A Phase III, Multicenter, Randomized, Placebo Controlled, Double-blind Study to Assess Efficacy and Safety of Crizanlizumab (5 mg/kg) Versus Placebo, With or Without Hydroxyurea/Hydroxycarbamide Therapy, in Adolescent and Adult Sickle Cell Disease Patients With Frequent Vaso-Occlusive Crises

A phase III, multi-center, randomized, placebo-controlled, double-blind study to assess efficacy and safety of crizanlizumab (5 mg/kg) versus placebo, with or without hydroxyurea/hydroxycarbamide therapy, in adolescent and adult Sickle Cell Disease patients with frequent vaso-occlusive crises.

开始日期2024-10-01

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT05469828 / Not yet recruiting临床1/2期IIT

Crizanlizumab Improves Tissue Oxygen Supply Demand Matching in Patients With Sickle Cell Anemia

Hypothesis
Efficient unloading of oxygen to regions of high metabolic demand requires a healthy microvasculature to sense local oxygen tension and regulate flow, accordingly. In sickle cell disease patients, the investigators have demonstrated oxygen supply-demand mismatch, or SDM, in proportion to anemia severity. SDM occurs in both the peripheral circulation and the brain, and four characteristics: 1) Hyperemia beyond expected for the level of anemia, 2) Corresponding loss of vascular dilatory reserve, 3) Impaired oxygen unloading to the tissues, and 4) Tissue hypoxia. In sickle cell disease, red blood cell (RBC) and white blood cell (WBC) adhere to vascular endothelium triggering transient or irreversible microvascular damage as well as releasing vasoactive substances that contribute to microvascular dysregulation. The investigators postulate that ongoing microvascular damage/dysregulation in the setting of increased total blood flow contributes to SDM. The investigators believe SEG101, by lowering RBC and WBC adhesion to the microvasculature, will improve SDM and tissue oxygenation.
Objectives
Primary - The investigators will test whether SEG101 improves SDM in patients with sickle cell anemia by measuring the change in tissue oxygenation measured by near infrared spectroscopy (NIRS).
Secondary/Exploratory - The investigators will identify end-organ disease and whether improvement of SDM by SEG101 occurs in patients with sickle cell anemia.

开始日期2024-07-01

申办/合作机构

Children's Hospital Los Angeles

[+1]

NCT05020873 / TerminatedN/A

Prospective, Observational Study in Sickle Cell Disease Patients on Crizanlizumab Treatment in Middle East Countries and India (SPOTLIGHT)

This is a multicenter, prospective, single-arm observational non-interventional study (NIS), which will be conducted in various countries in the Middle East and India.

开始日期2021-11-04

申办/合作机构

Novartis Pharmaceuticals Corp.

100 项与 Crizanlizumab-TMCA 相关的临床结果

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100 项与 Crizanlizumab-TMCA 相关的专利（医药）

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项与 Crizanlizumab-TMCA 相关的文献（医药）

2024-08-01·CLINICAL DRUG INVESTIGATION

Budget Impact of Disease-Modifying Treatments and a CRISPR Gene-Edited Therapy for Sickle Cell Disease

Article

作者: Huys, Isabelle ; Simoens, Steven ; Claes, Kathleen J ; Abdallah, Khadidja

BACKGROUND AND OBJECTIVE:

Treatment of sickle cell disease (SCD) has traditionally focused on symptomatic and preventative care. Recent advances in novel therapeutic developments, likely to be orphan-designated, are anticipated to carry a substantial price tag. This study assesses the potential budget impact of adopting disease-modifying treatments, crizanlizumab and voxelotor, and pioneering CRISPR gene-edited therapy, CTX001, in the Belgian healthcare system.

METHODS:

The perspective of the Belgian healthcare payer (RIZIV-INAMI including patient copayments), a 5-year horizon with a 2-10% uptake of disease-modifying interventions, and a 2% uptake of CTX001 were considered. Data, encompassing target population, current (chronic and acute management, curative hematopoietic stem cell transplantation) and new (crizanlizumab, voxelotor, and CTX001) interventions, clinical effectiveness, adverse events, healthcare resource utilization, and associated costs, were gathered through a comprehensive literature review (first phase) and two Delphi panels involving hematologists (second phase). The cost difference between a "world with and without crizanlizumab, voxelotor, and CTX001" was calculated to obtain the budget impact. Three scenario analyses were conducted: a 5-13% and 4% uptake analysis, a 10-18% and 8% uptake analysis, respectively for disease-modifying treatments (crizanlizumab and voxelotor) and CTX001, and a 0% crizanlizumab uptake and managed entry agreements analysis . A ± 20% univariate sensitivity analysis was performed to test the robustness of the analysis.

RESULTS:

The total five-year cumulative budget impact was estimated at €30,024,968, with 91% attributed to drug acquisition costs. The largest budget impact share was for CTX001 (€25,575,150), while crizanlizumab (€2,301,095) and voxelotor (€2,148,723) was relatively small. In scenarios one and three, a two-fold increase of the cumulative budget impact to €60,731,772 and a four-fold increase to €120,846,256 from the base case was observed. In scenario three, this budget impact decreased by 63% to €11,212,766. Patient population size, number of treated patients, and drug costs influenced the analysis the most, while discontinuation, acute crisis, and adverse event rates had comparatively minimal impact.

CONCLUSIONS:

Belgian decision-makers may consider alternative financing models, such as outcome-based risk-sharing agreements or annuities, to ensure sustainable coverage of these treatments. This study adheres to recommended practices for assessing budget impact of orphan drugs, distinguishing it from earlier studies with potentially weaker methodologies.

2024-06-17·JOURNAL OF CLINICAL INVESTIGATION

Crizanlizumab for retinal vasculopathy with cerebral leukoencephalopathy in a phase II clinical study

Article

作者: Rao, P Kumar ; Apte, Rajendra S ; Ford, Andria L ; Spiegelman, Dan ; Wang, Wilson X

BackgroundRetinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare, autosomal dominant, universally fatal disease without effective treatment options. This study explores the safety and preliminary efficacy of crizanlizumab, a humanized monoclonal antibody against P-selectin approved for the prevention of sickle cell crises, in slowing retinal nonperfusion and preserving vision in patients with RVCL-S.METHODSEleven patients with RVCL-S with confirmed exonuclease 3 prime repair exonuclease 1 (TREX1) mutations received monthly crizanlizumab infusions over 2 years. The study measured the nonperfusion index within 3 retinal zones and the total retina with fluorescein angiography, visual acuity, intraocular pressure (IOP), and optical coherence tomography central subfield thickness (CST) at baseline, 1 year, and 2 years. A mixed repeated-measures analysis was performed to assess the progression rates and changes from baseline.RESULTSEleven participants received crizanlizumab infusions. All of the participants tolerated crizanlizumab well, with 8 of 11 (72.7%) reporting mild adverse effects such as nausea, fatigue, and gastrointestinal symptoms. The change in total retinal nonperfusion was 7.22% [4.47, 9.97] in year 1 and -0.69% [-4.06, 2.68] in year 2 (P < 0.001). In the mid periphery, the change in nonperfusion was 10.6% [5.1, 16.1] in year 1 and -0.68% [-3.98, 5.35] in year 2 (P < 0.01), demonstrating a reduction in progression of nonperfusion in the second year of treatment. Visual acuity, IOP, and CST remained stable.CONCLUSIONCrizanlizumab has an acceptable safety profile. These results show promising potential for examining crizanlizumab in larger studies of RVCL-S and similar small-vessel diseases and for using the retina as a biomarker for systemic disease.Trial registrationClinicalTrials.gov NCT04611880.FUNDINGThe Clayco Foundation; DeNardo Education and Research Foundation Grant; Jeffrey T. Fort Innovation Fund; Siteman Retina Research Fund; unrestricted grant from Research to Prevent Blindness Inc.; National Heart,Lung, and Blood Institute (NHLBI), NIH (R01HL129241); National Institute of Neurological Disorders and Stroke (NINDS), NIH (RF1NS116565).

