Commissariat à l´énergie atomique et aux énergies Alternatives

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↓↓↓

People living with HIV need to take antiretroviral treatment for life to prevent the virus from multiplying in their body. But some people, known as 'post-treatment controllers,' have been able to discontinue their treatment while maintaining an undetectable viral load for several years. Starting treatment early could promote long-term control of the virus if treatment is discontinued. People living with HIV need to take antiretroviral treatment for life to prevent the virus from multiplying in their body. But some people, known as "post-treatment controllers," have been able to discontinue their treatment while maintaining an undetectable viral load for several years. Starting treatment early could promote long-term control of the virus if treatment is discontinued. Scientists from the Institut Pasteur, the CEA, Inserm, Université Paris Cité and Université Paris-Saclay, in collaboration with Institut Cochin[1] and with the support of MSD Avenir and ANRS Emerging Infectious Diseases, used an animal model to identify a window of opportunity for the introduction of treatment that promotes remission of HIV infection: it appears that starting treatment four weeks after infection promotes long-term control of the virus following the interruption of treatment after two years of antiretroviral therapy. These results highlight how important it is for people with HIV to be diagnosed and begin treatment as early as possible. The findings were published in the journal Nature Communications on January 11, 2024. Research on the VISCONTI cohort, composed of 30 post-treatment controllers, has provided proof of concept of possible long-term remission for people living with HIV. These individuals received early treatment that was maintained for several years. When they subsequently interrupted their antiretroviral treatment, they were capable of controlling viremia for a period lasting more than 20 years in some cases. At the time (in 2013), the team leading the VISCONTI study suggested that starting treatment early could promote control of the virus, but this remained to be proven. In this new study, the scientists used a primate model of SIV2 infection which allowed them to control all the parameters (sex, age, genetics, viral strain, etc.) that may have an impact on the development of immune responses and progression to disease. They compared groups that had received two years of treatment, starting either shortly after infection (in the acute phase) or several months after infection (in the chronic phase), or no treatment. The reproducible results show that starting treatment within four weeks of infection (as was the case for most of the participants in the VISCONTI study) strongly promotes viral control after discontinuation of treatment. This protective effect is lost if treatment is started just five months later. "We show the link between early treatment and control of infection after treatment interruption, and our study indicates that there is a window of opportunity to promote remission of HIV infection," comments Asier Sáez-Cirión, Head of the Institut Pasteur's Viral Reservoirs and Immune Control Unit and co-last author of the study. The scientists also demonstrated that early treatment promotes the development of an effective immune response against the virus. Although the antiviral CD8+ T immune cells developed in the first weeks after infection have very limited antiviral potential, the early introduction of long-term treatment promotes the development of memory CD8+ T cells, which have a stronger antiviral potential and are therefore capable of effectively controlling the viral rebound that occurs after treatment interruption. "We observed that early treatment maintained for two years optimizes the development of immune cells. They acquire an effective memory against the virus and can eliminate it naturally when viral rebound occurs after discontinuation of treatment," explains Asier Sáez-Cirión. These results confirm how important it is for people with HIV to be diagnosed and begin treatment as early as possible. "Starting treatment six months after infection, a delay that our study shows results in a loss of effectiveness, is already considered as a very short time frame compared with current clinical practice, with many people with HIV starting treatment years after infection because they are diagnosed too late," notes Roger Le Grand, Director of IDMIT (Infectious Disease Models for Innovative Therapies) and co-last author of the study. "Early treatment has a twofold effect: individually, as early treatment prevents diversification of the virus in the body and preserves and optimizes immune responses against the virus; and collectively, as it prevents the possibility of the virus spreading to other people," adds Asier Sáez-Cirión. Finally, these results should guide the development of novel immunotherapies targeting the immune cells involved in the remission of HIV infection. These are the initial results of the p-VISCONTI study, which began in 2015 in collaboration with the institutions cited above and received funding from MSD Avenir and the support of ANRS Emerging Infectious Diseases as part of the RHIVIERA consortium. [1] Institut Cochin is a biomedical research center affiliated with Inserm, the CNRS and Université Paris Cité. 2 SIV: simian immunodeficiency virus only affects non-human primates. SIV infection of animals recapitulates the key features of human HIV infection.

EMERYVILLE, Calif. and GRENOBLE, France, Nov. 15, 2023 /PRNewswire/ -- Injectsense Inc., a sensor-enabled digital health company, and sister company Injectpower, a developer of ultra-miniature solid-state microbatteries for medical applications, today announced combined funding of $9.4 million to bring highly integrated autonomous implantable devices – smaller than a grain of rice -- to production. Continue Reading Injectpower's solid-state microbattery for implantables or existing medical devices. The rechargeable lithium microbatteries can be as thin as a human hair and offer energy densities 5 to 10 times greater than current commercial capability and a lifetime of several thousands of cycles. The implantable sensors, which monitor key indicators over decades, offer a disruptive capability at a time when most diagnostic tools are a mere static snapshot. Physiological markers are typically dynamic and vary widely over a 24-hour period. Such is the case with glaucoma, where intraocular pressure (IOP) is measured in the doctor's office during daylight hours. Injectsense sensors measure IOP continuously, even during sleep, when pressure can spike significantly and cause vision loss over the long term. The funds will serve to further consolidate the two companies' combined global supply infrastructure to create an advanced medical device cluster for implantables based in France. The cluster will streamline business opportunities, enable improved supply chain management, and support Injectsense's February 2024 first-in-human studies for sensors that continuously measure intraocular pressure (IOP). Injectsense already produces hundreds of prototype devices and is ramping up to thousands in 2024. Besides IOP sensors, it is also producing sensors for intracranial pressure (ICP) measurement and is building a path to cardiovascular pressure monitoring applications.The funding consists of a $2.5M bridge investment from private investors for Injectsense as it moves into clinical IOP studies and final product development incorporating rigorous quality management systems. The funding also includes €6.5M (US$7M) for Injectpower, which is readying its energy-dense, solid-state lithium-ion technology for transfer to production."As a company driven by worldwide medical needs including learning more about the pathology of glaucoma, our infrastructure to support production must be global," said Ariel Cao, CEO/president and co-founder, Injectsense Inc. "We are excited to be moving towards full-scale battery production with the unique capabilities of Injectpower in our medical supply chain cluster, which will support our work in human clinical studies." Injectsense funding useInjectsense has provided sensors to Johns Hopkins University's Wilmer Eye Institute for animal testing under the guidance of Dr. Thomas Johnson III, M.D. The Institute is currently completing its study. The company used recent funding from the NIH for the latest iteration of its sensor. This version will be used for first-in-human studies by Dr. Juan Jose Mura in Santiago, Chile. The study will be conducted over months, with data available in late spring (and earlier for Injectsense's ophthalmic device partner), with the aim of collecting long-term safety and clinical data.The study will allow Injectsense to finalize its product development under its quality system for ramp-up to clinical studies in 2025. The Injectsense board of medical advisors, including glaucoma specialists from leading medical institutions, actively contribute on design considerations and in particular safety aspects of the in-office delivery and self-anchoring procedure. The final product, iOP-Connect™, will offer continuous and autonomous long-term measurement of IOP 24/7 over decades, with weekly recharging and data uploads. The iOP-Connect data analysis software will identify clinically actionable information based on parameters specified by the physician. Injectpower funding useInjectpower funding comes from private and commercial investors that include the IDEC Group, business angels from the French Silicon Valley as well as Bpifrance and banking partners. The company was founded in 2020 based on 20 years of technology development at French research institute CEA, and more than 40 patents. Injectpower aims to catalyze the energy storage market for medical implants. The company is building a proprietary 200mm MEMS fabrication facility in Grenoble, France, that will produce the batteries and other components.The company's technology enables customization of rechargeable lithium microbatteries as thin as a human hair. The batteries are safe and among the smallest and most integrated on the market today, offering energy densities 5 to 10 times greater than current commercial capability, high reliability and a lifetime of several thousands of cycles. The first components have already been developed, characterized and tested on a pre-commercial 200mm microelectronic supply chain with support from CEA/LETI, for Injectsense."We are convinced that the Injectpower solution is a game-changer in energy storage for medical applications," said Patrice Lafargue, president, IDEC Group, the leading investor in Injectpower through its investment fund Groupe IDEC Invest Innovation, and a major player in the pharmaceutical and cosmetics sector through its subsidiary IDEC Health. "Their vision addresses a true gap in this sector. We want to help the company to ready its product line and support them as they deploy this commercial tool in France." About Injectsense Injectsense is a sensor-enabled digital health company that enables tracking of progressive disease indicators and assessment of therapy effectiveness. The company's Silicon Valley and Twin Cities product teams combine cutting-edge advances in microelectronics with best-in-class medical device development and expertise. Its systems provide continuous, clinically actionable information through an implantable ultra-miniature sensor coupled with a secure digital health platform. Injectsense received Series B funding in April 2019 and is expecting to close a Series C round in 2024. Injectsense currently has development revenue from a major non-ophthalmic device company. It has established a supply chain with the capacity for hundreds of thousands of devices per month. The device is currently for clinical investigation only and is not commercially available. For more information visit injectsense.com. For more information contact: Tom Breunig Director of Communications Injectsense Inc. (510) 847-1637 [email protected] SOURCE Injectsense