Vascular occlusive disease

关注并星标CPHI制药在线 近日，辉瑞宣布自愿从目前已获批的市场中撤回所有批次的镰状细胞病（SCD）治疗药物Oxbryta（voxelotor），并且停止所有正在进行的临床试验和扩大该药物的准入计划。 Voxelotor是辉瑞于2022年，斥资54亿美元收购Global Blood Therapeutics（GBT）所得，这是一款针对SCD的口服药物，其通过增加血红蛋白对氧的亲和力起作用，可抑制镰状血红蛋白聚合以及由此导致的红细胞镰状化和破坏。2019年，FDA加速批准Voxelotor用于治疗成人和12岁及以上儿童的镰状细胞性贫血。 目前，Voxelotor已在全球35多个国家获批。去年，Voxelotor的全球销售额达到3.28亿美元，虽然表现不算强劲，但一直被辉瑞寄予厚望。 获益不再超过风险，voxelotor落寞退市 SCD是一种遗传性血液疾病，其病因是由于编码血红蛋白（HbS）β链的基因中出现突变而导致异常HbS的形成，在脱氧状态下，HbS常常聚合在一起，导致红细胞（RBC）变形呈现镰刀状，并失去弹性，SCD因此得名。 患有SCD的患者会出现包括贫血、免疫缺陷、多器官衰竭等多种症状。除此之外，VOC(血管阻塞危机)是SCD患者最常见的并发症之一。 VOC是由于镰刀状红细胞粘附，造成器官发生缺血性损伤并引发严重疼痛，大约有一半SCD患者经历过VOC。目前，针对VOC的疗法非常有限。 Voxelotor于2019年11月获FDA批准上市，并于2022年2月获EMA批准上市，用于治疗SCD，以减少贫血和VOC的发生频率。值得一提的是，voxelotor是FDA批准的首 款直接抑制镰状血红蛋白聚合的药物，曾被认为是SCD治疗领域一颗冉冉升起的明星。 然而在GBT440-032和GBT440-042两项注册性研究中，voxelotor的表现却不尽人意。GBT440-032试验旨在评估voxelotor对2~15岁SCD患者和中风高危儿童脑动脉血流的经颅多普勒超声测量的影响。数据显示，接受voxelotor治疗的患者比未用药时经历了更多的VOC，有8人死亡。 GBT440-042试验旨在评估voxelotor对12岁SCD患者腿部溃疡的影响。该试验的开放标签试验部分发生了 8 例死亡病例。 基于这两项临床试验数据，可以看出voxelotor在SCD患者群体中的临床获益不再超过风险，因此辉瑞决定撤市。 疗效不敌安慰剂，诺华也"难逃一劫" 在SCD治疗领域，除了voxelotor退市外，诺华的Crizanlizumab（商品名Adakveo）在上市3年后也被EMA宣布撤销上市。 Crizanlizumab是一种人源化单克隆抗体，可与P-选择素结合发挥治疗作用。P-选择素是一种在血管内皮细胞和血小板表面发现的蛋白质，主要引起细胞间相互作用，参与血栓形成或镰刀细胞病相关疼痛危象。Crizanlizumab于2019年11月获FDA批准上市，2020年10月在欧洲获批上市，是首款预防SCD所致VOC的靶向疗法。然而在2023年1月，诺华公布的Crizanlizumab预防SCD患者VOC 的III期STAND研究显示：与安慰剂相比，Crizanlizumab在两种不同剂量（5.0mg/kg，7.5mg/kg）水平下均未能降低VOC的发生率。 诺华表示，这些发现与之前的试验结果不一致，早前进行的SUSTAIN试验显示，5.0mg/kg的crizanlizumab优于安慰剂。 鉴于此，欧洲药品管理局人用药品委员会（CHMP）在2023年5月建议撤销crizanlizumab的有条件上市许可。 事实上，在crizanlizumab之前，仅有两款药物获批用于治疗SCD--Hydroxyurea（羟基脲）和Endari（L-谷氨酰胺口服粉剂），其中羟基脲因安全性问题使用受限。 谷氨酰胺口服粉剂于2017年获FDA批准用于SCD治疗，成为该领域20年来首 款获批新药。 基因治疗成为新希望 SCD药物的研发充满挑战，入局药企开始把希望寄托在具有一次性治愈潜力的基因治疗上，其中Vertex Pharmaceuticals/CRISPR Therapeutics进展较快。 2023年12月，Vertex Pharmaceuticals/CRISPR Therapeutics的基因编辑疗法Casgevy（exa-cel）获FDA批准上市，用于治疗12岁及以上患有复发性血管闭塞危象的SCD患者。这是一款自体细胞疗法，其利用CRISPR/Cas9基因编辑系统，在体外对来自患者的造血干细胞进行编辑，使血红细胞生产高水平的胎儿血红蛋白（HbF），来减少SCD患者的疼痛和VOC发生频率。Casgevy是首 款获FDA批准治疗SCD的基因疗法。 在研药物方面，Editas Medicine的在研CRISPR基因编辑疗法EDIT-301，是一种用于治疗SCD与输血依赖性β地中海贫血症（TDT）的在研细胞疗法。其由来自患者的CD34+造血干细胞和祖细胞构成，这些细胞在γ珠蛋白基因（HBG1和HBG2）启动子处被具高度特异性、效率性的工程化AsCas12a核酸酶编辑。 在针对SCD的初步临床试验中（n=4），患者1和患者2在使用EDIT-301治疗后五个月达到正常的血红蛋白水平，且两位患者在十个月和六个月的随访中都保持了正常的血红蛋白水平。同时，在这些患者中亦持续观察到大于40%的胎儿血红蛋白水平。患者3和患者4在分别三个月和两个月的随访中显示总血红蛋白和胎儿血红蛋白的增加，这些现象与前两位患者所见的相似。所有四位接受治疗的患者，从接受治疗以来都没有发生VOC事件。 基因治疗仿佛吹响了攻克SCD的冲锋号，作为全球最常见的单基因遗传病之一，SCD发病率越来越高，SCD的基因疗法，或许能带来治愈希望。 参考来源：        1.https://www.biopharmadive.com/news/pfizer-oxbryta-withdraw-pull-market-sickle-cell/728155/        2.https://ir.editasmedicine.com/news-releases/news-release-details/editas-medicine-announces-positive-initial-edit-301-safety-and END END END END 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

2024年9月25日，辉瑞公司宣布，自愿撤回目前所有获批用于治疗镰状细胞病（SCD）的OXBRYTA®(voxelotor）批次，还将停止voxelotor所有全球正在进行的临床试验和扩大可及性计划。 辉瑞的决定是基于全部临床数据，这些数据表明，OXBRYTA在获批的SCD患者群体中的群体益处不再大于风险。数据表明，血管闭塞危象和致命事件的发生率不平衡，需要进一步评估。辉瑞已将这些发现及其自愿从市场上撤回OXBRYTA并停止分销和临床研究的决定通知监管机构，同时进一步审查现有数据并调查这些发现。 辉瑞首席医疗官兼全球医疗与安全主管Aida Habtezion表示：“患者的安全和健康对辉瑞至关重要，我们认为这一举措符合患者的最佳利益。我们主要关注的是患有SCD的患者，这种疾病仍然是一种非常严重且难以治疗的疾病，治疗方案有限。我们建议患者联系他们的医生讨论替代治疗方法，同时我们继续调查数据结果。” 关于SCD SCD是一种终生的、使人衰弱的遗传性血液疾病，其中血红蛋白S（HbS）聚合导致红细胞镰状化，从而导致血管炎症和溶血性贫血。血管炎症和镰状红细胞可导致急性疼痛危象或血管闭塞危象以及渐进性终末器官损伤，包括中风。SCD并发症始于儿童早期，与预期寿命缩短有关。SCD的早期干预和治疗已显示出改变这种疾病进程、减少症状和事件、预防长期器官损伤和延长预期寿命的潜力。 关于OXBRYTA®（voxelotor） OXBRYTA(voxelotor）是一种针对SCD患者的口服、每日一次疗法。OXBRYTA通过增加血红蛋白对氧的亲和力来起作用。OXBRYTA可抑制HbS聚合，HbS聚合可导致红细胞镰状化和破坏，从而出现溶血和溶血性贫血，这是每个SCD患者面临的主要病症。 2019年，美国FDA加速批准OXBRYTA片剂用于治疗成人和12岁及以上儿童SCD患者。2021年12月，FDA扩大了OXBRYTA在美国治疗4岁及以上SCD患者的批准范围。 自2019年首次获批以来，OXBRYTA已在全球35个国家获批。 小结 自从辉瑞从新冠赚了一大笔之后，这几年时间每年都会花上几十到几百亿美元来收购其他公司，如2023年的430亿美元收购ADC药物公司Seagen，2022年的116亿美元收购小分子CGRP药物治疗偏头痛的公司Biohaven。本文的主角药物OXBRYTA正是辉瑞在2022年花了54亿美元收购GBT公司得来的。 当年收购GBT公司的时候，辉瑞扬言GBT公司拳头产品OXBRYTA及其他罕见血液病管线的全球销售峰值合计将超过30亿美元，然而现实是OXBRYTA仅卖了3年多时间就全球撤市了，最新2024上半年销售额为1.76亿美元，之前许下的恢宏目标，或许要画上一个句号了。 这一次全球撤市的关键点，在于血管闭塞危象和致命事件。OXBRYTA于2019在NEJM杂志上发表的数据显示，各试验组间的血管闭塞危象发生率无显著差异，年发生率在2.77%-3.19%，并且有降低的趋势。 这与当时流行的观点不太一样，SCD患者的血液黏度异常升高，若此时血红蛋白水平过度升高（如单纯输血），会增加血管闭塞危象的风险。OXBRYTA在当时没有观察到这种现象，OXBRYTA增加血红蛋白，但不会增加血管闭塞危象。 然而事与愿违，随着用药群体的扩大，用药时间的延长，很可能是OXBRYTA并没有打破过去流行的观点，OXBRYTA增加血红蛋白的同时，也增加了血管闭塞危象，从而导致这次全球撤市事件的发生。 更何况在OXBRYTA获批之后，2023年FDA同一天批准了两款基因疗法用于治疗SCD，Casgevy和Lyfgenia。根据他们发表在NEJM杂志上的数据显示，Casgevy至少12个月未出现血管闭塞危象，Lyfgenia至少6个月未出现血管闭塞危象。 和后浪们相比，并没有降低甚至可能增加血管闭塞危象的OXBRYTA，就有点力不从心了，这次全球撤市就显得顺理成章了。 ▲临床在研的HbS聚合抑制剂 ▲披露结构式的临床在研HbS聚合抑制剂 参考文献 1.https://investors.pfizer.com/Investors/News/news-details/2024/Pfizer-Voluntarily-Withdraws-All-Lots-of-Sickle-Cell-Disease-Treatment-OXBRYTA-voxelotor-From-Worldwide-Markets/default.aspx 2.https://www.pfizer.com/news/press-release/press-release-detail/pfizer-acquire-global-blood-therapeutics-54-billion-enhance 3.https://www-nejm-org.libproxy1.nus.edu.sg/doi/full/10.1056/NEJMoa1903212 4.https://www-nejm-org.libproxy1.nus.edu.sg/doi/full/10.1056/NEJMoa2117175 5.https://www-nejm-org.libproxy1.nus.edu.sg/doi/full/10.1056/NEJMoa2309676 6.https://s28.q4cdn.com/781576035/files/doc_financials/2024/q2/10-Q.pdf 免责申明 本公众号注明原创的内容权利均属九洲药业所有，未经授权，不得擅自使用或许可他人使用。如需获得授权，请和九洲药业提前联系。已获得授权的，应在授权范围内使用，并注明来源且不得再全部或部分转授权他人。 本公众号对转载、分享的内容、陈述、观点判断保持中立，不对所包含内容的合法性、准确性、可靠性或完善性提供任何明示或暗示的保证，该等内容版权归原作者所有，仅供学习参考之用，若对转载、分享的内容有任何权利疑问，烦请联系九洲药业。

Pfizer has announced an important decision to voluntarily withdraw all approved OXBRYTA® (voxelotor) lots for the treatment of sickle cell anemia (SCD) and to suspend clinical trials of voxelotor worldwide and its expanded access program. This move follows a review of recent clinical data showing that the overall benefit-risk ratio of OXBRYTA in the treatment of sickle-cell anemia no longer supports its continued use in the market. Specifically, the drug does not effectively manage complications and reduce the risk of death, and may increase the risk of serious adverse events such as vascular occlusive crises. Looking back, Pfizer paid as much as $5.4 billion to acquire this product, which has been successfully launched, and has high hopes for it. However, the rapid delisting of OXBRYTA has undoubtedly dealt a heavy blow to Pfizer's presence in this area, clouding the prospects for its sickle cell anemia treatment. Pfizer's investment in sickle cell anemia is based on the broad market demand for the disease. Although the incidence is low in developed countries, around 4.5 million people worldwide are affected by the disease, and more than 45 million carry the sickle cell gene. This large patient population provides Pfizer with significant market potential. As a result, Pfizer started laying out several years ago and acquired Global Blood Therapeutics (GBT) in 2022 for $5.4 billion, with OXBRYTA as one of its core products. However, although OXBRYTA inhibits sickle hemoglobin polymerization by enhancing hemoglobin's affinity for oxygen, thereby alleviating hemolytic anemia, its market performance has not met expectations. It is important to note that Pfizer's setback in sickle cell anemia is not an isolated event. The company also recently ended two late-stage clinical trials of another drug candidate, inclacumab, due to patient recruitment difficulties. This series of events shows that Pfizer's exploration of the sickle cell anemia market has not been easy. Still, Pfizer said it does not expect OXBRYTA's delisting decision to have a material impact on its financial outlook for 2024. This statement reflects Pfizer's steadiness and rationality in responding to market changes. From a larger perspective, Pfizer's failure in sickle cell anemia is also an inevitable result of increased competition in the industry. In recent years, with the rapid development of gene therapy and FDA approval of multiple gene therapies for sickle cell anemia, such as Vertex and CRISPR Therapeutics' Casgevy and Bluebird Bio's Lyfgenia, traditional medicines have faced unprecedented challenges. These gene therapies, which directly correct gene defects to achieve the goal of disease treatment or even a one-time cure, bring new hope to patients with blood diseases. Although gene therapy shows great potential in the field of medicine, its high cost remains a major challenge that cannot be ignored. For example, Vertex and CRISPR's Casgevy are priced at $2.2 million, while Bluebird Bio's Lyfgenia is priced at $3.1 million, sparking widespread social concern and deep concerns about its accessibility. In fact, most gene therapies cost more than $1 million, with some treatments costing as much as $3.5 million. Earlier this year, after an in-depth review by the Institute for Clinical and Economic Review (ICER), it was noted that a reasonable balance of cost-effectiveness could be achieved if Vertex and bluebird therapies were priced in the range of $1.35 million to $2.05 million. However, we should also face up to the whole new era created by cell gene therapy in the field of blood disease treatment, and its contribution and value cannot be ignored. Pfizer's recent failure in sickle-cell anemia once again highlights the complexity and uncertainty of the pharmaceutical industry. While Pfizer has long considered sickle-cell anemia products a strategic priority, its experimental drug rivipansel failed to perform as expected in the pivotal Phase III clinical study RESET, ultimately forcing the company to make a strategic change. In order to compensate for this deficiency, Pfizer chose to further improve its product line through mergers and acquisitions. Thanks to strong sales of COVID-19 vaccines, Pfizer now has ample financial firepower to fund its M&A strategy. However, "money for medicine" is not a long-term solution. As the dividend of COVID-19 gradually fades and the focus of the industry continues to shift, Pfizer has to face the reality of lower revenue expectations. Since the beginning of 2023, Pfizer shares have fallen by nearly half, from nearly $57 to $28.93. In response, Pfizer has launched a "cost reduction program" and plans to achieve $4 billion in savings by the end of 2024, $500 million less than previously expected. Company executives said the cost cuts will focus on research and development, but also involve optimizing sales and administrative functions. Entering the "post-COVID-19 era," Pfizer is experiencing unprecedented challenges and volatility. The decision to completely abandon the sickle cell anemia product line is not only a positive response to the current difficult situation, but also an important step in Pfizer's pursuit of greater certainty. However, in the face of the great pressure of competition from large manufacturers and the constantly changing industry environment, Pfizer's transformation road still has a long way to go. Whether it can find new growth points and achieve sustainable development in the future is still a problem worthy of attention.