2024-06-01·Antioxidants & redox signaling

Red Blood Cells as Therapeutic Target to Treat Sickle Cell Disease

Review

作者: Kundu, Suman ; Bhatt, Shruti ; Gupta, Kalpna ; Argueta, Donovan A.

Significance: Sickle cell disease (SCD) is the most common inherited diathesis affecting mostly underserved populations globally. SCD is characterized by chronic pain and fatigue, severe acute painful crises requiring hospitalization and opioids, strokes, multiorgan damage, and a shortened life span. Symptoms may appear shortly after birth, and, in less developed countries, most children with SCD die before attaining age 5. Hematopoietic stem cell transplant and gene therapy offer a curative therapeutic approach, but, due to many challenges, are limited in their availability and effectiveness for a majority of persons with SCD. A critical unmet need is to develop safe and effective novel targeted therapies. A wide array of drugs currently undergoing clinical investigation hold promise for an expanded pharmacological armamentarium against SCD. Recent Advances: Hydroxyurea, the most widely used intervention for SCD management, has improved the survival in the Western world and more recently, voxelotor (R-state-stabilizer), l-glutamine, and crizanlizumab (anti-P-selectin antibody) have been approved by the Food and Drug Administration (FDA) for use in SCD. The recent FDA approval emphasizes the need to revisit the advances in understanding the core pathophysiology of SCD to accelerate novel evidence-based strategies to treat SCD. The biomechanical breakdown of erythrocytesis, the core pathophysiology of SCD, is associated with intrinsic factors, including the composition of hemoglobin, membrane integrity, cellular volume, hydration, andoxidative stress. Critical Issues and Future Directions: In this context, this review focuses on advances in emerging nongenetic interventions directed toward the therapeutic targets intrinsic to sickle red blood cells (RBCs), which can prevent impaired rheology of RBCs to impede disease progression and reduce the sequelae of comorbidities, including pain, vasculopathy, and organ damage. In addition, given the intricate pathophysiology of the disease, it is unlikely that a single pharmacotherapeutic intervention will comprehensively ameliorate the multifaceted complications associated with SCD. However, the availability of multiple drug options affords the opportunity for individualized therapeutic regimens tailored to specific SCD-related complications. Furthermore, it opens avenues for combination drug therapy, capitalizing on distinct mechanisms of action and profiles of adverse effects.

