Beam的碱基编辑镰状细胞疗法显示出早期的希望，但致命性掩盖了结果-动脉网

Beam’s Base-Editing Sickle Cell Therapy Shows Early Promise, But a Fatality Overshadows Results

MedCity News 等信源发布 2024-11-06 05:17

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Beam Therapeutics’ experimental gene-editing therapy for sickle cell disease now has its first cut of patient data showing signs of treating the rare blood disorder in a way that could differentiate it from currently available gene therapies, but the early results reported Tuesday also include a fatality attributed to a drug used to prepare patients for the one-time treatment..

Beam Therapeutics针对镰状细胞病的实验性基因编辑疗法现在首次获得了患者数据，这些数据显示了治疗这种罕见血液疾病的迹象，可以将其与目前可用的基因疗法区分开来，但周二报道的早期结果还包括一种用于为患者一次性治疗做好准备的药物导致的死亡。。

Beam’s therapy, BEAM-101, is made by harvesting a patient’s stem cells and editing them in a lab using a technology called base-editing. Base editing enables precise edits to a single base in a genome. By contrast, double-stranded breaks in DNA made by the CRISPR technology have the potential to cause unwanted or off-target edits.

Beam的疗法Beam-101是通过采集患者的干细胞并在实验室中使用称为碱基编辑的技术对其进行编辑而制成的。碱基编辑可以对基因组中的单个碱基进行精确编辑。相比之下，CRISPR技术产生的DNA双链断裂有可能导致不必要的或脱靶的编辑。

The precision of base-editing is intended to be safer. In sickle cell disease, the Cambridge, Massachusetts-based company’s treatment is intended increase production of functional hemoglobin, which could in turn inhibit the process by which red blood cells take on the rigid, crescent shape characteristic of the disorder..

基本编辑的精度旨在更安全。在镰状细胞病方面，这家位于马萨诸塞州剑桥市的公司的治疗旨在增加功能性血红蛋白的产生，从而抑制红细胞呈现该疾病的刚性新月形特征的过程。。

Of the 35 patients enrolled in BEAM-101’s open-label Phase 1/2 study, eight have been dosed with the therapy as of a July 2 cutoff date. Beam said there were no serious adverse events reported in six patients who could be evaluated for safety. The patient who died experienced respiratory failure four months after infusion with BEAM-101.

在BEAM-101开放标签1/2期研究的35名患者中，截至7月2日截止日期，已有8名患者接受了治疗。Beam说，六名患者没有报告严重不良事件，可以对其进行安全性评估。死亡的患者在输注BEAM-101后四个月出现呼吸衰竭。

Beam said trial investigators determined this complication was likely due to busulfan, a chemotherapy..

Beam说，试验研究人员确定这种并发症可能是由于白消安（一种化疗药物）引起的。。

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加速索赔处理：缩短索赔期限的策略

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这些战略和做法可以大大缩短索赔的生命周期，从而更快地解决问题，改善财务成果。

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Infusing edited cells into the patient is just one part of a broader, multi-step process. One of those steps is a conditioning regimen that depletes a patient’s cells to help ensure that the newly infused cells can take their place, which is called engraftment. Busulfan is widely used in the conditioning of patients receiving stem cell transplants and gene therapy procedures.

将编辑过的细胞注入患者体内只是更广泛、多步骤过程的一部分。其中一个步骤是一种预处理方案，它消耗患者的细胞，以帮助确保新注入的细胞可以取代它们，这被称为植入。白消安广泛用于接受干细胞移植和基因治疗程序的患者的调理。

Respiratory complications are a known risk of the toxic drug, which is also used to condition sickle cell disease patients before they’re infused with the FDA-approved CRISPR gene therapies Casgevy, from Vertex Pharmaceuticals, and Lyfgenia, from Bluebird Bio..

呼吸系统并发症是一种已知的有毒药物风险，在镰状细胞病患者接受Vertex Pharmaceuticals的FDA批准的CRISPR基因疗法Casgevy和Bluebird Bio的Lyfgenia之前，该药物也被用于治疗镰状细胞病患者。。

The BEAM-101 trial has efficacy data for four patients. With the caveat that these are preliminary data from a small number of patients, the results are encouraging. All four experienced engraftment of neutrophils and platelets within one month of receiving the therapy, Beam said. The therapy led to higher levels of fetal hemoglobin and lower levels of sickle-shaped cells.

BEAM-101试验有四名患者的疗效数据。需要注意的是，这些是来自少数患者的初步数据，结果令人鼓舞。Beam说，这四个人在接受治疗后一个月内都经历了中性粒细胞和血小板的植入。该疗法导致胎儿血红蛋白水平升高，镰状细胞水平降低。

Beam also said signs of red blood cell destruction had normalized for all four patients and there were no cases of vaso-occlusive crises (VOCs), a complication that develops when sickled red blood cells impede blood flow, depriving organs of oxygen. Beam said data from more patients with longer follow-up will be presented next month during the annual meeting of the American Society of Hematology..

