Epidermolysis Bullosa Dystrophica

In laboratories around the globe, scientists are diligently researching the limitless potential of advanced therapeutic medicinal products (ATMPs). These groundbreaking therapies are changing the face of healthcare by harnessing the potential of the human body for healing. Using cells, proteins, antibodies, tissues and nucleic acids as “living” therapies is simultaneously promising, but also brings unique challenges from a manufacturing, supply chain, and patient treatment standpoint. The advent of ATMPs is a foundational milestone, the growth of which is comparable to the rise of the microprocessor in terms of its transformative potential for effecting change on humanity. The “holy grail” of ATMP-based treatments is to provide cures for some of the world’s most debilitating disease states, but for this to occur, a unified front is needed to democratize these therapies – collaboration from industry, academia, supply chain and, indeed, clinicians and hospitals is paramount to ensuring safe manufacturing and transit. The reasons for ATMPs garnering huge attention from the scientific community are well justified — ATMPs are now starting to demonstrate curative potential, not just symptomatic treatment, for a litany of rare or intractable diseases. These therapies also come in various forms — some can be classified as cell therapies, others as gene therapies, gene-modified cell therapies, nucleic acid drugs and other therapies including personalized cancer vaccines (PCVs), tissue engineered products, CRISPR-edited therapies and even radioligand therapies, among others. Still, despite their immense promise, additional research is needed before we fully understand and take advantage of the curative potential conferred by ATMPs. ATMPs have a long history but were not considered treatments in their earliest forms. In the 1950s, the concept of a “cell therapy” did not exist. Rather, experiments were being conducted to treat radiation victims with bone marrow transplants, but failed due to an unknown reason that we now know to be an immune response-mediated rejection. In 1956, the first ever bone marrow transplant was performed, with surprising results – an identical twin was the key to a successful engraftment, which led soon to the discovery of human leukocyte antigens (HLA), and the understanding that therapies from biological sources needed to match the donor and recipient HLA-type. Around the same time, Canadian researchers Till and McCulloch were performing similar experiments in irradiated mice and found injected bone marrow produces small nodules in the spleen. Since then, an immense body of work has shown that these cells can in fact self-renew and differentiate into multiple lineages, which led to the term “stem” cells, alluding to their being the origin of all tissues in our body. Today, we have reached new heights in our understanding of the complex signaling pathways and mechanisms of action that contribute to human disease. There are many milestones to speak of in the ATMP space, but most notable among them is a staggering 34,400 chimeric antigen receptor (CAR)-T cell therapies have been delivered to patients as of October 2023. There are now 34 FDA-approved cell or gene therapies in the commercial pipeline, with hundreds more in development. Today, there are six commercially approved CAR-T therapies on the market, and in some countries and regions, they are reimbursed by government health authorities, enabling