项与 Crizanlizumab-TMCA 相关的新闻（医药）

2024-08-14

·同写意

将价格打下来：印度、基因编辑和SCD疗法

本次以“突破瓶颈打造医健产业新引擎”为主题，设一场主论坛和八场主题论坛，从前沿创新突破、临床应用拓展、工艺技术优化、商业化开发等多个全新视角推动CGT技术开发与应用，成就健康产业未来。 26岁的Saritee Sanodiya，无数天都在怀疑自己能否过上“正常”生活。成长过程中，她经常因为血红蛋白水平突然下降等问题而去医院。高烧、剧烈头痛、极度疲劳、呼吸困难，这些症状可以持续几天甚至数周。“它们突然出现，这种痛苦很难描述，无法忍受。有时你会失去活下去的想法。” 医生通过输血治疗贫血，使用止痛药来缓解病人身体的不适。症状会逐渐消退，但几个月后又卷土重来。直到2018年，Sanodiya在第一次孕检时，进行了镰状细胞病（SCD）血液检测，笼罩在她身上的疑云才消散。阳性结果意味着，基因突变让她携带了非正常的红细胞。 Sanodiya从未听说过这种疾病。其实，跟她拥有相似遭遇的人恒河沙数，尤其在印度——这里是世界上SCD发病率最高的国家之一。好消息是，2023年FDA批准了两款基因疗法，能从根本上解决这种疾病。不过，一针高达上百万美元的售价，也直接宣告用得上它们的人群有限。许多中低收入国家的卫生保健系统，以及像Sanodiya这样的患者，都无法负担这些成本。目前，印度的研究人员试图开发类似的产品，并以更低的价格向国内市场提供。低价版基因疗法并不是印度在CGT领域的首次尝试。3月，Nature的一篇文章就介绍，当地一家药企ImmunoACT开发出的CAR-T疗法，单次治疗费用仅3-4万美元，几乎只有美国同类产品的十分之一。一系列因素促成了上述结果，例如，印度有特殊的专利保护法律、仿制药开发经验。可这种成功会不会在SCD基因疗法上得到复制，仍是一个未知数。 1 性命攸关 The Lancet Haematology介绍，作为一个多世纪以前科学文献中记录的首种单基因疾病，SCD仍然是一种发病率和死亡率很高的疾病。根据相关量化研究，科学家估计，全球每年有超过30万名婴儿在出生时患有纯合子型SCD，预计到2050年，患者规模将增加到40万以上。正常情况下，人的红细胞就像一个双凹圆盘，形态可变。但基因突变后，红细胞呈镰刀状，僵硬而粘稠，容易堵塞血管。与寿命约为120天的正常红细胞不同，这些镰状细胞只能存活10-20天。彩色显微镜图像显示镰状细胞（上）和镰状细胞性贫血患者的正常红细胞当血液循环中的血细胞减少，就会出现贫血。同时，肝脏的血液过滤能力难以应付大量死亡的镰状细胞，分解副产物——胆红素——便开始积聚，从而又导致黄疸。所以，这些非正常的红细胞让人产生衰弱性疼痛，并对大脑、肝脏、肾脏、心脏、肺和关节等器官造成渐进性损害。 Sanodiya确诊以来，除了怀孕那几个月，她每天都在服用羟基脲。这是一种应对SCD最常用的药片，有助于保持红细胞形状和柔韧性，减少血液中镰状细胞数量。理论上，每日使用羟基脲可以减少疼痛发作，并最大限度地减少输血和医院就诊的需要。不过，正如波士顿儿童医院和哈佛医学院的Vijay Sankaran指出的，“并不是每个患者都有相同的反应”。例如，Sanodiya就一直饱受折磨。今年4月，她的眼睛明显发黄，一叠的医疗记录显示，因为SCD不知跑了多少次医院，做了数不尽的胸部X光和血液检查。尽管医生们谨慎地尝试增加Sanodiya的羟基脲剂量，对于患有严重SCD的人，骨髓移植才是一种有效的治愈方法——在FDA批准两款基因疗法之前，这某种程度是唯一的希望。该手术涉及用匹配捐赠者（通常是兄弟姐妹）的健康细胞替换患者骨髓中的异常干细胞。印度赖布尔巴尔科医疗中心血液学家Dibyendu De表示，想要找到匹配的捐赠者非常困难。此外，如果没有经济援助或政府补贴，大多数人都无法负担手术治疗费用。 Sanodiya面临的情况正是如此。因为在私立医院接受紧急护理，她的家庭眼下负债累累。欧美市场的基因疗法成本高昂，客观上，却给印度的SCD患者提供另一种看得到的可能。“我们距离目标还很远，但事情正在朝着正确的方向发展。”Debojyoti Chakraborty是德里基因组学和综合生物学研究所的分子生物学家，正领导着一个开发SCD基因疗法的团队。他相信，这个目标在印度也可以实现，毕竟至少从机制上，海外同行已成功走了一遍。 2 基因疗法多年来，研究人员一直在寻找治疗SCD和β-地中海贫血——另一种遗传性血液疾病——的更优方案，以提高胎儿血红蛋白（HbF）水平。 HbF在出生时很高，并随着儿童长大而降低，被成人血红蛋白在很大程度上取代。不过，SCD患者的骨髓通常会产生一种异常形式的血红蛋白。增加HbF的数量，有助于阻止这种镰状血红蛋白的聚合，从而减轻疾病症状并延长寿命。 2008年，Sankaran及其同事取得了突破。他们发现，沉默一种名为BCL11A的基因，可以刺激成体细胞产生HbF。“这是一个重要的里程碑。”Sankaran评价说。为了安全地靶向BCL11A治疗SCD，该团队确定了基因中对BCL11A表达至关重要的区域，特别是在红细胞中。他们使用CRISPR基因编辑工具在这个区域进行切割并破坏DNA序列，降低BCL11A的表达，增强HbF的产生。波士顿儿童医院和哈佛医学院的医生兼干细胞生物学家Stuart Orkin表示，这是一种迂回的方法，但它确实带来了首批上市的SCD基因疗法。这种疗法名为Casgevy，由CRISPR Therapeutics和Vertex Pharmaceuticals开发。它需要从骨髓中取出造血干细胞，在BCL11A基因的精确位置切割两条DNA链，然后将这些编辑过的细胞输入患者体内。数据显示，Casgevy能将成人红细胞中的HbF水平提高到约30-40%。临床试验接受治疗的30人中，有29人在至少12个月内没有出现严重症状，并且没有人需要住院治疗。患者的长期状况如何还有待观察。但Sankaran说，这种疗法并不温和，患者必须接受彻底的化疗以清除原生干细胞，为编辑过的干细胞腾出空间。该过程可能导致不孕，患者患血癌的风险不大却会增加。上述担忧，也适用于另一种获批的SCD基因疗法，Lyfgenia。它由Bluebird Bio开发，将产生健康血红蛋白的正确基因传递给患者的造血干细胞。这个过程在实验室中进行，然后将经过修改的细胞送回患者体内。临床结果显示，在接受Lyfgenia治疗的33名SCD患者中，有32名在治疗后6至18个月内没有经历严重不良事件。从2023年到2024年，中东的巴林、沙特阿拉伯，以及美国、英国、欧盟等地的监管机构批准了至少一种此类疗法，用于治疗12岁及以上患有严重SCD的患者。但它们价格昂贵，生产制造的时间长。治疗过程可能长达一年。 “到2025年，如果我们能在美国使用基因疗法治愈20-50名SCD患者，那就算幸运了。”Akshay Sharma表示。他是圣犹达儿童研究医院的儿科血液学家，负责过包括Casgevy在内的SCD治疗临床试验。针对血红蛋白疾病的基因疗法目前获批的基因疗法，似乎也不太可能惠及中低收入国家的患者，虽然后者才是这种疾病的主要人群。 “这些公司对在非洲、印度或巴西进行试验不感兴趣，”Sharma解释道，“它们无法在那里收取200万至300万美元的费用；它们无法从中获利，所以不想这么做。” 将基因疗法引入这些地区，必须由这些地区的科学家自己来完成。背后不仅仅是成本问题。“如果我们不从头了解它们（基因疗法）如何与不同人群的细胞生物学和遗传学相互作用，我们就会浪费时间，以为我们开发出了一种万能药。”第三方组织全球基因治疗倡议的联合创始人Jennifer Adair说。 3 不再忽视 SCD所涉及的突变，原本是为了帮助疟疾高发地区的人类抵御感染。科学家已证明，镰状细胞不利于导致疟疾的寄生虫生长。但同时，它也引起SCD的肆虐。世界上超过一半的SCD患者生活在三个国家——尼日利亚、刚果民主共和国、印度。与世界上许多其他地区一样，几十年来，这种疾病在印度一直被忽视。印度SCD专家Dipty Jain表示，医护人员缺乏意识，意味着患者可能多年得不到诊断或被误诊，难以衡量这种疾病的真正负担。一些估计表明，可能有超过100万印度人受到影响，很大一部分来自部落社区，以及其他历史上处于弱势地位的群体。造成这种现象的原因，也许是在某些群体居住的地区疟疾肆虐，继而携带突变基因。此外，印度有着同族或同种姓通婚的古老习俗，为突变携带者生下患有SCD的孩子创造了更大概率。不过，Jain表示，SCD并不只发生在部落或其他边缘群体。