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-Exa-cel is the first CRISPR-based gene-edited therapy to be submitted for Health Canada review- TORONTO, April 1, 2024 /CNW/ - Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced its New Drug Submission (NDS) for exagamglogene autotemcel (exa-cel) has been accepted for Priority Review by Health Canada for the treatment of patients aged 12 years and older with sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs) and for the treatment of patients aged 12 years and older with transfusion-dependent beta thalassemia (TDT). "We are pleased that exa-cel has been accepted for Priority Review by Health Canada and look forward to bringing this therapy to eligible patients," said Michael Siauw, General Manager at Vertex Pharmaceuticals (Canada) Incorporated. The NDS will be part of an aligned review with Health Technology Assessment (HTA) organizations, the Canadian Agency for Drugs and Technologies in Health (CADTH) and the Institut national d'excellence en santé et en services sociaux (INESSS) in Quebec. With Priority Review, the conventional review timeline of 300 days is reduced to 180 days. The NDS is supported by results from the ongoing Phase 3 studies, CLIMB-111 and CLIMB-121, as well as an ongoing long-term follow-up study, CLIMB-131. Data from the Phase 3 studies were most recently presented at the American Society of Hematology (ASH) Annual Meeting and Exposition in December of 2023. About exagamglogene autotemcel (exa-cel) Exa-cel, formerly known as CTX001, 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. Exa-cel has been shown to reduce or eliminate VOCs for patients with SCD and transfusion requirements for patients with TDT. Earlier results from these ongoing trials were published in The New England Journal of Medicine in January of 2021 and presented at the ASH Annual Meeting and Exposition in December 2023. Exa-cel remains investigational in Canada and the safety and efficacy has not been established by Health Canada. Exa-cel is approved as CASGEVY® for certain indications in the United States, European Union, Great Britain, Kingdom of Saudi Arabia, and Bahrain. About CLIMB-111 and CLIMB-121 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 exa-cel 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 exa-cel infusion. Each patient will be asked to participate in CLIMB-131, a long-term follow-up trial. About CLIMB-131 The ongoing long-term, open-label trial, CLIMB-131, is designed to evaluate the safety and efficacy of exa-cel in patients who previously received exa-cel. 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. Stem cell transplant from a matched donor is a curative option but is only available to a small fraction of people living with SCD. About Transfusion-Dependent Beta Thalassemia (TDT) TDT is a serious, life shortening 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. Stem cell transplant from a matched donor is a curative option but is only available to a small fraction of people living with TDT. 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, 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, without limitation, statements made by Michael Siauw in this press release, and statements regarding Vertex's beliefs that the NDS for exa-cel will be part of an aligned review with HTA, CADTH and INESSS, and Vertex's expectations that the conventional review timeline will be reduced with Priority Review. While Vertex believes 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 regulatory authorities may not approve, or approve on a timely basis, our regulatory submissions for exa-cel, that data from a limited number of patients may not be indicative of final clinical trial results, and that data from the company's development programs may not support registration or further development of its compounds due to safety and/or efficacy, or 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 (SEC) and available through the company's website at and on the SEC's website at . You should not place undue reliance on these statements. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available. SOURCE Vertex Pharmaceuticals (Canada) Inc. Company Codes: NASDAQ-NMS:VRTX

作者｜Adolf   * 后台回复【 Exa-cel 】可获取本文相关资料！科学走进现实。说了那么多年的基因编辑，这是第一次真正意义上的被医药监管机构认可，我们也算见证历史了。2024年1月16日，CRISPR Therapeutics宣布，美国FDA已经批准其CRISPR/Cas9基因编辑疗法exagamglogene autotemcel（exa-cel，商品名：Casgevy）用于治疗12岁及以上患者的输血依赖性β地中海贫血（TDT）。这是继去年12月其获批用于复发性血管闭塞危象（VOC）镰状细胞病（SCD）后，exa-cel获FDA批准的第2项适应症。早在2023年11月，该产品在英国首次获批上市。Exa-cel（商品名：Casgevy）是什么？怎么设计的？作用机理是什么？今天就让我们一起来深度了解这款人类医药里程碑式的药物！  01  含着“金钥匙”出生的Exa-celExa-cel由CRISPR Therapeutics和Vertex Pharmaceuticals强强联合，共同推出，说它含着“金钥匙”出生一点不为过。Exa-cel最初由CRISPR Therapeutics开发。2015年，CRISPR与Vertex达成战略研究合作，使用CRISPR/cas9基因编辑技术发现和开发新的遗传性疾病治疗方法。根据修订后的协议，Vertex负责exa-cel的全球开发、制造和商业化，并与CRISPR在全球范围内以60/40的比例分摊项目成本和利润。CRISPR Therapeutics成立于2013年，由Emmanuelle Charpentier、Rodger Novak 和 Shaun Foy联合创办，其中Charpentier与另一位科学家Jennifer A. Doudna二人是最早于2012年公开发表CRISPR/Cas9研究成果的两个人，通过在原核细胞上的研究，证明了CRISPR成为新一代基因编辑工具的潜力，后二人因此获得了诺贝尔化学奖。后来，张锋首次将CRISPR/Cas9技术用于动物细胞，三人并称为“CRISPR三剑客”，Charpentier、Doudna和张锋分别创立了CRISPR 、Intellia和Editas。图注：CRISPR Therapeutics大楼Vertex Pharmaceuticals是创立于1989年的美国药企，曾多年深耕于罕见病囊性纤维化。目前该公司的产品销售额绝大部分来自囊性纤维化领域，2021年，全球最畅销的三款治疗囊性纤维化的产品均来自Vertex，分别为Trikafta，Orkambi和Kalydeco,销售额为51.81，7.81和7.29亿美元。2022年该公司全年总销售额89.3亿美元，净利润33.22亿美元，净利润高达37.2%。图注：Vertex Pharmaceuticals大楼  02  两种适应症SCD/TDT的致病机理镰状细胞病（SCD）是全世界最常见的遗传性血红蛋白病，每年的新出生的患儿数量高达300000人。正常的成人血红蛋白 (Haemoglobin Hb) 是一个结构复杂的蛋白，它是由两个α-珠蛋白亚基和两个β-珠蛋白亚基形成的四聚体。β-珠蛋白亚基由HBB 基因编码，当病患的HBB基因第六位氨基酸的密码子携带有A-T突变时，原有的谷氨酰胺 (Glu)会突变成缬氨酸 (Val)。因为疏水性缬氨酸残基具有粘附性，所以会在红细胞中沉淀形成刚性的半固体聚合物，进而导致相应红细胞的镰状化。镰状化会损害红细胞，导致慢性溶血和血管闭塞(VOC)。因此改善血红蛋白、改善VOC是SCD治疗的主要目的。β 地中海贫血(TDT)是指β珠蛋白的合成受部分或完全抑制的一种血红蛋白病。患儿出生时无症状，多于婴儿期发病，出生后3～6 个月内发病者占50%。发病年龄愈早，病情愈重。严重的慢性进行性贫血，需依靠输血维持生命。在人体中，有两个对于珠蛋白合成很重要的基因簇（如图1），α珠蛋白基因簇和β珠蛋白基因簇，其中γ-珠蛋白在胎儿发育的妊娠晚期表达，并与 α-珠蛋白亚基配对形成胎儿血红蛋白 (HbF)。HbF的表达会受到转录因子BCL11A的调控（如图2），在胎儿孕育6-9个月时下降，直至表达停止。与此同时，成人血红蛋白（α -珠蛋白+β-珠蛋白）的表达逐渐上升，进而取代HbF在体内的功能。患有 SCD 的新生儿和婴儿，由于突变仅发生在β-珠蛋白亚基上，因此HbF还是能够发挥正常功能的。只要 HbF 的表达保持在高水平，就不会出现SCD的症状，这也是为什么SCD患儿的症状多在出生后一年内HbF 被镰状珠蛋白取代时才出现。BCL11A是一种含锌指结构的转录因子，可抑制红细胞中的 γ 珠蛋白表达。BCL11A基因发生突变的患者，其HbF 在成年期能够持续高水平表达，因此显著减轻了 SCD 病症。这一遗传学上的现象为Exa-cel的开发，提供了理论的基础。图1 珠蛋白基因组示意图图2 BCL11A 调控HbF表达示意图  03  Exa‑cel是怎么做的？Exa‑cel 是一种细胞治疗药物，由经过改造的造血干细胞和祖细胞 (hHSPC)组成。改造过程（如图3）：先收集患者自体CD34+ hHSPC，再通过电转的方式将Cas9蛋白与sgRNA递送到hHSPC内，CRISPR复合体会结合在位于BCL11A基因内含子上的红细胞特异性增强子GATA1区域，并切割双链DNA，利用非同源重组（NHEJ）产生indel，破坏该增强子，降低BCL11A在红细胞中的表达水平，从而特异性提高HbF在红细胞中的表达。改造后hHSPC经体外扩大培养，再重新输注到患者体内，从而缓解TDT和SCD症状。图3 Exa‑cel作用机制示意图  04  Exa-cel为何走在前列？在基因编辑这个赛道，CRISPR 、Intellia和Editas三家明星药企均处于世界前列，那么CRISPR公司究竟是如何率先推出全球第一个基因编辑产品的呢？有如下几点原因。4.1 产品设计足够安全众所周知体内基因编辑最大的阻碍是脱靶问题，组织脱靶和基因脱靶都有不可控的一面，因此需要更多的临床试验和长期的安全评估。而Exa‑cel针对CD34+HSPC基因组的编辑过程仅在离体状态中短暂进行，因此当Exa‑cel回输给患者时，细胞中不存在残留的基因编辑活性。4.2 编辑位点细致的考量BCL11A红细胞特异性增强子区域天然就有发生突变的现象，突变携带者HbF表达水平提高、SCD症状减轻，且没有其他的临床表现，是一个安全的编辑位点；编辑的位点位于非编码的内含子上，且距离编码区有25kb以上的距离，因此对BCL11A蛋白本身的功能不会造成影响；编辑的区域为红细胞特异性增强子，因此仅仅会影响BCL11A在红细胞中的表达，对其他的造血细胞例如B细胞HSC等则没有影响；sgRNA的靶序列在基因组中是唯一的，从而实现在设计角度的高特异性。4.3 优异Exa‑cel的临床表现对SCD 疗效的证据来自于关键的 1/2/3 期临床研究CLIMB 121。CLIMB 121是一项多国、单臂、临床1/2/3 期研究，旨在评估Exa‑cel对 12 至 35 岁患有严重 SCD 且反复出现 VOC（血管闭塞危象）的患者进行单剂量治疗的安全性和有效性，该项研究一共入组了44 名受试者。CLIMB 121主要疗效终点是达到 VF12，即在患者进行Exa‑cel 输注后 12 个月内没有发生sVOC的受试者比例。次要疗效终点（HF12）是在Exa‑cel 输注后12个月内，受试者中不再因 sVOC 住院的受试者在总给药人数中的占比。而第三个次要疗效终点，则包括达到VF12的患者中未出现sVOC的持续时间、未达到VF12患者中sVOC年化率的降低水平，以及HbF≥20%的受试者比例。图4 Exa‑cel临床效果统计从结果来看（图4），在可评估疗效的 30 名受试者中，有29 名(96.7%) 达到了 VF12 的主要疗效终点。在达到 VF12 的 29 名受试者中，28 名受试者的不因sVOC 住院平均持续时间为22.3 (SD 7.2) 个月，最长为 45.5 个月。所有 30 名(100%) 可评估受试者均达到了 HF12。图5 Exa‑cel药效学统计临床疗效终点同样也得到药效学终点的支持（如图5）。在Exa‑cel输注后，患者体内观察到高比例的HbF 阳性细胞 (≥ 90%)，且F 细胞的比例与HbF 的表达保持持续增长。在 4 年随访期间，F 细胞比例的平均值从第 6 个月起≥ 93%，从第 12 个月起≥ 96%。与HbF 表达的增加相一致，患者自Exa‑cel输注后 12个月开开始不再需要接受任何因 SCD 相关指征引起的红细胞输注治疗，红细胞输注量较基线减少了 100%。而在基线时，患者接受的红细胞输注量每年平均为 8.4 (14.9) 单位。图6 骨髓和外周血中BCL11A基因的编辑效率此外，骨髓和外周血中BCL11A基因的编辑是稳定的。在SCD 受试者中，从第 2 个月到第 42 个月，骨髓 CD34+ 细胞的基因平均编辑率≥80%，外周血中CD34+细胞的基因编辑率≥70%。在第12 个月和第 24 个月时，骨髓细胞基因组编辑比例最低的患者也达到了 VF12 的主要终点。稳定、持久的基因编辑与稳定、持久的 HbF 表达是相一致的，这表明消除病患 VOC 这一临床收益也将是稳定、持久的。对TDT的疗效的证据来自于另一项临床研究NCT05477563。该研究招募52名患有TDT且需要常规输血来维持生命的病人，年龄在12-35岁。从临床研究结果来看，35名接受Exa‑cel输注的患者中有32名（91.4%）在12个月内无需进行输血，而且平均总血红蛋白和胎儿血红蛋白水平均显著提高，而且长期维持较高水平（如图7）。图7 总血红蛋白和胎儿血红蛋白水平4.4 TDT/ SCD缺乏有效的治疗手段目前的治疗手段有三种。一是服用羟基脲，羟基脲是一种核糖核苷酸还原酶抑制剂，它原本是化疗药物，用于治疗慢性粒细胞白血病、骨髓增生性疾病等适应症。但由于羟基脲的安全性和增加HbF表达等生理功能，该药物被大量使用于治疗镰状细胞病，可以显著降低患者血管闭塞的发生率、病患的住院率和死亡率。二是输血，输血是治疗和预防镰状细胞病及其并发症的重要手段，这种疗法主要是通过输注健康人的血液或者健康人的红细胞，来降低镰状红细胞的比例，从而改善微血管的血流供应，降低内皮损伤和炎症损伤相关的风险。但随着持续输血，铁过载会不可避免地会发生，并可能导致心脏和肝脏的衰竭以及多种并发症。三是造血干细胞移植，造血干细胞移植是目前唯一可以治愈镰状细胞病的方法，来自于健康供体的造血干细胞可以分化为含有正常血红蛋白的红细胞，但这种疗法由于缺乏合适的供体而受到严重的限制。这三种治疗手段，不管是服用羟基脲还是输血，都是治标不治本，需要长期且频繁的接受治疗，而造血干细胞移植又受到供体的严格限制。所以，Exa‑cel作为一种一次性单剂量细胞治疗药物应运而生，它的出现及时又合理。参考资料：[1]Gregory J. Kato, Frédéric B. Piel, Clarice D. Reid. Sickle cell disease. Nature (2018) 18010.[2]Frangoul, H, D Altshuler, MD Cappellini, et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. N Engl J Med. 2021[3] Wang L, Li L, Ma Y, Hu H, et al. Reactivation of γ-globin Expression through Cas9 or Base Editor to Treat β-Hemoglobinopathies. Cell Research. 2020[4]https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-october-31-2023-meeting-announcement-10312023#event-materials[5] https://www.fda.gov/media/173472/download[6] https://www.casgevy.com/sickle-cell-disease/study-results[7] https://www.casgevy.com/beta-thalassemia/study-information  2024活动预告  6月13-14日，十年一药，日出东方！BiG十周年  关键词：  源头创新与转化、创新技术平台（PROTAC/分子胶；双抗ADC；小核酸药物；AI+大分子）、临床研究&国际化开发策略（肿瘤/CNS/自免/代谢疾病领域）▼关于BiGBiomedical Innovation Group2014年2月，一个专业机构：BiG生物医药创新社（Biomedical Innovation Group）在充满药味的上海张江应运而生，伴随着中国新药的黄金十载，BiG以“开放、民主、平等“的精神为宗旨，旨在为中国生物医药行业的发展创造一个滋养原创的生态环境。共建Biomedical创新生态圈！如何加入BiG会员？

The UK recently became the first country in the world to approve a CRISPR-based gene-editing therapy, but the National Institute for Health and Care Excellence has said it now needs more evidence before making it routinely available on the NHS.Vertex Pharmaceuticals and CRISPR Therapeutics' Casgevy (exagamglogene autotemcel) gained clearance from the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) last year for the treatment of sickle cell disease (SCD) and transfusion-dependent beta thalassaemia (TDT). NICE is still assessing the therapy for TDT, while it published draft guidance in SCD on Thursday.In its documents, NICE said that although study results suggest that Casgevy can stop vaso-occlusive crises (VOCs) in some people with SCD, the trial was limited by its small size and lack of comparator arm. The cost-effectiveness body added that “it was not clear how well it will work in the longterm.”Along with questions on efficacy, NICE raised concerns over Casgevy’s price, which it said “is higher than what [it] normally considers to be a cost-effective use of NHS resources.” The agency added that even when taking into account the innovative nature of the technology, the cost-effectiveness estimate for Casgevy is still above its threshold.More to come.