their use in larger patient populations. Thanks to key pioneers in the field of ATMPs, we can now confidently report that therapies like CAR-T cells are forming a new foundation for cancer treatment. Of course, the story does not end here. Numerous other ATMPs are now being developed with greater potential for human treatment, such as allogeneic therapies, which can be delivered to an even larger patient population. These require larger bioreactors and healthy donor cell material but offer the promise of lower cost and wider accessibility. Similarly, a large body of work is being done to create therapies for the treatment of rare or orphan diseases. These include gene therapies based on adeno-associated viruses (AAV) that are being developed for both prevalent and rare disease states, such as congenital blindness, sickle cell disease, hemophilia B, dystrophic epidermis bullosa, and even diabetes and spinal muscular atrophy. As examples of commercial successes in this area, Luxturna, Zolgensma, Lyfgenia, and Vyjuvek are approved gene therapies for some of these rarest indications. More recently, new non-viral methods of production are being explored to avoid speculation around the possibility of replication competency that could arise from the use of viral vectors during production. For example, Vertex Pharmaceuticals and CRISPR Therapeutics made history by gaining the first FDA approval for a CRISPR-based drug, exagamglogene autotemcel (Casgevy) for the treatment of sickle cell disease with vaso-occlusive crisis, coinciding with a record number of 14 review designations awarded by the FDA to CRISPR-based therapies in 2023, according to data and analytics firm GlobalData. In 2023, a record six orphan drug designations, four fast track designations, two regenerative medicine advance therapy designations, and a single rare pediatric disease designation were granted, and priority review was awarded to 10 different CRISPR drugs, representing a 55% increase from 2021 and 2022. These numbers indicate an increased priority and appetite for ATMPs by regulators and manufacturers. At the end of 2023, there were more than 100 different approved gene, cell, and RNA therapies throughout the world, with over 3,700 more in development. Nucleic acid therapies gained infamy during the pandemic as a rapid and effective way to resolve a key global crisis through mRNA technology, but they also exposed weaknesses and revealed opportunities for new ATMP modalities. In more recent times, mRNA therapies are being used to create personalized cancer vaccines (PCVs), demonstrating their continued usefulness to larger patient populations with severe illnesses in a post-Covid world. Similarly, the advent of nuclear medicines, which has existed for decades, has brought a new contender to the sphere of radioligand therapy (RLT). This therapeutic modality is demonstrating efficacy for some of the most intractable solid tumor cancers, such as metastatic castration-resistant prostate cancer. While the focus for ATMPs has been on treating cancers like B cell lymphomas and leukemias, as well as rare disease like hemophilia B and sickle cell disease, novel application areas are emerging, such as treatments for diabetes, Alzheimer’s, and even cardiovascular disease. With this excitement comes the realization there is still work to be done to understand the underlying biology behind these ATMPs. As an example, it was recently reported that a small proportion of patients having received CAR-T