伦敦帝国理工学院研究SCD健康负担的流行病学家Frédéric Piel称，全球卫生界一直对印度SCD有误解，认为它的主要症状较轻。但实际上，印度中部许多患者都出现了严重症状。印度科学家花了很长时间，才改变了这种看法。需要指出，在实际情况中，一些医生对这种疾病仍然缺乏足够重视。印度非营利性镰状细胞组织全国联盟秘书Gautam Dongre介绍，SCD患者经常因反复发作的疼痛而到医疗中心就诊，医生和护士可能会尽量减轻他们的痛苦，而不是优先为他们提供紧急护理。让这种疾病更加不为人知的是，它迫使人们退出社会。对于Jitendra Kumar Sahu，尽管他想学习，但辍学是他唯一的选择。因为SCD，Sahu每年几乎只能上学几个月。他很少参加体育或其他需要体力的课外活动，而且这种疾病对他的髋关节损害非常严重，以至于这个21岁的年轻人，在今年4月进行了髋关节置换手术。 “我感到很难过。”Sahu说，由于他可能无法工作，常常看不到未来的希望。他也担心家人正遭受的经济困难，医疗费用让他们负债累累。 SCD还带有社会耻辱感。许多年轻人的父母，尤其是女性会担心，患有SCD的孩子可能很难结婚。这种恐惧可能导致一些家庭不愿透露病情，或避免谈论患有这种症状的生活会是怎样。其他情况下，耻辱感来自于公众的误解，即认为SCD只发生在社会弱势群体中。Dongre形容，如果不是这个群体的人被诊断出患有SCD，“他们会感到尴尬、害怕，要么不承认，要么不寻求治疗”。精神健康负担是一个持续的挑战。应对终身疾病的挣扎、缺乏社会和医疗环境的支持以及经济困境，都可能导致人们感到沮丧、焦虑和抑郁。Dongre说，他的两位SCD患者同事最近自杀身亡。 2023年7月，印度政府启动了一项计划，旨在遏制SCD向下一代传播，并在2047年前基本消除该病的流行。计划的目标之一是提高社会的认识，并在2026年前对SCD流行的国内17个州多达7000万人进行筛查。在溶解度测试中，镰状细胞的存在会使制备溶液变得浑浊印度有超过100万的社区卫生工作者，全部由女性组成，这个团体被称为ASHA（印地语，意为“希望”）。她们是传播SCD意识和实现筛查目标的关键，尤其在印度农村地区。 Jain担任了国家镰状细胞消除任务的负责人，他表示，婚前或产前筛查将是关键。印度政府希望提供随时可用的遗传咨询服务，帮助新婚夫妇或父母了解他们基因的兼容性，以及遗传SCD的几率。另一个目标，是确保患者能够享受到优质的护理，包括羟基脲和输血等。虽然它们并不治本，但对许多人来说，获得这些疗法并不容易。作为计划的一部分，政府将在17个州内确定并升级一些三级医疗中心，以便为符合条件的患者提供骨髓移植服务。有的官员将视线转移到更有效的解决方案上：在印度，开发SCD基因疗法。 4 针对突变今年4月，25名SCD患者与家人聚集在印度杜尔格的一家医院。与他们会面的，除了Chakraborty之外，还有同样来自德里基因组学和综合生物学研究所的化学家Souvik Maiti。 Chakraborty和Maiti是印度CRISPR基因编辑疗法项目的共同负责人，如果一切顺利，他们计划在2025年开始一项人体临床试验，并从杜尔格所在的恰蒂斯加尔邦招募3到5人参与I期临床。不同于旨在提高HbF水平的Casgevy，也不像诱导产生具有健康血红蛋白的红细胞的Lyfgenia那样，印度团队的目标疗法，是直接纠正导致SCD的突变。由于这是单一突变，“如果你纠正了它，你就会把SCD患者变成携带者”。换言之，接受治疗后的患者，将不用忍受SCD的各种严重症状。对于CRISPR编辑工具，印度团队选择了一种经过改造的蛋白酶FnCas9，而不是业界更常用的SpCas9。在2019年的一项研究中，研究人员报告称，FnCas9能以极高的特异性与需要编辑的DNA区域结合。但未经改造的FnCas9效率不佳，因此该团队进行加工，以保留其特异性并提高效率。作为概念验证，他们在实验室中借助这种工程化蛋白酶，纠正了人类细胞中一种罕见遗传性眼病的突变。研究人员还使用基于FnCas9的工程化疗法纠正小鼠SCD的突变。不过，这些结果尚公开未发表。该团队已在美国获得FnCas9的专利。Chakraborty表示：“专利让我们可以对外授权CRISPR系统。”他认为，这可能会激励印度Biotech有朝一日将相关疗法推向市场。这种印度本土化改造的基因疗法售价拟定在6万美元左右，一个比现有的竞品要低得多的数字。但不得不说，许多患者仍然负担不起。Chakraborty寄希望于政府资助，以覆盖大部分剩下的费用。与其他基因疗法类似之处是，临床医生需要首先将干细胞从患者的骨髓提取到血液中，然后收集这些细胞给到研究人员进行编辑，同时患者接受化疗以杀死剩余的骨髓干细胞。在杜尔格举行的见面会上，Chakraborty向患者介绍了接受Casgevy或Lyfgenia治疗后的获益，以及可能由于化疗引起的生育问题。这些基因疗法是新疗法，因此很难知道患者是否持续感觉良好，以及是否完全治愈。 Chakraborty向患者介绍SCD基因疗法 Chakraborty提到Victoria Gray，她是2018年接受SCD基因疗法的第一位患者，该疗法正是2023年获批上市的Casgevy。 5年多以来，Gray都没有出现严重的疼痛症状，也无需住院。“我没有输过血，没有出现过危急情况，也不再依赖药罐。”她回顾说。 Chakraborty和Maiti领导的团队，并不是印度唯一一个开发SCD基因疗法的团队。韦洛尔基督教医学院的科学家一直在与埃默里大学合作，测试类似于Lyfgenia的方法，通过递送正确的基因来表达健康的成人血红蛋白或HbF。这些疗法似乎可以缓解小鼠的疾病症状。此外，印度研究人员还在开发另一种基于CRISPR的基因编辑技术。埃默里大学医学院细胞和基因治疗项目主任Trent Spencer表示：“目前我们正在与印度的一些公司洽谈，还有一些公司对实际生产基因治疗产品感兴趣，但目前尚未达成最终合作。” 早前的2月，德国公司Miltenyi Biotec也宣布，将在印度设立一个细胞和基因治疗中心。这家Biotech希望通过提供实践培训、专业知识和制造技术，来帮助印度的研究人员。它还与印度转化卫生科技研究所合作开发基因疗法，重点关注癌症和SCD。 5 打下价格在美国，科学家正开展临床试验，以测试Casgevy和Lyfgenia对12岁以下儿童是否同样有效。这些研究尤为重要，因为SCD是全球5岁以下儿童死亡的第12大原因。世界各地许多专注于基因疗法的科学家，也在尝试寻找比BCL11A更好的靶点来提高HbF水平。跟Chakraborty、Maiti所做的类似，他们也在努力纠正导致SCD的潜在突变。为了使治疗更安全，研究人员尝试绕过化疗的方法。不过，任何基因疗法都很难扩大规模。 Orkin认为：“如果我们的目标是减轻疾病负担，那就真的需要开发体内基因疗法，或者是一种更好的药丸。” 体内基因治疗指的是，将编辑后的基因直接递送到指定的细胞，而不必经过取出细胞、编辑再重新放回体内的过程。在最近的一项概念验证研究中，费城儿童医院和宾夕法尼亚大学的研究人员使用脂质纳米颗粒——嵌有能识别特定细胞受体的抗体——将基因编辑工具送到小鼠的造血干细胞里。他们发现，这种“一劳永逸”的方法不需要化疗或干细胞移植，大大增加了健康血红蛋白的产生，而且血液中几乎没有形成新的镰状细胞。 “结果非常令人兴奋，不过仍处于初步阶段。”Thompson表示，这可能会使更多的患者可以使用这些疗法。当然，体内基因疗法也是极具挑战性的。现阶段，Spencer警告说：“当你从人体中取出细胞，改变基因就已经够难的了；而当细胞还在人体中，选择性地改造细胞仍然非常非常复杂。” 另一方面，Sankaran认为，过分关注SCD的基因疗法，可能会影响到开发比羟基脲更好的口服药物。小分子药物比基因疗法更具成本效益，也更容易获得。自2017年以来，FDA已批准了一种名为crizanlizumab的单抗，以及voxelotor、L-glutamine两种新的口服药物，用于治疗SCD。但就像羟基脲一样，它们无法治愈SCD，也不是全球都能轻易获得的。 “我们仍然认为，羟基脲可能是我们拥有的最有效的药物。”Sankaran说。同时，对于印度许多SCD患者，Chakraborty、Maiti等研究人员所做的工作带来了一线希望。“我们的科学家正在努力开发一种治疗方法，这对我这样的患者和后代来说是一件大事。”Sanodiya期待说。参考资料： 1.Sickle cell disease in India: The quest for a cure；C&EN's 2.镰状细胞病：易被忽视的全球健康问题急需采取行动；柳叶刀TheLancet 同写意媒体矩阵，欢迎关注↓↓↓

