University College London

-Eisai Initiates Phase II Clinical Study on Sporadic Early Alzheimer's Disease- TOKYO, Oct. 30, 2024 /PRNewswire/ -- Eisai Co. Ltd (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") announced today that the latest findings on anti-MTBR (microtubule binding region) tau antibody E2814 were presented at the 17th annual Clinical Trials on Alzheimer's Disease (CTAD) conference, held in Madrid, Spain, and virtually. Eisai also announced initiation of a Phase II study (Study 202) on E2814 for sporadic early Alzheimer's Disease (AD). Impact of the anti-MTBR tau antibody E2814 on tau pathology biomarkers in Dominantly Inherited Alzheimer's Disease (DIAD) E2814 is an investigational anti-MTBR tau antibody designed to target the microtubule binding region (MTBR) of tau. In AD patients, neurofibrillary tangles (NFT) are a pathological hallmark, and they are believed to spread through synaptically connected pathways in the brain, forming the tau propagation hypothesis. It is thought that tau propagation is driven by the specific tau species containing MTBR, tau seeds that spread tau pathology to different brain regions important for cognition and function. Eisai conducted a Phase I/II clinical study (Study 103, NCT04971733; 7 participants) of the anti-MTBR tau antibody E2814 in patients with Dominantly Inherited Alzheimer's Disease (DIAD) beginning in June 2021. This study aimed to evaluate the safety and tolerability of E2814 in DIAD patients, with a primary objective of assessing the target engagement of E2814 with MTBR-tau species in their cerebrospinal fluid (CSF). In addition, pharmacodynamic evaluation was performed using multiple biomarkers related to AD tau pathology. In the study, DIAD patients with clinical symptoms were administered E2814 for 12 to 24 months. Data from the Dominantly Inherited Alzheimer Network Observational Study (DIAN-obs), an observational cohort of DIAD, were used as references to evaluate biomarkers changes in E2814 treatment. Compared to the reference data from DIAN-obs, patients who received E2814 showed approximately 75% and 50% reductions of CSF MTBR-tau243 and p-tau217, respectively, reflecting tau pathophysiology. Additionally, brain tau accumulation observed by tau PET was stabilized or trended toward decrease in DIAD subjects administered E2814. These results suggest that E2814 inhibited tau propagation and suppressed the accumulation of tau aggregates in brains of people living with DIAD. This will be further investigated in the ongoing Phase II/III Tau NexGen study (NCT05269394) with DIAD patients and the Phase II 202 study (NCT06602258) with sporadic early Alzheimer's disease (AD) patients. Initiation of Phase II clinical study (Study 202) In September 2024, Eisai initiated a Phase II clinical study (Study 202) for individuals with early AD in the United States. The study is also scheduled to be conducted in Japan in the future. This study is a placebo-controlled, double-blind, parallel-group, dose exploration