Recombinant Human Coagulation Factor VIII (Takeda)

每年4月17日是世界血友病日，自18世纪被发现以来，血友病一直是医学界探索的难题。经过上百年的不懈努力，当下血友病主要治疗药物实则是经历了四代更迭：20世纪70年代初，人类开始使用血源性的凝血因子制品治疗血友病，以baxter的Recombinate为代表的第一代凝血因子药物应运而生；20世纪90年代，由于第一代血源性凝血因子药物存在过度依赖血浆带来的传染性病原体感染风险，baxter开发了第二代血友病治疗药物重组凝血因子产品Advate，之后该技术得到广泛推广，沿用至今；2014年，为解决重组凝血因子产品给药频率的临床需求，bioverativ与赛诺菲共同开发的Alprolix作为首个长效重组凝血因子制品在美国获批，开创了血友病治疗的第三代产品；2017年，为解决部分血友病患者的抗药物抗体并发症问题，罗氏开发了首个不依赖凝血因子的非因子替代治疗药物“艾美赛珠单抗”，成为了第四代血友病治疗产品。显然，人类在血友病治疗领域取得显著进步，过去很长一段时间，血友病治疗完成了从凝血因子到非凝血因子替代疗法的探索。但目前临床上对于半衰期短、关节损害并发症等血友病的治疗担忧依旧存在，以及临床上对更长效、更高效、更安全的药物需求仍未被满足。不过，随着近年来基因疗法的崛起以及部分基因疗法的获批上市，也逐渐给血友病治疗的新变革，也让人们真正看到了血友病“一针治愈”的曙光。两大类血友病A与血友病B血友病是一种X染色体连锁的隐性遗传性出血性疾病，病理机制为凝血因子基因缺陷导致其水平和功能减低而使血液不能正常凝固，主要患病表现为关节、肌肉、内脏和深部组织自发性出血或外伤出血后止血困难。按照缺乏的凝血因子不同，血友病可以分为两种类型：缺乏凝血因子FVIII（八因子）的为血友病A，缺乏凝血因子FIX（九因子）的为血友病B。还可以根据FVIII或FIX的活性水平，将血友病A和血友病B分为轻型、中型和重型。血友病的发病率没有明显的种族或地区差异，所有血友病患者中，血友病A患者占80%~85%，血友病B患者占15%~20%。由于血友病的遗传与性染色体有关，基因在性染色体的X染色体上，而女性的一对性染色体是XX，达成血友病的遗传条件相对“苛刻”，因此血友病患者患病以男性为主，女性极其罕见。根据弗若斯特沙利文数据，全球血友病患病人数复合增长率为1.3%，从2015年的74.2万上升到2019年的78.3万，预计到2030年患者人数将增长到89万人，血友病也是“高发”的罕见病之一，治疗方案也就受血友病患者人群的密切关注。现有疗法替代治疗占主导地位血友病治疗的主要目的是预防危及生命的出血和治疗肌肉和关节出血，目前血友病的治疗方案包括凝血因子替代疗法和非因子疗法。第一/二代产品：血源性与重组凝血因子凝血因子替代治疗的主要作用机制是通过健康凝血因子的替换和补充，在无出血时进行预防治疗，在出血发生时及时加强凝血功能，最初采用新鲜冷冻血浆、冷沉淀物，20世纪70年代初开始使用血源性的凝血因子制品，即血源性人凝血因子（血源FVIII和FIX），也是第一代血友病治疗药物。到20世纪90年代，一种不依赖血浆供应，降低了传染性病原体感染的风险的凝血因子制品问世（重组FVIII和FIX），成为了第二代血友病治疗药物。表1 凝血因子替代治疗第一/二代药物分类产品企业工艺第一代产品MonoclateCSL血源FVIIIRecombinateBaxter血源FVIIIHemofil MBaxter血源FVIIIAlphanateGrifols血源FVIIIProplexBaxter血源 FIXMononineCSL血源 FIXAlphaNineGrifols血源 FIX第二代产品AdvateBaxter重组FVIIIRecombinateBaxter重组FVIIIKogenate拜耳重组FVIIIKovaltry拜耳重组FVIIIHelixateCSL重组FVIIIXyntha辉瑞重组FVIIINovoeight诺和诺德重组FVIII安佳因神州细胞重组FVIIIBeneFlX辉瑞重组FIX图片来源：公开数据整理第三代产品：长效凝血因子2014年，首个长效重组凝血因子制品Alprolix在美国获批，通过FEG修饰、B区糖基化、Fc融合蛋白、白蛋白融合蛋白等方法长效化地重组FVIII或重组FIX。将原有凝血因子的半衰期延长一倍以上，减少了预防性治疗的给药频率，并有效提高了患者的依从性，成为血友病替代疗法的第三代治疗药物。表2 凝血因子替代治疗第三代药物分类产品企业工艺第三代产品AdynovateBaxterPEG 全长重组蛋白FVIIIKovaltry拜耳PEG 截断重组蛋白FVIIIN8-GP诺和诺德B 区糖基化蛋白FVIIIEloctate赛诺菲Fc 融合蛋白 FVIIIAfstylaCSL白蛋白融合蛋白 FVIIIAlprolixBioverativ/赛诺菲Fc 融合蛋白 FIXIdelvionCSL白蛋白融合蛋白 FIX图片来源：公开数据整理（欢迎补充）目前，已上市的三代血友病治疗药物中，第二代重组FVIII和FIX获批数量最多，据不完全统计，目前全球有超10款重组FVIII和FIX产品上市，Baxter旗下的Recombinate是全球首个上市的重组凝血因子（1992年获批），之后拜耳、辉瑞、诺和诺德等跨国巨头也投身重组凝血因子赛道，并相继推出了自己的产品。并且，在治疗格局上，我国血友病A/B两者间呈现相对显著的差异，对于血友病A患者而言，2021年以前其治疗基本依赖进口药品，价格相对昂贵，直至2021年7月神州细胞的安佳因作为国产第一款重组凝血Ⅷ因子获批上市，打破了重组凝血Ⅷ因子的进口垄断。