基因疗法细胞疗法免疫疗法临床研究

2024-07-08

·医药魔方

Science重磅！诺华、BMS皆看好的WIZ分子胶

诺华、BMS皆看好的WIZ分子胶是何背景？首先梳理一下时间线： 2023年9月14日，BMS在R&D Day上提到了其分子胶平台CELMoD的重磅管线：经基因验证的可导致胎儿血红蛋白 (HbF) 持续存在的靶点与镰状细胞性贫血患者的临床结果改善有关。BMS已经发现了临床前模型中降解HbF基因靶点，并增加HbF表达的口服分子胶药物。不过BMS并未公开相关靶点。 2023年11月2日，诺华的生物化学家Pamela Ting在美国血液学年会上介绍了大型CRBN偏向配体库筛选发现的WIZ分子胶，并验证了WIZ是一种以前未被识别的HbF阻遏蛋白。由于WIZ是一类转录因子，属于“undruggable”靶点，很难开发抑制剂/PROTAC，分子胶似乎是小分子药物的唯一选择。 2024年7月1日，BMS的SCD小分子治疗药物BMS-986470进入临床，从Phase I/II入组人数184例看，BMS对此可谓相当重视。同样的，靶点并未公开。 2024年7月5日，诺华的WIZ分子胶见刊于Science正刊，报道了首个WIZ分子胶结构dWIZ1与dWIZ2，并介绍了相关生物学机制。在人源化小鼠与NHP模型中，dWIZ-2口服给药也能有效降解WIZ，并诱导HbF的表达，且未观察到明显的不良反应。表明口服WIZ分子胶可作为作为全球可使用的镰状细胞病（SCD）/地中海贫血症的治疗方法。目前诺华的WIZ分子胶处于IND-Enabling阶段，落后于BMS。 WIZ分子胶专利分析当然我们已经可以通过专利分析知道，BMS的BMS-986470也是一个WIZ分子胶。那么，诺华与BMS的专利是什么样的呢？专利申请信息与相关代表性结构与活性数据如下。可以很明显的发现文章中的dWIZ-1与dWIZ-2均来自WO2021124172A1专利中的I-5与I-50。从专利申请时间上看，可见诺华对WIZ分子胶早有布局，首篇专利优先权日是2019年底，公开于2021年中，可见其功底深厚。相比之下，BMS的专利则是申请于诺华专利公开后，近期才公开。虽然两者的分子结构差异较大，但不免给人一种BMS借鉴了诺华立项的嫌疑。不过奇怪的是，dWIZ-2在文章中与专利中的数据有较大出入（多半是写错了）。但至少可以确认的一点是，该专利的化合物无论是成药性还是生物学活性在诺华所有专利中并非最优。此外，dWIZ-2的选择性也存在问题。根据专利WO2022254362A1的数据显示，dWIZ-2存在一定的SALL4降解活性（这里的dWIZ-2数据与文章较吻合）。根据诺华四篇专利的SA分析大致能够推断，WO2022195454A1中的Ex.141很可能便是诺华想要推向临床的PCC分子。至于BMS的专利，公开信息较少，且各实施例相似度较高，不好做推测，姑且猜测是Ex.10。至于两者实际结构、临床前活性与安全性数据，只能等待后续进一步的公开了。顺带说一句，国内格博生物也有WIZ分子胶管线，专利未公开，期待其研究成果。 WIZ分子胶开发价值与优势 WIZ分子胶用于治疗SCD其实并非首例。早在2007年，便有泊马度胺治疗SCD的临床前概念验证研究。 2011年Blood的文章表明泊马度胺在转基因镰状细胞小鼠中增加胎儿血红蛋白的产生，而没有羟基脲的骨髓抑制作用，进一步验证了这一点。而到了2012年，尚未被BMS收购的Celgene兴致勃勃的开展了泊马度胺治疗SCD的临床试验研究，但却以失败告终。究其原因也可以从诺华这篇Science文章中窥见一些端倪：泊马度胺能够诱导HbF表达的同时，存在促进成红细胞的增殖和分化的活性，这对SCD治疗不利。而WIZ分子胶却没有这一缺陷。猜测泊马度胺的HbF诱导活性便来自于其存在一定的WIZ降解活性。由于WIZ在多种组织中表达，其降解的安全性还需要进一步评估，以便将其应用于临床试验。不过既然BMS已经将其推向临床且相当重视，相信其安全性有一定保证。当然这个项目好坏自然要从SCD的流行病学、市场空间与即有疗法谈起。首先聊聊流行病学： SCD仍然是一个深刻的、全球未满足的医疗需求。目前，SCD影响全世界740万人，并且估计患病率在增加，每年有超过50万儿童出生时患有SCD。尽管在SCD患者的护理方面取得了有意义的进展，并且对病理生物学有了详细的了解，但是疾病的总死亡率也在增加，仅2021年估计有37.6万名患者死于SCD。那么，全球各地区的发病情况又是如何？从地图上看，欧亚大部分国家的SCD发病率为0。很明显，SCD发病率最严重的国家主要位于非洲，不过很明显这些患者支付能力不足。其次是西欧和美洲（从遗传学上分析，很明显是当年的黑奴贸易导致的）。单论全球最大的药物市场美国，约有10万名SCD患者，并且新生儿中约有110万人是HbAS基因携带者。从MNC对SCD治疗药物的积极布局上看，SCD的市场情况比较积极。目前SCD最有效的口服疗法是羟基脲（HU），但由于骨髓抑制和需要密切的实验室监测（会引起严重的毒副反应，有一定的致癌风险），HU的广泛使用受到限制。诺华的crizanlizumab（2023销售额1.95亿美元）用于预防镰状细胞贫血症（SCD）患者的血管阻塞危机（VOC）；而辉瑞的voxelotor（2023销售额3.28亿美元）是一种每日一次的口服疗法，通过增加血红蛋白对氧的亲和力来发挥治疗SCD的作用。但这些均为间接治疗药物。新兴的基于基因工程（通过基因编辑或RNAi技术敲除靶基因）的SCD疗法已有药物获批，并有多个处于临床试验阶段。该方法通过自体造血干细胞和祖细胞(HSPCs)的清髓性移植，通过基因修饰破坏HBG1/2的阻遏物。抛开干细胞疗法高昂的治疗费用不谈（两款基因编辑药物定价分别为157.5万美元与220万美元），其复杂性和临床实施可能会限制其可及性和影响，特别是在SCD负担最大的亚非拉国家。因此，安全、有效、全球可获得的HbF诱导药物仍然是一个重要的未满足的需求。诺华Science文章表明，与基因敲除BCL11A相比，基因敲除WIZ的细胞表现出相当的HbF诱导水平，并且WIZ降解诱导了比HU更多的HbF。表明通过WIZ敲除策略能够取得与BCL11A敲除相当的疗效。而作为一种化学敲除策略，WIZ分子胶在口服生物利用度、系统性分布、可扩展改造、可逆性等方面具有优势。当然，其最大的优势便是作为小分子的成本与患者依从性，这能极大的拓展市场渗透率，有望解决全球未满足的临床需求。那么，一旦WIZ分子胶完成了临床概念验证，相信其市场前景是巨大的。最后再升华一下，既然广大的亚非拉国家深陷于SCD的水深火热，基于国内的一带一路战略，开发国有的低成本、自有知识产权的WIZ分子胶药物，拯救亚非拉人民，迫在眉睫！分子胶的理性设计此前的文章（分子胶的理性设计(3)：Monte Rosa教你如何“调教”CRBN）介绍了Monte Rosa总结的分子胶理性设计四步走策略。挖掘CRBN既有底物便是首步策略。Monte Rosa发文总结了一些CRBN固有底物（红色为已开发靶点），WIZ赫然在列。表明CRBN与WIZ本来便存在一定的弱PPI，而WIZ分子胶则是稳定这一PPI（泊马度胺的HbF诱导活性可能便来自于其存在一定的WIZ降解活性）。当然，新靶点分子胶的发现离不开基于大型CRBN配体库，针对适应症的表型筛选策略，monte Rosa如此，诺华也是如此（WIZ分子胶的发现便是基于筛选2814个CRBN偏向分子的库）。至于目前全行业内如何去实现分子胶的理性设计呢？最近迫于压力制作宣传材料，想来想去还是从分子胶入手。想要从专利的角度作为切入点，整合其他渠道信息，分析一下分子胶的研究进展与产业现状。所以最近公众号断更了好久，恰逢BMS-986470上临床，与诺华的Science文章见刊，就利用存货水一篇文章吧（其实是想通过专利角度预判一波，没想到行业进展速度比我快）。嗯，做完这个发现自己两年前做的分子胶行业调研报告是真垃圾。欢迎加我微信进人在药途读者交流群讨论。添加微信请主动备注姓名、公司/学校、职位和来意。过往文章豪森的FastFollow巅峰之作：国内首个WRN专利，仅晚原研4天！ 12周减重6.2%！硕迪生物的GLP-1R 小分子激动剂 GSBR-1290长啥样？减肥新希望？从一篇新公开GPR75拮抗剂专利引发的思考胆固醇水平降低78%！阿斯利康口服PCSK9小分子AZD0780长啥样？竞争格局如何？平台为王！分子胶赛道最新交易与公司布局全解析 PROTAC希望之光：Kymera口服STAT6 PROTAC KT-621临床前数据公开 3.45亿美元，嘉越医药Pan-RAS分子胶长啥样？ Nature:多价策略制胜!礼来全球首个Lp(a)小分子设计思路深度剖析分子胶的理性设计(3)：Monte Rosa教你如何“调教”CRBN 口服PCSK9小分子AZD0780：MK0616遭逢劲敌，阿斯利康胜算几何？一天两篇Nature正刊！WRN大放异彩：HRO761与VVD-214 研发前沿|吸金2.31亿美元：AKT-1 E17K，肿瘤精准疗法的下一个风口？ AACR24|RMC-6236结构正式公开，那些年6236的follower们 AACR24 | 首次公开CDK2抑制剂-AZD8421 研发前沿|KRAS G12D(ON)抑制剂RMC-9805结构与临床前数据公开研发随笔|百济自己有专利，为何要买昂胜的CDK2抑制剂？研发前沿|数十亿美元重磅交易——CDK2近期专利盘点（1） Metoo项目怎么做：loxo-435的设计优化思路万物皆可偶联：IgG降解剂与Biohaven的胞外蛋白降解平台研发前沿|VX-548全球首个follower：恒瑞再次展现中国速度 Pan-KRAS内卷加剧，Revolution计划年内启动三期注册性临床欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本文仅代表个人观点，不代表公司立场

蛋白降解靶向嵌合体

2024-06-14

·BioSpace

Vertex Presents Positive Long-Term Data On CASGEVY™ (exagamglogene autotemcel) at the 2024 Annual European Hematology Association (EHA) Congress

Results from CLIMB-111, -121 and -131 accepted for oral presentation Data from these trials, with the longest follow-up of more than five years, demonstrate transformative, consistent and durable benefit of CASGEVY™ Safety pro with busulfan conditioning and autologous hematopoietic stem cell transplant BOSTON--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced longer-term data for CASGEVY™ (exagamglogene autotemcel [exa-cel]) from global clinical trials in people with severe sickle cell disease (SCD) or transfusion-dependent beta thalassemia (TDT). The results, presented at the annual European Hematology Association (EHA) Congress, confirm the transformative, consistent and durable clinical benefits of CASGEVY over time. CASGEVY is the first and only approved CRISPR-based gene-editing therapy. The data being presented are from more than 100 patients (46 SCD; 56 TDT) treated with exa-cel in clinical trials, with the longest follow-up now extending more than 5 years. The efficacy results are consistent with the previously reported primary and key secondary endpoints analyses from these exa-cel studies and continue to demonstrate transformative clinical benefit with durable and stable levels of fetal hemoglobin (HbF) and allelic editing. “The transformative benefit seen in patients with sickle cell disease in the trial is impressive given the significant and cumulative burden of disease faced by people living with this blood disorder,” said Haydar Frangoul, M.D., M.S., Medical Director of Pediatric Hematology and Oncology at Sarah Cannon Research Institute and HCA Healthcare’s TriStar Centennial Children’s Hospital. “I am eager to offer this therapy and the opportunity of a potential functional cure to my eligible patients.” “The comprehensive data set presented today for adult and adolescent TDT patients adds to the growing body of evidence for CASGEVY, and it is important to now ensure the availability of this innovative treatment to patients in the real world as soon as possible,” said Franco Locatelli, M.D., Ph.D., Professor of Pediatrics at the Catholic University of the Sacred Heart of Rome, Director of the Department of Pediatric Hematology and Oncology at Bambino Gesù Children’s Hospital. “With the longest follow up now more than five years, alongside stable editing and sustained fetal hemoglobin levels, I have conviction in the durable benefit to the patients treated with CASGEVY.” New data presented from CASGEVY pivotal trials In SCD 36/39 (92.3%) evaluable patients (those with at least 16 months of follow-up) were free from vaso-occlusive crises (VOCs) for at least 12 consecutive months (VF12), consistent with the previously reported primary endpoint data. Mean duration of VOC-free was 27.9 months, with a maximum of 54.8 months. 38/39 (97.4%) patients with at least 16 months of follow-up were free from hospitalizations related to VOCs for at least 12 consecutive months (HF12), consistent with the previously reported key secondary endpoint data. In TDT 49/52 (94.2%) evaluable patients (those with at least 16 months of follow-up) were transfusion-independent for at least 12 consecutive months with a mean weighted hemoglobin of at least 9 g/dL (TI12), consistent with the previously reported primary endpoint data. Mean duration of transfusion independence was 31.0 months, with a maximum of 59.4 months. All TDT patients dosed with at least 16 months of follow up are transfusion free. Two of the three patients who did not achieve TI12 in CLIMB-111 achieved TI12 in the long-term follow-up study, CLIMB-131, and have been transfusion independent for over one year. The third has been transfusion free for 3.4 months. Both SCD and TDT patients reported sustained and clinically meaningful improvements in their quality of life, including physical, emotional, social/family and functional well-being, and overall health status. In both SCD and TDT patients, edited levels of BCL11A alleles were stable over time in bone marrow and peripheral blood indicating successful editing in the long-term hematopoietic stem cells. All patients engrafted neutrophils and platelets after exa-cel infusion. The safety pro exa-cel was generally consistent with myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplant. These longer-term data for CASGEVY from the CLIMB clinical trials will be shared as outlined below: Abstracts S273 and S274 will be oral presentations entitled “Exagamglogene Autotemcel For Severe Sickle Cell Disease,” and “Exagamglogene Autotemcel For Transfusion-Dependent Beta-Thalassemia,” on Sunday, June 16 at 12:15 CEST and 12:30 CEST, respectively. Abstracts P1493 and P1525 will be poster presentations entitled “Health-Related Quality Of Life Improvements After Exagamglogene Autotemcel In Patients With Severe Sickle Cell Disease,” and “Health-Related Quality Of Life Improvements After Exagamglogene Autotemcel In Patients With Transfusion-Dependent Βeta-Thalassemia,” on Friday, June 14 at 18:00 CEST. These presentations will include updated pivotal trial data from patients treated with CASGEVY in CLIMB-111 and CLIMB-121 and followed in CLIMB-131. Vertex will also share five health economics abstracts at the EHA Congress. Abstract P1483 is entitled “Adherence, Treatment Use, and Clinical Outcomes in Patients With Sickle Cell Disease With Recurrent Vaso-Occlusive Crises Treated With L-Glutamine, Voxelotor, or Crizanlizumab in the United States.” Abstract P1506 is entitled “Mortality and Clinical Complications Among Patients with Sickle Cell Disease With Recurrent VOCs in Canada.” Abstract P1507 is entitled “Treatment Utilization and Clinical Complications in Patients with Sickle Cell Disease Receiving Frequent Red Blood Cell Transfusions in the United States.” Abstract P2191 is entitled “Clinical Complications and Treatment Use Among Patients With Sickle Cell Disease With Recurrent Vaso-Occlusive Crises in the Netherlands.” Abstract PB3248 is entitled “Clinical Complications Among Patients With Transfusion-Dependent Beta-Thalassemia in the Netherlands.” About Sickle Cell Disease (SCD) SCD is a debilitating, progressive, life shortening genetic disease. SCD patients report health-related quality of life scores well below the general population and significant health care resource utilization. SCD affects the red blood cells, which are essential for carrying oxygen to all organs and tissues of the body. SCD causes severe pain, organ damage and shortened life span due to misshapen or “sickled” red blood cells. The clinical hallmark of SCD is vaso-occlusive crises (VOCs), which are caused by blockages of blood vessels by sickled red blood cells and result in severe and debilitating pain that can happen anywhere in the body at any time. SCD requires lifelong treatment and significant use of health care resources, and ultimately results in reduced life expectancy, decreased quality of life and reduced lifetime earnings and productivity. In Europe, the mean age of death for patients living with SCD is around 40 years. Stem cell transplant from a matched donor is a potentially curative option but is only available to a small fraction of people living with SCD because of the lack of available donors. About Transfusion-Dependent Beta Thalassemia (TDT) TDT is a serious, life-threatening genetic disease. TDT patients report health-related quality of life scores below the general population and significant health care resource utilization. TDT requires frequent blood transfusions and iron chelation therapy throughout a person’s life. Due to anemia, patients living with TDT may experience fatigue and shortness of breath, and infants may develop failure to thrive, jaundice and feeding problems. Complications of TDT can also include an enlarged spleen, liver and/or heart, misshapen bones and delayed puberty. TDT requires lifelong treatment and significant use of health care resources, and ultimately results in reduced life expectancy, decreased quality of life and reduced lifetime earnings and productivity. In Europe, the mean age of death for patients living with TDT is 50-55 years. Stem cell transplant from a matched donor is a potentially curative option but is only available to a small fraction of people living with TDT because of the lack of available donors. About CASGEVY™ (exagamglogene autotemcel [exa-cel]) CASGEVY™ is a non-viral, ex vivo CRISPR/Cas9 gene-edited cell therapy for eligible patients with SCD or TDT, in which a patient’s own hematopoietic stem and progenitor cells are edited at the erythroid specific enhancer region of the BCL11A gene through a precise double-strand break. This edit results in the production of high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth. CASGEVY has been shown to reduce or eliminate VOCs for patients with SCD and transfusion requirements for patients with TDT. CASGEVY is approved for certain indications in multiple jurisdictions for eligible patients. About the CLIMB