Beam还说，所有四名患者的红细胞破坏迹象均已恢复正常，并且没有血管闭塞性危象（VOCs）的病例，这种并发症是镰状红细胞阻碍血流，剥夺器官氧气时产生的。Beam说，更多随访时间更长的患者的数据将在下个月的美国血液学会年会上公布。。

The investment firm William Blair see some early signs of differentiation for BEAM-101. In a note sent to investors, analyst Sami Corwin said the Beam therapy’s ability to elicit higher fetal hemoglobin levels, resulting in lower sickle cell hemoglobin, could translate into extended VOC-free intervals that preserve organ health in the long term.

投资公司威廉·布莱尔（WilliamBlair）看到了BEAM-101的一些早期分化迹象。分析师萨米·科尔温（SamiCorwin）在发给投资者的一份报告中表示，Beam疗法能够提高胎儿血红蛋白水平，从而降低镰状细胞血红蛋白，这可能转化为延长的无VOC间隔时间，从而长期保持器官健康。

Corwin also said the measures of higher fetal hemoglobin and lower sickle cell hemoglobin closely mimic what’s observed in asymptomatic sickle cell mutation carriers, which could result in a differentiated product profile in the long term..

科尔温还表示，胎儿血红蛋白升高和镰状细胞血红蛋白降低的测量结果与无症状镰状细胞突变携带者的观察结果非常相似，从长远来看，这可能会导致产品差异化。。

Regarding the deceased patient, Corwin said lung toxicity is a known complication of busulfan, and it can occur months to years following treatment. She added that prior to the death, this patient’s blood appeared to be correcting and normalizing, which suggests BEAM-101 was working.

关于死者，科尔温说，肺毒性是白消安的已知并发症，可能在治疗后数月至数年发生。她补充说，在死亡之前，该患者的血液似乎正在纠正和正常化，这表明BEAM-101正在工作。

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卫生系统在门户网站上花费了数十亿美元，而对语音频道现代化的投资（这是医疗保健消费者的主要偏好）却处于次要地位。

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“While the patient death is unfortunate, we see the event as highlighting the need for less toxic preconditioning options, and we think Beam is leading the space in this regard,” Corwin wrote.

科尔温写道：“虽然病人的死亡是不幸的，但我们认为这一事件突出了对毒性较小的预处理方案的需求，我们认为Beam在这方面处于领先地位。”。

That less toxic option comes from another BEAM program called Engineered Stem Cell Antibody Paired Evasion, or ESCAPE, which is intended to avoid the need for busulfan. ESCAPE has two components, Beam explained in an investor presentation. The first, BEAM-103, is a monoclonal antibody that leads old and diseased cells to be suppressed and eliminated, making room for edited cells to replace them.

这种毒性较小的选择来自另一个名为工程干细胞抗体配对逃避（ESCAPE）的BEAM程序，该程序旨在避免使用白消安。Beam在投资者演示文稿中解释说，ESCAPE有两个组成部分。第一种是BEAM-103，它是一种单克隆抗体，可以抑制和消除旧的和患病的细胞，为编辑后的细胞替代它们腾出空间。

The edited patient cells make up the second component, BEAM-104. Modifications to those cells include an edit to avoid binding to BEAM-103. By escaping the antibody, BEAM-104 cells can multiply and engraft..

编辑的患者细胞构成第二个组件BEAM-104。对这些单元的修改包括编辑以避免与BEAM-103结合。通过逃避抗体，BEAM-104细胞可以繁殖和移植。。

Beam has preclinical proof-of-concept date for ESCAPE. In tests in two monkeys, each receiving different dose levels of the ESCAPE regimen instead of busulfan, Beam said the antibody-based conditioning was well tolerated with no need for supportive care. Beam also said both monkeys showed rapid increases in fetal hemoglobin levels that reached about 55% measured 35 weeks after administration of the therapy.

。在两只猴子的测试中，每只猴子接受不同剂量水平的逃逸方案而不是白消安，Beam说这种基于抗体的调理耐受性良好，不需要支持治疗。Beam还说，这两只猴子的胎儿血红蛋白水平在服用该疗法35周后迅速升高，达到约55%。

More data for ESCAPE are set to be presented at the ASH conference..

更多逃生数据将在ASH会议上公布。。

“Our proof-of-concept data for ESCAPE in non-human primates demonstrate that base editing could enable antibody conditioning and engraftment for stem cell transplant without chemotherapy, a potential breakthrough in the field of hematology and for patients,” Giuseppe Ciaramella, president of Beam, said in a prepared statement..

Beam总裁朱塞佩·夏拉梅拉（GiuseppeCiaramella）在一份准备好的声明中表示：“我们关于非人灵长类动物逃逸的概念验证数据表明，碱基编辑可以实现抗体调理和干细胞移植植入，而无需化疗，这是血液学领域和患者领域的潜在突破。”。。

Image: Meletios Verras, Getty Images

图片：Meletios Verras，Getty Images

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