therapy had also developed secondary cancers in the form of T cell malignancies, which now requires a box label warning. There are also known side effects for CAR-T therapies, which include cytokine release syndrome (CRS), immune effector-cell associated neurotoxicity syndrome (ICANS). Some patients, despite the high levels of response to the therapies broadly seen, do not survive their cancers in the end. Even with these setbacks, it is generally agreed the overall benefits of these ATMPs greatly outweigh their risks. Looking ahead, we must respond to the ever-increasing demand for ATMPs to ensure a consistent supply chain for the patients who require them.

▲5月30-31日 第八届广州生物医药创新者峰会 扫码立即报名 注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需得到授权。近日，致力于开发治疗严重疾病的基因和细胞疗法的Abeona Therapeutics公布了2023年全年财务业绩，并介绍了公司主要目标的最新进展。2023年，Abeona年度许可及其他收入为350万美元，同比大增148%，主要和与Taysha Gene Therapies签订基于AAV的雷特综合症基因疗法的许可协议支付的临床里程碑款项相关。研发费用为3110万美元，同比增长7%，与 BLA 活动相关的人员增加有关。截至2023年12月31日，Abeona现金、现金等价物、受限现金和短期投资共计 5,260万美元，与去年基本持平；2023年用于运营活动的净现金为3700万美元，同比下降15%。Abeona还公布了近期进展：2023年11月27日，FDA同意优先审查pz-cel(prademagene zamikeracel，EB-101)用于治疗隐性营养不良性大疱性表皮松解症（RDEB）的生物制剂许可申请（BLA），处方药使用者付费法案（PDUFA）的目标日期为2024年5月25日。Pz-cel是一款体外基因校正的自体细胞疗法，将COL7A1胶原蛋白基因插入到患者自身的皮肤细胞（角质形成细胞）中，再将这些工程化后的细胞送回患者体内。EB-101能够促进7型胶原蛋白的生产，进而帮助患者的伤口愈合。此疗法已获得美国FDA突破性疗法认定，孤儿药资格、罕见儿童疾病资格以及欧洲药品管理局（EMA）的孤儿药资格。关键的3期VIITAL™ 研究评估了pz-cel对 RDEB 患者的疗效、安全性和耐受性。VIITAL™研究达到了两个共同的主要疗效终点，表明在大面积慢性RDEB伤口愈合和减轻疼痛方面，pz-cel具有显著的统计学意义和临床意义。Abeona 还宣布，FDA已完成了对其位于俄亥俄州克利夫兰的生产设施的许可前检查 (PLI)，该检查与公司针对隐性营养不良型大疱性表皮松解症（RDEB）的pz-cel生物制品许可申请 (BLA) 有关。2024年1月，FDA完成了对Abeona的生物研究监测 (BIMO) 检查和有关pz-cel BLA的中期会议。BIMO检查完成后，FDA检查员没有发布任何意见或FDA 483表格。在BLA周期中期审查会议上，FDA 重申目前不打算为pz-cel召开咨询委员会。此外，FDA建议，尽管审查正在进行中，但目前预计不会对pz-cel BLA进行风险评估和缓解策略（REMS），并再次确认了PDUFA的目标日期为2024年5月25日。2024年3月，Abeona 收到了书面企业检查报告 (EIR)，这是FDA关于BIMO检查的正式报告。检查结果确定，研究中心的监测或管理、知识产权责任、研究中心文件的保存或安全监督方面不存在缺陷。Abeona 继续推进关键的商业活动，为可能在美国推出pz-cel做准备，包括与EB治疗机构进行入职讨论、与支付方接触、聘用关键的商业角色以及开展市场调研。公司最近完成了支付方市场调研，结果表明，pz-cel的报销价格与获批基因疗法的价值相当，后者在一次性应用后可提供多年的持久疗效。总结去年Krystal Biotech开发的基因疗法Vyjuvek获得美国FDA的批准上市。这一批准拿下了多个“第一”，它是FDA批准的第一款可重复给药的基因疗法，也是首个FDA批准的外用基因疗法。同时，它为营养不良性大疱性表皮松解症（DEB）患者带来了首款获批的基因疗法。如果pz-cel获批，则将成为第二款获批治疗DEB的基因疗法，将为DEB患者提供又一个突破性治疗选择。参考资料：公司官网版权声明：本文转自细胞基因治疗前沿，如不希望被转载的媒体或个人可与我们联系，我们将立即删除 活动推荐  8月 • 第六届CMC-China博览会  关键词：  生物药、小分子创新药、药学CMC&创新&CXO、原辅包（点击下方图片查看详情）▼【关于药融圈】药融圈PRHub旨在帮助生物医药科技型企业进行品牌推广及商务拓展服务，针对客户的真实需求制定系统化解决方案，通过“翻译-降维-场景化”将客户的品牌信息以直白易懂的方式被公众知悉，同时在流量渠道覆盖100万+垂直用户基础上实现合作目的，帮助合作伙伴完成从品牌开始到商务为终的闭环营销服务。我们已经完成了数十场线下1000人规模的生物医药研发类会议，涵盖小分子新药，大分子新药，改良型新药，BD跨境交易等多个领域，服务了百余家上市/独角兽/生物技术/制药企业。

日前，Almirall和Eloxx Pharmaceuticals宣布，两家公司已就ZKN-013项目签订独家许可协议。根据协议，Almirall将获得ZKN-013的全球开发和商业化权利，包括用于孤儿皮肤病的治疗。该药物在健康受试者中的1期临床试验即将展开。 ZKN-013是Eloxx专有TURBO-ZM平台所开发的主打项目。该平台利用化学技术开发新型核糖体调节剂，以开发新的潜在疗法。ZKN-013是一种口服无义突变通读药物，它使宿主细胞能够克服无义突变，这些突变会产生过早终止密码子，进而导致无功能的蛋白质产生。由于这类突变所造成的疾病包含隐性营养不良性大疱性表皮松解症（RDEB）、交界性大疱性表皮松解症（JEB）和家族性腺瘤性息肉病（FAP）。ZKN-013有望成为这些疾病的疗法。 临床前实验结果显示，ZKN-013在RDEB/JEB患者细胞和多发性肠肿瘤（APCmin）小鼠中表现出强大的疗效。ZKN-013可诱导RDEB患者细胞产生功能性全长COL7蛋白。ZKN-013也正在开发用于治疗具有无义突变的FAP患者，其特征是结肠息肉增殖并进展为结肠癌。FAP是一种罕见的胃肠道疾病，患者因APC基因突变而进展为结肠癌。 作为该协议的一部分，Eloxx将获得300万美元的预付款，以及整个潜在开发阶段的额外付款，包括高达4.7亿美元的监管和其他相关里程碑款项。 参考资料：[1] Almirall and Eloxx Pharmaceuticals Enter into Exclusive Agreement to license ZKN-013 for rare dermatological diseases. Retrieved March 15, 2024 from https://www.almirall.com/newsroom/news/almirall-and-eloxx-pharmaceuticals-enter-into-exclusive-agreement-to-license-zkn-013-for-rare-dermatological-diseases 内容来源于网络，如有侵权，请联系删除。