之后，正大天晴的注射用重组人凝血因子Ⅷ等产品他也相继提交了上市申请，用药成本有望持续降低；而对于血友病B而言，其治疗药品近年来已基本实现了国产替代，且其在医保与厂家补贴之下，基本实现了零用药成本。第四代产品：非因子疗法虽然大多数血友病患者可以通过凝血因子替代疗法来进行防治，但是有一部分的血友病患者接受替代疗法后，症状未见缓解。据悉，大约25%的血友病A患者和5%的血友病B患者，在接受第Ⅷ/Ⅸ凝血因子治疗后，体内产生了注射因子的抑制剂（抗药物抗体），这是治疗过程中最严重的并发症之一。对于产生抑制剂的患者，原则上需要采用免疫耐受诱导（ITI）治疗，利用高水平的因子让这些抑制剂饱和。如果免疫耐受诱导不合适或者失败，这需要使用非因子疗法，例如使用艾美赛珠单抗、去氨基-8-D-精氨酸加压素( DDAVP)、解热镇痛治疗、抗纤维蛋白溶解药物等。表3 非因子疗法的相关分类治疗手段细分类别药物类型治疗原理治疗特点非因子治疗非因子替代治疗艾美赛珠单抗通过模拟 FⅧa 的辅因子功能，可同时桥接 FIXa 和 FX，使 FX在没有 FⅧ 的情况下得以继续激活，重新恢复生理性凝血通路。效果好，用药频次低，维持剂量给药频次最低可达每4周1次，但存在血栓性血管病的副作用，价格显著高于重组八因子产品去氨基-8-D-精氨酸加压素( DDAVP)DDAVP注射剂、鼻喷剂轻型和中型可能有效，重型患者无效疗效不及 FVIII解热镇痛治疗乙酰氨基酚和弱或强阿片类药物，或应用 COX-2 类解热镇痛药对重症患者无效治标不治本抗纤维蛋白溶解药物氨甲环酸、6-氨基己酸、止血芳酸等常用药物有氨甲环酸、6-氨基已酸、氨甲苯酸等。对口腔、舌、扁桃体、咽喉部出血及拔牙引起的出血有效，但对关节腔、深部肌肉和内脏出血疗效较差图片来源：公开数据整理其中，使用由罗氏研发的艾美赛珠单抗是非因子治疗中较为重要的一种，即非因子替代治疗，也被称为血友病治疗的第四代药物。2017年在美国获批上市，是一种双特异性单克隆抗体药物，其作用机制是在患者体内同时桥接凝血因子IXa(FIXa)和凝血因子X(FX)，通过模拟FⅧ的辅因子功能，使FX在FⅧ异常的情况下可以正常激活，从而重新恢复患者的凝血功能。艾美赛珠单抗是近20年来FDA批准的首个用于治疗A型血友病的创新药，根据罗氏财报，2023年艾美赛珠单抗销售额达45.95亿美元，同比增长16%，在罗氏畅销产品榜单中排名第二。2018年底，艾美赛珠单抗已在我国获批用于存在凝血因子Ⅷ抑制物的A型血友病患者。打破局限基因疗法点燃治愈希望虽然，替代治疗（含凝血因子和艾美赛珠单抗）在一定程度上的确缓解了血友病患者的症状，在血友病治疗市场占据了主导地位。但现有治疗方式依旧存在明显的弊端，如凝血因子在体内的代谢时间较短，大约在12小时至20多小时之间，因此患者一般情况下需要每周输注2-3次凝血因子来防止出血，并且需要终身维持输注；艾美赛珠单抗虽降低了用药频次，但仍需要维持最低每4周1次的用药需求，且存在血栓性血管病的副作用、费用也不低，目前国内艾美赛珠单抗仍未纳入医保，30mg的价格是8100元一支，60mg艾美赛珠的价格是16200元一支，需终身服药。为了从根本上解决这些问题，基因治疗应势而起。基因治疗通过输注正确的基因，使其在体内表达凝血因子，理论上可以使患者通过一次性的治疗实现凝血因子的永久表达，从而达到一次输注、终身治愈的目标。已上市产品截止目前，最常见的血友病基因疗法是使用AAV载体包装Ⅷ因子的基因。AAV载体通过载体递送到达患者靶细胞内维持游离状态，实现Ⅷ因子在靶器官内持续表达。2022年至今，全球范围内已获批上市了3款针对血友病的基因疗法，都是以AAV载体为载体的产品，即Roctavian、Hemgenix以及Beqvez。表4 血友病基因疗法产品药物名称首次上市时间首次审批机构研发企业适应症售价Roctavian2022.08EMABioMarin Pharmaceutical严重血友病A成人患者150万欧元Hemgenix2022.12FDAUniQure血友病B成人患者350万美元Beqvez2024.01Health Canada辉瑞18岁及以上中度至重度B型血友病且对AAV血清型Rh74的中和抗体检测为阴性的成年患者未公布图片来源：公开数据整理其中，辉瑞的Beqvez今年1月刚在加拿大获批上市用于治疗18岁或以上中重度至重度乙型血友病成人患者，尚未在美国获批上市，FDA于2023年6月接受了辉瑞的生物制品许可申请，预计将于2024年第二季度做出审批决定。根据辉瑞2022年12月所公布的BENEGENE-2积极数据，该基因疗法使患者的ABR降低了71%，年化凝血因子输注率降低了92%。根据研究者公开信息，最早接受基因治疗的一例血友病B患者已经达到接近十年的长期表达，目前基因治疗血友病至少能够保持凝血因子表达5-10年以上，但距离终生表达的期望还存在差距，对于丢失表达的患者，唯有寄希望未来通过基因治疗技术的改进和发展实施第二次和第三次基因治疗。临床阶段产品由于基因治疗被证实，确实为血友病患者带来了治愈希望，全球药企对血友病的基因疗法保持较高的研发热情，除已上市药物，目前全球范围内针对血友病基因疗法的管线超15条，其中有3条已进入临床Ⅲ期，含Sangamo/辉瑞的SB-525、Spark Therapeutics的SPK-8011以及信念医药的BBM-H901。