赠者（一个亲兄弟姐妹）和各种药物来确保身体适应新细胞。

As for exa-cel, interim data reported in June showed that of 15 of 16 sickle cell patients treated (94%) did not have the debilitating pain episodes—also known as vaso-occlusive crises—for at least 12 consecutive months, which was the primary endpoint measured. The benefits are expected to be life-long, Vertex and CRISPR have said..

至于exa cel，6月份报告的中期数据显示，接受治疗的16名镰状细胞患者中有15名（94%）至少连续12个月没有出现衰弱性疼痛发作，也称为血管闭塞性危机，这是测量的主要终点。Vertex和CRISPR表示，这些益处有望终身受益。。

Another trial with exa-cel in TDT patients showed that 89% achieved the primary endpoint of transfusion independence for at least 12 consecutive months. The FDA is scheduled to make a decision on exa-cel in that indication by March 30 of next year.

另一项针对TDT患者的exa-cel试验显示，89%的患者至少连续12个月达到了输血独立性的主要终点。FDA计划在明年3月30日之前对该适应症中的exa-cel做出决定。

With the treatment, bone marrow stem cells are taken from patients and CRISPR is used to modify the marrow before the cells are reinfused by way of a stem cell transplant. The therapy allows the production of fetal hemoglobin (HbF), replacing the defective hemoglobin of people with the diseases.

通过这种治疗，从患者身上提取骨髓干细胞，并在通过干细胞移植重新融合细胞之前，使用CRISPR修饰骨髓。该疗法可以产生胎儿血红蛋白（HbF），替代患有疾病的人的缺陷血红蛋白。

Lasting up to a year, the process is laborious for patients and requires a hospital stay of a month or more as patients are treated and monitored after reinfusion.

这一过程长达一年，对患者来说很费力，需要住院一个月或更长时间，因为患者在回输后接受治疗和监测。

‘Not at the end of the road’

“不在路的尽头”

While hailing exa-cel as a significant breakthrough in finding a cure for SCD, experts agree that there’s a long way to go to simplify its administration and ensure its safety and reliability.

专家们称赞exa-cel在寻找SCD治疗方法方面取得了重大突破，但同时也认为，要简化其管理并确保其安全性和可靠性，还有很长的路要走。

During the FDA advisory committee meeting in October, Daniel Bauer, Ph.D., of the Boston Children’s Cancer and Blood Disorders Center, presented research that showed that CRISPR can cause unanticipated mutations but emphasized that the benefits of exa-cel outweigh the risks.

在10月的FDA咨询委员会会议上，波士顿儿童癌症和血液疾病中心的Daniel Bauer博士介绍了一项研究，表明CRISPR可以引起意想不到的突变，但强调exa-cel的益处大于风险。

“We’re not at the end of the road,” Bauer told reporters during a Zoom session on Tuesday. “This is an important milestone but it’s still a very challenging therapy to deliver that requires collection of stem cells and ex-vivo manipulation and treatment with chemotherapy to ablate the blood system.”  .

“我们还没有走到尽头，”鲍尔在周二的Zoom会议上告诉记者。“这是一个重要的里程碑，但它仍然是一种非常具有挑战性的治疗方法，需要收集干细胞，进行离体操作，并通过化疗消融血液系统。”。

Related

相关

As Vertex preps for exa-cel launch, exec touts 'very large' opportunity but tempers early expectations

在Vertex为exa cel发布做准备时，exec吹嘘“非常大”的机会，但缓和了早期的期望

While most researchers were going in a different direction a decade ago, Bauer and Stuart Orkin, M.D., of the Harvard Stem Cell Institute, were employing CRISPR to lay the groundwork for the development of exa-cel, with their efforts funded by the Doris Duke Foundation.

虽然十年前大多数研究人员都朝着不同的方向发展，但哈佛干细胞研究所的鲍尔和斯图亚特·奥金医学博士正在利用CRISPR为exa-cel的开发奠定基础，他们的努力得到了多丽丝·杜克基金会的资助。

A decade later, Bauer and Orkin are thrilled with the development of the treatment. Orkin called the trial results—showing 94% of patients symptom free—“spectacular” and “well above the threshold of clinical benefit.”

十年后，鲍尔和奥金对这种治疗方法的发展感到兴奋。Orkin称，试验结果显示94%的患者无症状-“壮观”且“远高于临床获益阈值”

Related

相关

Vertex, CRISPR gain 'historic' nod in UK for exa-cel. But will cost watchdogs embrace the gene editing therapy?

Vertex，CRISPR在英国获得exa cel的“历史性”点头。但是，成本监管机构会接受基因编辑疗法吗？

The forefathers of exa-cel steer clear of calling it a cure however. Even the earliest trial patients aren’t far enough removed from treatment to be declared free of SCD and the potential long-term side effects of the therapy, Bauer said.

然而，exa-cel的先辈们并不认为它是一种治疗方法。鲍尔说，即使是最早的试验患者，也不足以被宣布没有SCD和该疗法潜在的长期副作用。

“(Cure is) an exciting term but it’s a hard-to-define term,” Bauer said. “I think we would all agree that it takes a long time of observation to say that someone’s been cured.”

鲍尔说：“治愈是一个令人兴奋的术语，但它很难定义。”。“我想我们都会同意，要说有人已经治愈需要很长时间的观察。”