Vandefitemcel

作为生物制药的一大前沿，细胞疗法越来越受业界重视，也成为不少国家抢占的高地，日本就是这样的代表。 2012年，因发现诱导多能干细胞（iPSC）技术，日本京都大学教授山中伸弥获得诺贝尔奖。此后，日本政府开始积极在细胞治疗领域布局。 通过建立《再生医学促进法》《再生医学安全法》等特殊法规监管途径，十多年来，日本不遗余力地鼓励细胞疗法的开发和商业化，批准了许多产品。它们大部分是由日本公司推出的，但也包括来自欧美MNC的CAR-T疗法。 然而，由于某些产品的疗效缺乏可预测性，日本近期修改了该领域的法规，谨慎地缩小附条件批准范围，降低价格补贴。 商业探索喜忧参半，一些细胞产品已退出日本市场。对于其他国家，能从日本的处境看到多少自己的影子？ 1 18种获批细胞疗法 到目前为止，日本已经批准了18种细胞疗法，包括两款基于附条件批准框架的产品。 适应症分布上，用于治疗血液瘤的产品最多，共计6种。在神经、眼科、骨科等其他疾病领域，也都有疗法覆盖。 从地域看，12种疗法来自日本，占比近七成。其中，光是J-TEC就推出5种。2015年之前，J-TEC的Jace（自体培养表皮）和Jacc（自体培养软骨）是日本仅有的两款获批细胞产品。 改变日本细胞疗法产业环境的关键之年是2012年，山中伸弥因相关研究获得诺贝尔奖。此后，被视为具有广阔前景的iPSC领域，也开始受到日本政府层面的支持。 很多适应症都是在那之后获得批准的。最近一款上市产品，是由日本公司SanBio开发的同种异体间充质干细胞疗法Akuugo，用于改善与创伤性脑损伤相关的慢性运动性麻痹。7月底，Akuugo首次获得附条件批准。 2 安倍“十年战略” 2013年，时任日本首相安倍晋三在其经济政策中指出，政府应牵头推动创新医疗研发的全国性举措，并承诺到2022年这10年间，投资1100亿日元（约合7.53亿美元）支持再生医学发展。 到2014年，安倍政府通过内阁府推动《健康医疗战略推进法》出台，并于2015年成立了专门负责协调和支持国内药物研发项目（不仅仅是细胞疗法）的日本医学研究开发机构（AMED）。 AMED旨在通过横跨厚生劳动省（MHLW）、经济产业省（METI）以及文部科学省（MEXT）三个部门，架起政府、公司和学术机构的桥梁。 从2015年到2020年，AMED每年提供约140亿到160亿日元（约合0.97亿到1.11亿美元）用于支持国内药物研发，其中近一半（65亿日元）用于iPSC领域。 3 附条件批准框架 大约在安倍政府提供资金支持的同一时间，日本颁布了《再生医学促进法》，对《药品和医疗器械法案》进行修订，引入细胞和基因疗法等再生医学产品的附条件批准框架。 改革前，小分子药物等疗法必须经过昂贵且繁琐的三个阶段临床试验，才能获得日本药品和医疗器械管理局（PMDA）的批准。 为了缩短上市时间，该方案允许在若干条件下，提前批准已证实安全性和具备“潜在”疗效的疗法。之后，这些产品需要开展上市后的试验以确认疗效，并在附条件批准期内提交申请以获得全面批准。 Nature刊登的一篇文章介绍，基于这个框架，再生医学疗法开发商将不必按照阶段推进临床，而是在一项试验研究中证明疗效。如果变化足够显著，则一次试验中至少要有10名患者；如果改善幅度较小，则要有几百名患者。 2014年11月，PMDA在一份解释性文件中表示，对iPSC相关产品的高期望和解决潜在安全风险的监管方法是该方案的关键。 从2017年开始，附条件批准框架扩大到包括非再生创新药物。 4 分化的商业市场 得益于这些转变，监管部门自2015年以来越来越频繁地对细胞和基因疗法产品点头。然而，日本也不得不的面临随之而来的问题，例如，产品附条件批准后的疗效不及预期，日本国民健康保险（NHI）计划中的成本与效益平衡压力。 2015年，JCR Pharmaceuticals申报的同种异体骨髓源间充质干细胞（MSC）产品Temcell、Terumo申报的自体成骨肌源性细胞片产品HeartSheet，分别获得附条件批准。 Temcell基于2003年由Osiris Therapeutics授权的MSC技术开发，被批准用于移植物抗宿主病，这是一种发生在同种异体骨髓移植患者中的严重并发症。Temcell每次治疗价格约为1400万日元，并成为日本最成功的细胞疗法之一，在2023年创造32亿日元（2210万美元）的收入。 不过，HeartSheet就没那么幸运了。最初，HeartSheet获得治疗严重心力衰竭的5年有条件批准，但由于其适应症小等诸多限制，后来在上市后试验中招募患者时遇到困难。 附条件批准期延长至8年后，Terumo在2023年申请全面批准，但未能证明其有效性。最终，Terumo决定在今年将HeartSheet撤出市场。 另一个与之相似的案例，是日本公司Nipro开发的自体骨髓来源MSC产品Stemirac，附条件批准期间从2018年到2025年，用于改善与创伤性脊髓损伤相关的神经症状和功能障碍。 自COVID-19以来，Nipro在Stemirac商业化方面受阻。最近该公司表示，它的目标是在2025年申请全面批准，并扩大与医疗机构的合作，以获得收入。 5月，Nipro披露的最新财务报告说：“COVID-19的两年中，由于优先考虑重症患者，对Stemirac的管理一直很困难，其收入未能达到最初的预测。” 5 收窄加速通道 附条件批准框架施行十年后，今年3月，MHLW发布一项新指南，以说明如何通过上市后的研究计划来认定细胞疗法的有效性。 指南提到，药企和监管机构应事先明确附条件批准后所开展试验的适当性，应涉及病例数、开展试验的地点数、参数的客观性、病例的随机化、评价的盲法、对照组的建立等方面。为此，指南还提出了统计学上可推测有效性的参考基准。 MHLW此举的背景是，2020年到2023年，日本政府根据此前“十年战略”的框架，对未来的创新药品政策进行一系列讨论。 6月，因为附条件批准期限届满，AnGes撤回了日本首款基因疗法Collategene的制造和营销批准申请。随着Collategene、HeartSheet等几款产品证明其疗效的失败，MHLW认为，通过哪种类型的数据，并以怎样的准确性“推测”疗效，成为日本的关键挑战之一。 “重要的是要有某种指导方针来推定有条件批准的效力。”去年，MHLW在就这一问题撰写的最终报告里写道。 截至2024年，没有任何附条件批准的细胞治疗产品在日本成功获得全面批准。 6 国家医保“砍价” 日本细胞疗法开发商面临的另一个挑战是，NHI降低了报销价格。有几种产品由于价格昂贵，已根据成本效益评估（CEA）框架进行了审查。 CEA框架自2019年推出，旨在通过增加另一种价格评估选项，来“补充日本的药品定价体系”，帮助维持NHI报销费率内的财务平衡。CEA导致的最大降价幅度为15%。MHLW指出，如果产品在初始定价中获得的溢价低于25%，则降价幅度将限制在10%以内；如果溢价超过25%，则降幅最高不超过15%。 数种CAR-T细胞疗法——包括吉利德的Yescarta，BMS的Breyanzi和Abecma，诺华的Kymriah——已在日本获得了报销价格。 MHLW最初通过成本计算方法，在2019年将Kymriah的报销价格定为约3411.37万日元（约合23.43万美元）。这是在诺华的基因疗法Luxturna于2023年登陆日本市场前，在NHI获得的最高价格。 2021年，通过CEA审查，和安进的Blyncito、辉瑞的Besponsa等其他几种疗法进行比较后，MHLW将Kymriah的价格下调了4.3%，至3264.78万日元。该机构指出，Kymriah在首次定价时的生产成本缺乏透明度（低于50%）。 Yescarta、Breyanzi和Abecma预计也将在日本的CEA框架下接受审查。 7 本土尚有后来者 尽管监管立场日趋谨慎，日本目前还有其他细胞疗法处于临床开发当中。 Healios K.K.的同种异体骨髓来源的多能祖细胞候选药物HLCM051，目前正处于治疗急性呼吸窘迫综合征的III期研究。1月，在美国开展的另一项治疗缺血性卒中的III期项目中，HLCM051错过了主要终点。 另一家专注于CAR-T疗法的日本公司Noile-Immune，旗下NIB101、NIB102已处于I期临床，分别靶向GM2和GPC3。 2023年6月，Noile-Immune在本土IPO，但目前股价跌幅超过70%。 Noile-Immune遭遇了几次挫折，包括终止与武田就NIB102的研发合作。不过，该公司近期表示，它仍将继续推进NIB102。 参考资料： 1.Progress Or Hype? Looking At A Decade Of Cell Therapy In Japan；Pink Sheet 2.Japan to offer fast-track approval path for stem cell therapies；Nature 3.医薬品医療機器総合機構（PMDA）のウェブサイト；PMDA 4.BRIEF—Collategene sales rights deal terminated in Japan and the USA；Pharma Letter 5.Japan’s CEA Scheme: How It Works And Impact So Far；Pink Sheet 6.Cell Therapy HLCM051 Fails to Improve Stroke Outcomes Despite Safe Profile；NeurologyLive 同写意媒体矩阵，欢迎关注↓↓↓

– World’s First Therapeutic Agent for Regenerating Brain – TOKYO, Japan I July 31, 2024 I SanBio Co., Ltd. (TOKYO:4592) (head office: Tokyo, representative director & CEO: Keita Mori) hereby announces that today on July 31 2024, it obtained conditional and time-limited marketing approval for the human somatic stem cell-processed product “AKUUGO ® suspension for intracranial implantation” (INN: vandefitemcel; hereafter, “AKUUGO ® ”) in Japan, for the indication of improving chronic motor paralysis resulting from traumatic brain injury. Traumatic brain injury (TBI) is caused by a strong external force, such as from a traffic accident or a fall, applied to the head, damaging the brain tissue within the skull. The manifestation and timing of symptoms of TBI vary widely among patients, and depending on the affected area of the brain, patients may experience aftereffects such as motor dysfunction or higher brain dysfunction. Studies suggest that destroyed or damaged brain tissues do not regenerate naturally, and patients who enter the chronic phase of TBI and develop motor paralysis face lifelong impacts on their daily and social lives, indicating that there is a significant unmet medical need. AKUUGO ® has been shown to be effective in improving chronic motor paralysis associated with TBI, and is the world’s first and only allogeneic cell therapeutic agent* approved for this indication. AKUUGO ® is also a world first in that it facilitates the regeneration of brain, and its approval for practical clinical use marks a significant milestone. AKUUGO ® is an allogeneic cell product manufactured by culturing bone marrow-derived mesenchymal stem cells collected from healthy donors and transiently transfecting the human Notch-1 intracellular domain gene into the cultured cells to enhance their ability to regenerate nerve cells. The transplantation of AKUUGO ® into damaged nerve tissues in the brain is expected to trigger the release of FGF-2 (a type of protein) and other substances, which in turn will promote the natural regenerative ability of damaged nerve cells and induce proliferation and differentiation of nerve cells. The results of basic research have also shown that AKUUGO ® has protective effects on nerve cells, induces angiogenesis, and demonstrates immunomodulating effects. Mori Keita CEO of SanBio commented as follows. “We are extremely pleased to announce that we have obtained conditional and time-limited approval for AKUUGO ® after 24 years in operation, enabling us to provide it as a new treatment option for TBI patients in Japan. AKUUGO ® , which is directly administered to the brain, represents an innovative and crucial choice for patients with chronic motor paralysis associated with TBI. Through AKUUGO ® , we hope to bring hope to the lives of as many TBI patients as possible.” The approval of AKUUGO ® was based on the results of the global Phase 2 clinical trial SanBio conducted in Japan and the United States. Dr. Nobuhito Saito, Professor of Neurology at the University of Tokyo led the clinical trial, commented as follows. “Traumatic brain injury can affect various areas of the brain, and the site and extent of the damage determine the duration and severity of symptoms, as well as aftereffects. Rehabilitation in the acute phase is effective in restoring a certain level of motor function; however, because damaged brain cells do not regenerate, there has been no effective treatment for chronic motor deficit and other aftereffects of traumatic brain injury. The approval of AKUUGO ® may provide a new treatment option for patients suffering from the chronic aftereffects of traumatic brain injury, and I look forward to seeing further progress in research and analysis.” Dr. David O. Okonkwo, Professor of neurological surgery and director of the Neurotrauma Clinical Trials Center at University of Pittsburg commented as follows. “Patients with chronic traumatic brain injury experience lifelong disability affecting quality of life, particularly those with motor deficits. Living with traumatic brain injury also places burdens on the caregivers who support them. The approval of AKUUGO ® is a breakthrough and opens a new chapter in the treatment of motor deficits in chronic traumatic brain injury.” Dr. Hideyuki Okano, a Keio University professor and SanBio’s founding scientist who has supported the Company over many years, commented as follows. “For more than 20 years, SanBio has conducted R&D in the field of brain regenerative medicine. I’m pleased that AKUUGO ® has been approved for treating chronic motor paralysis resulting from traumatic brain injury, the first such treatment to be approved in the world, and thrilled to offer the product as a new treatment option to patients in Japan. The approval of AKUUGO ® in Japan, ahead of anywhere else in the world, brings us closer to achieving our goal of supporting patients with central nervous system disorders, especially brain disorders, around the world who still suffer from the lack of effective treatment options.“ Reference Product Overview *About allogeneic cell transplantation Regenerative medicine therapies can be classified into autologous and allogeneic cell therapies. In autologous cell transplantation, the patient’s own cells are harvested and used, but cell processing procedures are time-consuming and labor-intensive. In allogeneic cell transplantation, on the other hand, cells are collected from a donor and cultured in large quantities. Since allogeneic cell medicines can be mass produced, they can treat a large number of patients. About Traumatic Brain Injury Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. The estimated global incidence of acute TBI during 2016 was 27 million cases, and the estimated global prevalence of chronic impairment secondary to TBI was 55.5 million cases* 1 . Overall, TBI and long-term motor deficits secondary to TBI significantly impair a person’s self-care, employability, and quality of life, and are major burdens on healthcare systems worldwide. In the United States, approximately 43% of surviving hospitalized persons with TBI experience long-term disabilities* 2 , and it is estimated that 3.17 million people are living with long-term disabilities secondary to TBI* 3 . There are about 60,000* 4 TBI patients in Japan, and of which, 20%* 5 are estimated to suffer from aftereffects of the injury. About “AKUUGO ® suspension for intracranial implantation” AKUUGO ® suspension for intracranial implantation(INN: vandefitemcel) is a human (allogeneic) bone marrow-derived modified mesenchymal stem cell that is produced by modifying and culturing mesenchymal stem cells derived from the bone marrow aspirate of healthy adults. The transplantation of AKUUGO ® into damaged nerve tissues in the brain is expected to trigger the release of FGF-2 (a type of protein) and other substances, which in turn will promote the natural regenerative ability of damaged nerve cells and induce proliferation and differentiation of nerve cells. The conditional and time-limited approval was based on the results of SanBio’s global Phase 2 clinical trial. The primary endpoint of the trial—mean change from baseline in Fugle-Meyer Motor Scale (FMMS) score at 24 weeks after treatment—was met, with the AKUUGO ® -treated group reporting 8.3-point improvement versus 2.3 for the control group, demonstrating a statistically significant difference. The final analysis of the study was presented at the annual meeting of American Academy of Neurology. We are pushing forward with R&D targeting multiple indications, including chronic effects associated with chronic cerebral infarction. About SanBio Group (SanBio Co., Ltd. and SanBio, Inc.) SanBio is engaged in the regenerative cell business—we research, develop, manufacture, and sell regenerative cell medicines. In July 2024, under the Sakigake Designation Program, we obtained conditional and time-limited approval for our mainstay product AKUUGO ® for the indication of improving chronic motor deficit resulting from traumatic brain injury. Going forward, we will continue focusing our R&D efforts on central nervous system disorders with significant unmet medical needs that cannot be addressed by existing medicine or drugs. The Company is headquartered in Tokyo, Japan and Oakland, California, and additional information about SanBio Group is available at https://sanbio.com/en/ References 1 James SL, et al. “Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990- 2016: a systematic analysis for the Global Burden of Disease Study 2016.” Lancet Neurol 2019;18:56-87. 2 Selassie AW, et al. “Incidence of long-term disability following traumatic brain injury hospitalization, U.S.”, 2003. J Head Trauma Rehabil 2008;23:123-31 3 Zaloshnja E, Miller T, Langlois JA, Selassie AW. Prevalence of long-term disability from traumatic brain injury in the civilian population of the United States, 2005. J Head Trauma Rehabil. 2008 Nov-Dec;23(6):394-400. 4 The number of patients under “19 Injury, poisoning, and other consequences of external causes (intracranial injuries)” in Patient Survey 2020, the Ministry of Health, Labour and Welfare 5 The number of patients under “T905 After effects of intracranial injury” in Patient Survey 2020, the Ministry of Health, Labour and Welfare SOURCE: SanBio