表5 全球针对血友病的基因疗法临床Ⅱ期以上管线产品研发企业研发进度SB-525Sangamo/辉瑞临床Ⅲ期SPK-8011Spark Therapeutics临床Ⅲ期BBM-H901信念医药临床Ⅲ期DTX-201拜耳临床Ⅱ期ASC-618ASC Therapeutics临床Ⅱ期SHP-654Baxalta临床Ⅱ期TI-168Teralmmune inc临床Ⅱ期BAX-335Baxalta临床Ⅱ期Verbrinacogene setparvovecFreeline Therapeutics临床Ⅱ期VGB-R04天泽云泰临床Ⅱ期ZS-801至善唯新临床Ⅱ期图片来源：公开数据整理结语诚然，现有血友病治疗方案之下，诸多副作用等因素导致其新药临床需求迫切，但基因治疗一劳永逸的纠正血友病患者体内的基因异常或基因缺陷的理想与现实中5-10年的表达期却存在较大的心理预期差。另外，经济问题也是让血友病走向治愈的一道坎，虽然基因疗法有望实现治愈，但是高昂的价格阻碍了药物的大范围推广，uniQure上市半年却仅有1名患者接受了相关治疗，就算如今全球接受了血友病基因治疗的病患也是寥寥可数，多数血友病患者都是望而却步。总之，血友病治疗发展还需要多方共同努力，如企业研发更便捷有效的治疗药物、政府完善更便捷的支付支付方式、全社会提升对血友病的认知等，共同推进血友病治疗真正走向治愈。参考资料：《2024 CASH丨张磊教授：一次输注，终生治愈，血友病基因治疗前景可期》血液病研究院血液学研究所《三代血友病治疗药物及长效重组凝血因子简析》中国生物圈免责声明“药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！

Angus Smith joins as Chief Financial Officer Wing-Yen Wong, M.D., joins as interim Chief Medical Officer CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Be Biopharma, Inc. (“Be Bio”), a company pioneering the development of engineered B Cell Medicines (BCMs), today announced the appointment of Angus Smith as Chief Financial Officer (CFO) and Wing-Yen Wong, M.D., as interim Chief Medical Officer (CMO). Mr. Smith brings more than 15 years of experience in the biotechnology and life sciences industry, having held C-level positions in several public companies, including his most recent role as the CFO of Affimed N.V. and co-President of the company’s U.S. subsidiary, where he was responsible for implementing a new business plan and for raising over $400M in capital to support clinical development efforts. Mr. Smith also brings nearly a decade of investment banking experience, providing strategic and financial advice across the healthcare sector. Dr. Wong brings over 35 years of experience as a practicing clinician and professor at Children’s Hospital of Los Angeles, and leading development efforts in several companies including BioMarin, Biogen, and Baxter. Most recently Dr. Wong was Group Vice-President, Head of Global Medical Affairs and Scientific Strategy at BioMarin where she was involved in the development of the most recently approved hemophilia gene therapy. “We are thrilled to welcome Angus and Wing to Be Bio,” said Joanne Smith-Farrell, Ph.D., Chief Executive Officer. “We are rapidly transitioning from a research-based company to one focused on delivering innovative medicines to patients, with our first program in hemophilia B entering the clinic this year. These accomplished and experienced leaders will further strengthen our leadership team. Angus’s long track record of financial operating experience and