study, evaluating the safety, tolerability, and biomarker efficacy of E2814 in people living with early AD receiving lecanemab as a backbone anti-Aβ therapy. Eisai positions neurology as a key therapeutic area, and it will continue to create innovation in the development of novel medicines based on cutting-edge neurology research as it seeks to contribute further to improving the benefits of affected individuals and their families in diseases with high unmet needs, such as dementia including AD. This release discusses investigational uses of agents in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that such investigational agents will successfully complete clinical development or gain health authority approval. [Notes to editors] About E2814 An investigational anti-microtubule binding region (MTBR) tau antibody, E2814 is being developed as a disease-modifying agent for tauopathies including sporadic Alzheimer's disease (AD). Phase I clinical studies are underway. E2814 was discovered as part of the research collaboration between Eisai and University College London. E2814 is designed to prevent the spreading of tau seeds within the brains of affected individuals. In addition, E2814 has been selected as an anti-tau therapy in a Phase II/III Tau NexGen study for the treatment of DIAD, conducted by DIAN-TU led by Washington University School of Medicine in St. Louis, is underway. Biomarkers related to AD tau pathology As fluid biomarkers related to AD tau pathology, tau containing the residue 243 (MTBR-tau243) and tau phosphorylated at the residue 217 (p-tau217) in CSF have been reported.1 In addition, positron emission tomography (tau PET), which specifically detects tau aggregates, is used as an imaging biomarker. These biomarkers are included in the Revised criteria for diagnosis and staging of Alzheimer's disease published by the National Institute on Aging and the Alzheimer's Association (NIA-AA) in June 2024.2 References Horie K, et al. CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer's disease. Nat Med. 2023. 29. 1954-1963 Jack Jr. CR, et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement. 2024. 20. 5143-5169 SOURCE Eisai Inc. 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Media Release SYDNEY, AUSTRALIA, Oct. 28, 2024 (GLOBE NEWSWIRE) -- Immutep Limited (ASX: IMM; NASDAQ: IMMP) ("Immutep” or “the Company”), a clinical-stage biotechnology company developing novel LAG-3 immunotherapies for cancer and autoimmune disease, today announces it will present new data from Cohort B of the TACTI-003 Phase IIb trial in first line recurrent/metastatic head and neck squamous cell carcinoma patients with negative PD-L1 expression (CPS <1) at the European Society for Medical Oncology Immuno-Oncology (ESMO I-O) Congress 2024 taking place 11-13 December in Geneva, Switzerland. Presentation details: Title:TACTI-003 Cohort B: Eftilagimod Alpha (Soluble LAG-3) and Pembrolizumab in First-Line Recurrent or Metastatic Head & Neck Squamous Cell Carcinoma with CPS <1Presenter:Martin Forster, M.D., Ph.D., University College London (UCL) Cancer Institute and UCL Hospital NHS Foundation, London, UKPresentation Number: 152PDate and Time:Thursday, 12 December 2024 at 12:30 – 13:30PM CET Abstracts will be made available on the ESMO I-O website on 5 December 2024 at 00:05 CET. The poster containing new data, not in the abstract, will be available on the Posters & Publications section of Immutep’s website after its presentation on 12 December 2024. About Immutep Immutep is a clinical-stage biotechnology company developing novel LAG-3 immunotherapy for cancer and autoimmune disease. We are pioneers in the understanding and advancement of therapeutics related to Lymphocyte Activation Gene-3 (LAG-3), and our diversified product portfolio harnesses its unique ability to stimulate or suppress the immune response. Immutep is dedicated to leveraging its expertise to bring innovative treatment options to patients in need and to maximise value for shareholders. For more information, please visit www.immutep.com. Australian Investors/Media:Catherine Strong, Sodali & Co+61 (0)406 759 268; catherine.strong@sodali.com U.S. Media:Chris Basta, VP, Investor Relations and Corporate Communications+1 (631) 318 4000; chris.basta@immutep.com

来源：药渡 撰文：哥哈骎     编辑：维他命 在基因治疗领域，监管决策的每一次松动都可能对未来的治疗标准和患者的治疗方案产生深远影响。FDA的CBER主任Peter Marks在批准Sarepta Therapeutics的杜氏肌营养不良症（DMD）基因疗法Elevidys时，采取了相对宽松的尺度。 这一决定不仅在FDA内部引发了争议，也为其他公司在开发和审批新疗法时带来了复杂的挑战。随着时间的推移，这种宽松的审批标准逐渐显现出其潜在的风险和影响，使得监管机构在面对新疗法时陷入进退两难的境地。如今辉瑞的DMD临床数据出炉，将新的难题摆在了FDA面前。 01 临床失败导致项目终止 辉瑞的这款DMD基因疗法是fordadistrogene movaparvovec。今年8月，辉瑞宣布其III期试验 (NCT04281485) 失败并终止了这一项目，此前一名患者在II期研究中死亡。辉瑞DMD基因疗法的临床试验令整个DMD领域感到惊讶，也必然令Elevidys获批时所造成的巨大争议“前度刘郎今又来”，使得后来者的监管批准面临非常复杂的局面。 虽然从科学角度来看，fordadistrogene movaparvovec发挥了应有的作用。在III期临床试验中接受该疗法的男孩产生了大量微型抗肌萎缩蛋白（Microdystrophin）。理论上，这种结果应该有助于减缓DMD。然而，参与者根本没有受益，多项肌肉功能测试的结果与安慰剂相比没有改善。 10月12日，在捷克布拉格召开的第29届世界肌肉学会国际年会上公布了此试验结果，立即在DMD领域引发了轩然大波。虽然辉瑞此前已经做出了终止该项目的决定，然而尴尬的是，Sarepta的Elevidys当初引发巨大争议的加速批准依靠的就是微型抗肌萎缩蛋白这一生物标志物，而且目前仍然有多家制药公司开发DMD疗法，微型抗肌萎缩蛋白仍然是他们仰仗的临床终点。 02 辉瑞DMD疗法失败背后的博弈 辉瑞壮志未酬的DMD疗法再次将微型抗肌萎缩蛋白是否适合作为DMD疗法开发的生物标志物推到了争论的风口浪尖之上。医药界原本就对FDA凭借微型抗肌萎缩蛋白加速批准DMD疗法颇有微词，辉瑞失败的临床研究再次为反对者提供了有利的背书。 微型抗肌萎缩蛋白最初是在20世纪90年代设计的，因为完整的抗肌萎缩蛋白“本尊”对应的基因体量太大，无法装载入基因治疗的递送病毒中。科学家们因此退而求其次地衍生出了缩小版的微型抗肌萎缩蛋白作为管理DMD的手段。开发者认为，微型抗肌萎缩蛋白能够保留抗肌萎缩蛋白的关键功能，因此可以移花接木地用于DMD基因疗法开发。 Sarapta的DMD基因疗法Elevidys当年凭借加速批准的途径上位，依靠的就是微型抗肌萎缩蛋白作为生物标志物，然而Sarepta当时进行的唯一随机试验却失败了。FDA的审查人员原本甚至连Sarepta的BLA申请都不愿意接受，但CBER主任Peter Marks几乎依靠一己之力就否决了手下的决定，并且有些令人惊讶地加速批准了Elevidys。 这个决定也同时表明，FDA接受微型抗肌萎缩蛋白作为加速批准的生物标志物，辅以一些肌肉功能改善的数据，而不是完整的随机III期试验。值得注意的是，加速上市后的Elevidys在上市后验证性III期试验中并未达到主要终点，但次要终点得以实现。Peter Marks再次力排众议，将Elevidys的加速批准升级为标准批准，标签几乎扩大到所有患者范围。 就在Elevidys的争议声在话题不断的医药开发领域中几乎要消失的时候，辉瑞的DMD疗法的失败又将问题呈现在世人面前。世界肌肉学会国际年会上公布的数据显示，使用辉瑞基因疗法fordadistrogene movaparvovec的男孩产生了几乎同健康人群数量相差无几的微型抗肌萎缩蛋白（健康人群体内生成的是完整的抗肌萎缩蛋白），然而他们的肌肉能力并没有得到任何益处。公布这一结果的伦敦大学学院儿科神经病学主任Francesco Muntoni甚至表示，他宁愿结果是没有产生微型抗肌萎缩蛋白，这样更容易解释结果。罗彻斯特大学医学中心的神经学家Emma Ciafaloni表示，FDA应该重新审视是否应该将微型抗肌萎缩蛋白作为合理的生物标志物。 