Studies The ongoing Phase 1/2/3 open-label trials, CLIMB-111 and CLIMB-121, are designed to assess the safety and efficacy of a single dose of CASGEVY in patients ages 12 to 35 years with TDT or with SCD, characterized by recurrent VOCs, respectively. The trials are now closed for enrollment. Patients will be followed for approximately two years after CASGEVY infusion. Each patient will be asked to participate in the ongoing long-term, open-label trial, CLIMB-131. CLIMB-131 is designed to evaluate the safety and efficacy of CASGEVY in patients who received CASGEVY in other CLIMB studies. The trial is designed to follow patients for up to 15 years after CASGEVY infusion. U.S. INDICATIONS AND IMPORTANT SAFETY INFORMATION FOR CASGEVY (exagamglogene autotemcel) WHAT IS CASGEVY? CASGEVY is a one-time therapy used to treat people aged 12 years and older with: sickle cell disease (SCD) who have frequent vaso-occlusive crises or VOCs beta thalassemia (β-thalassemia) who need regular blood transfusions CASGEVY is made specifically for each patient, using the patient’s own edited blood stem cells, and increases the production of a special type of hemoglobin called hemoglobin F (fetal hemoglobin or HbF). Having more HbF increases overall hemoglobin levels and has been shown to improve the production and function of red blood cells. This can eliminate VOCs in people with sickle cell disease and eliminate the need for regular blood transfusions in people with beta thalassemia. IMPORTANT SAFETY INFORMATION What is the most important information I should know about CASGEVY? After treatment with CASGEVY, you will have fewer blood cells for a while until CASGEVY takes hold (engrafts) into your bone marrow. This includes low levels of platelets (cells that usually help the blood to clot) and white blood cells (cells that usually fight infections). Your doctor will monitor this and give you treatment as required. The doctor will tell you when blood cell levels return to safe levels. Tell your healthcare provider right away if you experience any of the following, which could be signs of low levels of platelet cells: severe headache abnormal bruising prolonged bleeding bleeding without injury such as nosebleeds; bleeding from gums; blood in your urine, stool, or vomit; or coughing up blood Tell your healthcare provider right away if you experience any of the following, which could be signs of low levels of white blood cells: fever chills infections You may experience side effects associated with other medicines administered as part of the treatment regimen for CASGEVY. Talk to your physician regarding those possible side effects. Your healthcare provider may give you other medicines to treat your side effects. How will I receive CASGEVY? Your healthcare provider will give you other medicines, including a conditioning medicine, as part of your treatment with CASGEVY. It’s important to talk to your healthcare provider about the risks and benefits of all medicines involved in your treatment. After receiving the conditioning medicine, it may not be possible for you to become pregnant or father a child. You should discuss options for fertility preservation with your healthcare provider before treatment. STEP 1: Before CASGEVY treatment, a doctor will give you mobilization medicine(s). This medicine moves blood stem cells from your bone marrow into the blood stream. The blood stem cells are then collected in a machine that separates the different blood cells (this is called apheresis). This entire process may happen more than once. Each time, it can take up to one week. During this step rescue cells are also collected and stored at the hospital. These are your existing blood stem cells and are kept untreated just in case there is a problem in the treatment process. If CASGEVY cannot be given after the conditioning medicine, or if the modified blood stem cells do not take hold (engraft) in the body, these rescue cells will be given back to you. If you are given rescue cells, you will not have any treatment benefit from CASGEVY. STEP 2: After they are collected, your blood stem cells will be sent to the manufacturing site where they are used to make CASGEVY. It may take up to 6 months from the time your cells are collected to manufacture and test CASGEVY before it is sent back to your healthcare provider. STEP 3: Shortly before your stem cell transplant, your healthcare provider will give you a conditioning medicine for a few days in hospital. This will prepare you for treatment by clearing cells from the bone marrow, so they can be replaced with the modified cells in CASGEVY. After you are given this medicine, your blood cell levels will fall to very low levels. You will stay in the hospital for this step and remain in the hospital until after the infusion with CASGEVY. STEP 4: One or more vials of CASGEVY will be given into a vein (intravenous infusion) over a short period of time. After the CASGEVY infusion, you will stay in hospital so that your healthcare provider can closely monitor your recovery. This can take 4-6 weeks, but times can vary. Your healthcare provider will decide when you can go home. What should I avoid after receiving CASGEVY? Do not donate blood, organs, tissues, or cells at any time in the future What are the possible or reasonably likely side effects of CASGEVY? The most common side effects of CASGEVY include: Low levels of platelet cells, which may reduce the ability of blood to clot and may cause bleeding Low levels of white blood cells, which may make you more susceptible to infection Your healthcare provider will test your blood to check for low levels of blood cells (including platelets and white blood cells). Tell your healthcare provider right away if you get any of the following symptoms: fever chills infections severe headache abnormal bruising prolonged bleeding bleeding without injury such as nosebleeds; bleeding from gums; blood in your urine, stool, or vomit; or coughing up blood These are not all the possible side effects of CASGEVY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of CASGEVY Talk to your healthcare provider about any health concerns. Please see full Prescribing Information including Patient Information for CASGEVY. About Vertex Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has approved medicines that treat the underlying causes of multiple chronic, life-shortening genetic diseases — cystic fibrosis, sickle cell disease and transfusion-dependent beta thalassemia — and continues to advance clinical and research programs in these diseases. Vertex also has a robust clinical pipeline of investigational therapies across a range of modalities in other serious diseases where it has deep insight into causal human biology, including acute and neuropathic pain, APOL1-mediated kidney disease, IgA nephropathy, autosomal dominant polycystic kidney disease, type 1 diabetes, myotonic dystrophy type 1 and alpha-1 antitrypsin deficiency. Vertex was founded in 1989 and has its global headquarters in Boston, with international headquarters in London. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia, Latin America and the Middle East. Vertex is consistently recognized as one of the industry's top places to work, including 14 consecutive years on Science magazine's Top Employers list and one of Fortune’s 100 Best Companies to Work For. For company updates and to learn more about Vertex's history of innovation, visit or follow us on LinkedIn, YouTube and Twitter/X. (VRTX-GEN) Vertex Special Note Regarding Forward-Looking Statements This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, the statements by Haydar Frangoul, M.D., M.S., and Franco Locatelli, M.D., Ph.D., in this press release, and statements regarding our expectations for and the anticipated benefits of CASGEVY, our plans to share longer-term data for CASGEVY from the CLIMB clinical trials and to share health economics abstracts at the EHA Congress, and our plans for and design of the CLIMB studies. While we believe the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that data from the company's development programs may not support registration or further development of its compounds due to safety, efficacy, and other reasons, and other risks listed under the heading “Risk Factors” in Vertex's most recent annual report and subsequent quarterly reports filed with the Securities and Exchange Commission at and available through the company's website at . You should not place undue reliance on these statements, or the scientific data presented. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available. View source version on businesswire.com: Contacts Vertex Pharmaceuticals Incorporated Investors: InvestorInfo@vrtx.com Media: mediainfo@vrtx.com or International: +44 20 3204 5275 or U.S.: 617-341-6992 or Heather Nichols: +1 617-839-3607 Source: Vertex Pharmaceuticals Incorporated View this news release online at:

临床结果细胞疗法上市批准临床研究

100 项与 Crizanlizumab-TMCA 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	Crizanlizumab-TMCA	B06AX01	DB15271

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
镰状细胞血症	美国	Novartis Pharmaceuticals Corp.	2019-11-15
血管闭塞危机	美国	Novartis Pharmaceuticals Corp.	2019-11-15

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
新型冠状病毒感染	临床2期	美国	Novartis AG	2020-07-09
慢性肾病	临床2期	美国	Novartis Pharmaceuticals Corp.	2019-12-10
慢性肾病	临床2期	巴西	Novartis Pharmaceuticals Corp.	2019-12-10
慢性肾病	临床2期	法国	Novartis Pharmaceuticals Corp.	2019-12-10
慢性肾病	临床2期	希腊	Novartis Pharmaceuticals Corp.	2019-12-10
慢性肾病	临床2期	爱尔兰	Novartis Pharmaceuticals Corp.	2019-12-10
慢性肾病	临床2期	黎巴嫩	Novartis Pharmaceuticals Corp.	2019-12-10
慢性肾病	临床2期	荷兰	Novartis Pharmaceuticals Corp.	2019-12-10
慢性肾病	临床2期	巴拿马	Novartis Pharmaceuticals Corp.	2019-12-10
慢性肾病	临床2期	西班牙	Novartis Pharmaceuticals Corp.	2019-12-10

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临床结果

适应症

分期

评价

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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


NCT03264989 (CTgov)	临床2期	血管闭塞危机 \| 镰状细胞血症	57	Crizanlizumab (Crizanlizumab 5.0 mg/kg)	製鏇願蓋夢繭顧積積獵(醖衊鏇製襯壓鏇襯製網) = 鏇醖艱窪製觸範壓築鑰夢鹹壓淵遞獵憲繭範淵 (淵選鏇鹹壓構簾鹹醖壓, 廠積網鏇襯構夢鏇鏇製 ~ 鹹鹽鏇構築構廠夢壓製) 更多	-	2024-04-23
				Crizanlizumab (Crizanlizumab 7.5 mg/kg)	繭遞遞構憲願衊願構廠(窪醖艱窪鬱齋鏇艱顧鑰) = 膚積蓋鏇鬱遞夢構廠製鬱憲鬱遞淵鏇衊餘餘艱 (獵鏇鹽願網衊鹹繭糧觸, 構壓蓋窪築簾簾鹽簾積 ~ 鏇積醖襯醖膚廠積餘艱) 更多
NCT03814746 (STAND, CTgov)	临床3期	血管闭塞危机 \| 镰状细胞血症	253	Crizanlizumab (SEG101) (Crizanlizumab (SEG101) at 5.0 mg/kg)	壓鹹淵糧範襯窪淵鏇選(網窪醖窪襯餘餘觸齋構) = 顧選範糧遞構選窪遞築壓膚範襯網壓醖壓觸繭 (構範餘廠糧獵醖憲糧壓, 餘鬱壓鏇獵齋鹽鏇壓網 ~ 蓋艱淵遞選顧遞餘膚蓋) 更多	-	2024-01-08
				Crizanlizumab (SEG101) (Crizanlizumab (SEG101) at 7.5 mg/kg)	壓鹹淵糧範襯窪淵鏇選(網窪醖窪襯餘餘觸齋構) = 夢憲糧築獵夢廠鬱製選壓膚範襯網壓醖壓觸繭 (構範餘廠糧獵醖憲糧壓, 構網鬱艱夢憲壓製壓窪 ~ 簾製鏇遞廠觸衊鬱淵衊) 更多
NCT03474965 (SOLACE-KIDS, EHA2023)	临床2期	镰状细胞血症	50	Crizanlizumab 5 mg/kg	淵製鹽淵膚鬱廠鬱顧壓(獵窪觸顧夢鏇淵襯憲蓋) = 鏇構構廠積膚醖夢選襯鏇鹹鹹願夢衊餘壓選獵 (網淵鏇廠淵糧繭積襯鹽 ) 更多	-	2023-06-08
NCT03264989 (Pubmed) 人工标引	临床2期	镰状细胞血症	57	crizanlizumab (5.0 mg/kg)	鹹憲齋衊鬱糧窪選廠願(廠鹽鏇鑰齋築鑰襯獵鹽) = 窪壓鏇簾淵壓鏇壓遞壓鏇鬱膚襯簾廠遞艱製積 (積觸顧構夢積襯築繭構 ) 更多	积极	2022-11-10
				crizanlizumab (7.5 mg/kg)	鹹憲齋衊鬱糧窪選廠願(廠鹽鏇鑰齋築鑰襯獵鹽) = 鬱願繭艱糧憲範鹹壓衊鏇鬱膚襯簾廠遞艱製積 (積觸顧構夢積襯築繭構 ) 更多
NCT03720626 (CSEG101A2001M, EHA2022)	N/A	血管闭塞危机 \| 镰状细胞血症	188	Crizanlizumab	積願壓構餘鹹鹽艱窪艱(遞獵獵觸壓壓願繭壓夢) = 選膚選夢餘膚餘積觸廠醖願鏇製顧餘遞齋選鹹 (鑰遞衊齋鹹夢範壓膚選 )	-	2022-05-12
NCT04435184 (CRITICAL, Pubmed \| JACC Basic Transl Sci)	临床2期	新型冠状病毒感染	54	Crizanlizumab	範餘壓獵鏇製壓鹽糧憲(襯獵積壓餘遞艱繭淵鬱) = 遞鏇顧範範廠範鬱築鑰鬱製製製構餘鬱簾壓窪 (淵鹹範繭積壓鬱齋餘顧 )	-	2021-12-08
				Placebo	衊鏇簾廠夢繭構遞製鑰(願積糧醖艱鹹觸積糧鑰) = 齋鹽淵範醖繭壓簾遞鏇鏇鹽觸鬱構製膚鏇蓋繭 (鏇築艱淵醖艱淵構廠觸 )
NCT04435184 (CRITICAL, CTgov)	临床2期	新型冠状病毒感染	54	Crizanlizumab (Crizanlizumab)	襯繭鑰蓋鏇襯憲獵廠襯(艱觸遞窪築鹽遞蓋窪壓) = 憲積鏇壓餘製鹽壓顧遞鏇窪鏇鏇鏇願遞齋鹹構 (選築構築網膚製觸膚衊, 膚簾願觸齋糧範餘遞觸 ~ 憲願構築繭壓範鏇願餘) 更多	-	2021-11-09
				0.9% saline (Placebo Saline)	襯繭鑰蓋鏇襯憲獵廠襯(艱觸遞窪築鹽遞蓋窪壓) = 觸憲襯網窪醖選鹽選艱鏇窪鏇鏇鏇願遞齋鹹構 (選築構築網膚製觸膚衊, 選鏇鏇鏇鑰艱遞鹹蓋鹽 ~ 鬱夢淵夢夢窪糧構憲糧) 更多
NCT01895361 (SUSTAIN, CTgov)	临床2期	疼痛 \| 镰状细胞血症	198	SelG1 (High-dose SelG1 (Selg1 5.0 mg/kg))	醖夢鏇遞鏇遞廠廠鏇繭(壓窪衊廠襯構顧蓋顧繭) = 鹽艱築鏇糧醖蓋壓構鏇齋願築窪壓網艱鏇蓋窪 (廠網遞齋選觸窪衊鑰壓, 範鏇鹽築鹹壓網夢網夢 ~ 廠窪鏇壓觸鑰顧鑰淵觸) 更多	-	2020-01-31
				SelG1 (Low-dose SelG1 (Selg1 2.5 mg/kg))	醖夢鏇遞鏇遞廠廠鏇繭(壓窪衊廠襯構顧蓋顧繭) = 窪鏇願餘醖齋衊壓衊艱齋願築窪壓網艱鏇蓋窪 (廠網遞齋選觸窪衊鑰壓, 積構醖餘構憲壓廠憲夢 ~ 憲壓窪鬱齋築鏇鹽網窪) 更多
NCT01895361 (SUSTAIN, Pubmed \| Br Dent J) 人工标引	临床2期	疼痛 \| 镰状细胞血症	198	Crizanlizumab	願蓋鑰鏇艱衊構衊築淵(淵齋憲鑰繭製鏇鏇窪鏇) = 鏇築築獵築鹽壓範壓壓觸艱夢顧構顧構觸築鏇 (鹹憲遞鏇衊醖願衊觸淵 ) 更多	积极	2017-02-02
				Placebo	願蓋鑰鏇艱衊構衊築淵(淵齋憲鑰繭製鏇鏇窪鏇) = 遞襯範夢鬱願淵窪獵鹹觸艱夢顧構顧構觸築鏇 (鹹憲遞鏇衊醖願衊觸淵 ) 更多