fundraising will be important as we advance multiple programs to the clinic, while Wing’s expertise in drug development and as a clinical scientist is particularly important as we pioneer a new class of cellular medicines, Engineered B Cell Medicines (BCMs), to dramatically improve the lives of patients.” Angus Smith Mr. Smith brings more than 15 years of experience in the biotechnology and life sciences industry, including his most recent role as the CFO of Affimed N.V. and, prior to that, at Rockwell Medical. At Affimed, Mr. Smith led all finance, accounting, and investor relations functions, implemented a new business plan and financing strategy, and raised more than $400 million. Mr. Smith began his career in healthcare investment banking, serving most recently as a Director in the Healthcare Investment Banking Group at Cantor Fitzgerald. During his nearly decade-long investment banking tenure, Mr. Smith provided strategic and financial advice to life sciences and healthcare companies. He has worked on a substantial number of transactions across the healthcare sector with an aggregate transaction value of more than $15 billion. Mr. Smith holds a B.A. in Mathematical Economics from Colgate University. Wing-Yen Wong, M.D. Dr. Wong brings over 35 years of experience as a practicing clinician and working in the biotechnology industry with a focus in the treatment and management of patients with hemophilia, sickle cell disease (SCD) and pediatric hematology/oncology. Most recently Dr. Wong was Group Vice-President, Head of Global Medical Affairs and Scientific Strategy at BioMarin and Vice President, Global Medical, Hematology and Immunology at Biogen. Prior to Biogen, Dr. Wong was the Head of Clinical Research and Global Senior Medical Director of Hemophilia/Hematology at Baxter Healthcare Corporation where she directed medical and clinical functions, including global medical support of licensed products, clinical development and new product approvals. During her tenure at Baxter, Dr. Wong successfully directed the BLA submission and launch of multiple hemophilia products including RIXUBIS®, FEIBA®, OBIZUR and ADVATE®. Prior to her work in industry, Dr. Wong spent over 15 years as a practicing clinician and professor at Children’s Hospital Los Angeles and the Los Angeles County (LAC) and University of Southern California (USC) Medical Center. As a clinician, Dr. Wong presented