风口浪尖上的FDA拒绝了对辉瑞的数据发表评论。但FDA使用外交辞令表示，每种医疗产品都是独一无二的，微型抗肌萎缩蛋白是否可以作为生物标志物用于加速批准，需要具体问题具体分析。前FDA高级官员Wilson Bryan曾经对微型抗肌萎缩蛋白作为生物标志物的做法表示怀疑，如今得到了辉瑞数据的支持后，他再次表示，依靠这些衍生基因的水平不能可靠地预测DMD的临床益处。 不仅是微型抗肌萎缩蛋白是否合适这个基本点，就连生产、表征和测量这种蛋白上的差异也使得这个问题更加复杂。每个微型抗肌萎缩蛋白都有差异，DMD领域对这些差异与疗效相关性存在争议。 然而先河一开就很难完全关闭，目前多家制药公司仍在凭借微型抗肌萎缩蛋白试图通过加速批准入市。例如Solid Bio的首席执行官Bo Cumbo就表示，他们没有改变寻求加速批准的计划。Cumbo称，“无论如何，FDA已经承认微型抗肌萎缩蛋白是生物标志物。Sarepta就是依靠这个获批的。”Solid目前正在美国进行一项为期18个月的单组试验，主要针对年龄较大但仍能走动的男孩。正如Cumbo透露的，Solid Bio计划根据微型抗肌萎缩蛋白水平和一些临床数据寻求FDA的加速批准。Solid还将在美国以外开展一项随机试验，以期获得更广泛的批准。 对于辉瑞失败的临床数据和对生物标志物有效性的挑战，Cumbo从辉瑞对微型抗肌萎缩蛋白的测量方式提出了质疑。目前尚没有确定放之四海而皆准的抗肌萎缩蛋白水平测量手段。辉瑞使用液相色谱的方法，Sarepta使用的则是western blot。Cumbo指出，辉瑞III期临床试验中的微型抗肌萎缩蛋白水平明显高于临床I期的数据，而辉瑞在III期招募的患者的抗肌萎缩蛋白水平也高于标准DMD患者的平均水平。Cumbo表示，他相信Sarepta和辉瑞的药物确实有效，但需要进行更长时间的研究，并在合适的患者身上进行研究，这有助于帮助研究人员清楚地了解微型抗肌萎缩蛋白如何减缓肌肉功能下降。 RegenxBio的DMD基因疗法开发同样也瞄准了微型抗肌萎缩蛋白这一生物标志物，他们也在FDA之前决策的加持下“不改初衷”，坚持以此作为加速批准的基石。与Solid Bio一样，RegenxBio打算在其监管提交文件中采取微型抗肌萎缩蛋白加运动功能数据的策略。 虽然几乎所有专家都认为辉瑞失败的基因疗法不会迫使FDA躬身自省地反思对Elevidys的完全审批决定，但目前医生对于Elevidys的接受度不高也是事实，主要是因为其益处不够明显，而且还是一款一针几百万美元的基因疗法，面对的是“开弓没有回头箭”的局面。 辉瑞的数据造成的最主要影响，是行业对于微型抗肌萎缩蛋白作为DMD加速批准的生物标志物的合理性，以及FDA在批准DMD基因疗法时对于临床设计和终点设定以及评估方面的重新审视。对于微型抗肌萎缩蛋白的怀疑扩大将是必然的趋势。今年7月发表在Nature上的一篇文章介绍了将完整抗肌萎缩蛋白基因通过一种新病毒注入患者体内的设计，或许代表着DMD疗法开发未来的方向。 03 反思与展望 辉瑞的杜氏肌营养不良（DMD）基因疗法临床试验失败不仅引发了行业的广泛关注，也让人们重新思考以微型抗肌萎缩蛋白作为疗效标志物的局限性。虽然FDA在批准Sarepta的Elevidys时基于微型抗肌萎缩蛋白的生成展现了相对宽松的态度，但随着辉瑞的失败，业内对这一审批策略提出了更多质疑。对于复杂的遗传疾病如DMD，微型抗肌萎缩蛋白的生成确实显示出一定的生物学效应，但其与实际临床疗效的关系却并不明确。这次失败表明，依赖尚未充分验证的生物标志物来推动加速批准，可能导致疗法无法实现预期的长期临床益处。 FDA近年来对一些罕见病疗法，特别是基于生物标志物的加速批准，采取了较为灵活的政策。这一做法初衷良好，为治疗选择有限的罕见病患者提供更快的药物上市渠道。然而，这种政策也带来了潜在风险。生物标志物的使用虽然能够提供早期疗效的指示，但它们可能无法充分代表疗法的实际临床效果或患者的长期获益。 Elevidys的批准就是这种宽松政策的体现。FDA基于微型抗肌萎缩蛋白作为生物标志物，快速推动了这一DMD疗法的上市，这一决定在当时反映了监管机构对满足罕见病治疗需求的迫切性。然而，辉瑞此次试验的失败再次揭示出，这样的妥协可能导致疗效尚不明确的疗法进入市场，不仅可能增加患者的经济负担，也有可能降低公众对新疗法的信任度。 未来，FDA和其他监管机构或将需要重新审视目前在罕见病领域的审批策略。尽管罕见病患者急需新药物，政策灵活性对于推动疗法的早期开发和上市至关重要，但药物的长期安全性和临床有效性不应因加速上市的需求而被弱化。监管机构需要在加速审批与充分验证之间找到更合理的平衡点，确保新疗法能够真正改善患者的生存质量和预后。 在DMD基因疗法的未来开发中，完整抗肌萎缩蛋白基因的递送或许将成为新的方向。相比微型抗肌萎缩蛋白，完整基因的引入更接近人体自然生理状态，可能为患者提供更长效和更显著的疗效。一些研究团队已经开始尝试通过创新的基因递送技术来实现这一目标，这有望成为DMD治疗领域未来的重要突破。 辉瑞DMD疗法的失败为整个行业提供了重要的反思机会，显示出主要依靠生物标志物的加速审批模式存在的局限。生物标志物仍然是药物开发的重要工具，但它们必须与恰当的临床终点相结合，才能真正推动有效疗法的开发。未来，FDA可能需要在审批过程中更多依赖随机对照试验的结果，并加强对疗效和安全性长期观察的要求，确保新药不仅带来生物学上的作用，还能为患者的生活质量带来切实的提升。 参考文献： 1.Tasfaout, H. et al. Split intein-mediated protein trans-splicing to express large dystrophins. Nature 632, 192–200 (2024). https://doi.org/10.1038/s41586-024-07710-8 2.Mast, J. et al. Perplexing results from Duchenne muscular dystrophy trial raise questions about gene therapies. STAT. 21. 10. 2024. 3.Wave’s stock swells as it eyes approval following Phase II DMD victory. Clinical Trials Arena. 25. 09. 2024. 专栏作者 哥哈骎 南开大学本科、硕士，德国比勒菲尔德大学博士。多肽化学、多肽API GMP生产专家、欧洲制药公司首席科学家； 拥有Lean Six Sigma黑带认证； 著有专著《Side Reactions in Peptide Synthesis》。 *声明：本文仅是介绍医药疾病领域研究进展或简述研究概况或分享医药相关讯息，并非也不会进行治疗或诊断方案推荐，也不对相关投资构成任何建议。内容如有疏漏，欢迎沟通指出！ 2025版《中国药典》收官在即，药包材标准体系最新动向盘点 年薪3亿美元不是梦？生物科技与制药CEO年收入调查（附2024年行业收入报告） 深度盘点：5种Biotech转型之路