and published numerous studies and papers on her research in hemophilia and hematology and has served as a reviewer for medical journals including the American Journal of Hematology, Hemophilia and the Lancet. In 2003, Dr. Wong was appointed by the Secretary of Health and Human Services as a member of the Advisory Committee on Blood Safety and Availability. Dr. Wong earned her M.D. at the USC, Keck School of Medicine and a BA at Occidental College. She served a Fellowship at the LAC and USC Medical Center in pediatric hematology-oncology and was appointed Associate Professor of Pediatrics at the University of Southern California. About Engineered B Cell Medicines – A New Class of Cellular Medicines The B cell is a powerful cell that produces thousands of proteins per cell per second at constant levels, over decades. Precision genome editing can now be used to engineer B Cells that produce therapeutic proteins of interest, driving a new class of cellular medicines – Engineered B Cell Medicines (BCMs) – with the potential to be durable, allogeneic, redosable and administered without pre-conditioning. The promise of BCMs could transform therapeutic biologics with broad application – across protein classes, patient populations and therapeutic areas. About Be Biopharma Be Biopharma (“Be Bio”) is pioneering Engineered B Cell Medicines (BCMs) to dramatically improve the lives of patients who are living with Hemophilia B and other genetic diseases, cancer, and other serious conditions. With eyes locked on the patient, our team of purpose-driven scientists, technologists, manufacturing experts and business builders collaborate to create a bold new class of cell therapies. Be Bio was founded in October 2020 by B cell engineering pioneers David Rawlings, M.D., and Richard James, Ph.D., from Seattle Children’s Research Institute. Be Bio is backed by ARCH Venture Partners, Atlas Venture, RA Capital Management, Alta Partners, Longwood Fund, Bristol Myers Squibb, Takeda Ventures, Seattle Children’s Research Institute and others. Since our founding, Be Bio’s investors have committed over $180 million to enable the Company to re-imagine medicine based on the power of B cell therapy. For more information, please visit us at Be.Bio and our LinkedIn page. View source version on businesswire.com: Contacts Investor Contact: ir@be.bio Source: Be Biopharma, Inc. View this news release online at: