Tesidolumab

BFC Capital Market Update (November 2 - November 8) Market Overview Global Markets and Healthcare Sectors Post Strong Gains Amid Mixed Performance Last week, U.S. markets saw notable gains, with the Dow Jones Industrial Average up 4.6%, the S&P 500 rising 4.7%, and the Nasdaq Composite gaining 5.7%. In China, the Shanghai Composite Index and CSI 300 Index advanced by 5.5%, while the Hang Seng Index increased by 1.1%. In the healthcare sector, the U.S. Nasdaq Biotechnology Index rose 4.1%. Chinese healthcare indices also posted gains, with the SSE Health Care Index up 4.9%, the CSI Healthcare Index rising 6.4%, and the Hang Seng Healthcare Index recording a weekly increase of 2.9%. Major Biopharma Updates CARsgen Therapeutics Stock Rises 57.8% as Promising Preliminary Data for Off-the-Shelf CAR-T Therapy CT0590 Unveiled at 66th ASH Annual Meeting CARsgen Therapeutics（02171.HK, 科济药业） saw a cumulative increase of 57.8% last week. On November 6, the company announced that data for Zevor-cel (Zevorcabtagene autoleucel), CT071, and CT0590 would be presented in poster format at the 66th ASH Annual Meeting, with abstracts now available on the ASH website. Notably, this is the first human Phase I trial data for CT0590, an off-the-shelf CAR-T therapy targeting BCMA and NKG2A. Among the five enrolled participants, with a median follow-up of 16.6 months (ranging from 5.1 to 24.2 months), three patients achieved remission, including two with stringent complete response (sCR) and one with partial response (PR). Of the two patients with sCR, one with relapsed/refractory multiple myeloma (RRMM) has maintained remission for 23 months (sCR ongoing), while another with primary plasma cell leukemia (pPCL) has a duration of response (DOR) of 20 months. These preliminary results suggest that the CT0590 off-the-shelf CAR-T cell therapy is safe and capable of achieving deep and durable clinical remission. Hengrui Pharmaceuticals' Irinotecan Liposome Combination Therapy Shows 37% Reduction in Mortality Risk for Advanced Pancreatic Cancer in Phase III Trial On November 6, Hengrui Pharmaceuticals（600276.SH,恒瑞医药） announced results from a randomized, double-blind, parallel-controlled, multicenter Phase III clinical trial of Irinotecan Liposome (II) combined with 5-FU/LV as a second-line treatment for locally advanced or metastatic pancreatic cancer in patients who had previously failed gemcitabine treatment. The results indicated that the Irinotecan Liposome (II) combination therapy reduced the risk of death by 37% compared to the control group in pancreatic cancer patients. Business Development Updates In the past week, PharmaEngine secured Taiwan distribution rights for LIPORAXEL from Shanghai RMX Biopharma. Novo Nordisk partnered with Ascendis Pharma to use TransCon technology for semaglutide and other therapies. Royalty Pharma acquired U.S. royalty rights for Syndax's Niktimvo against GVHD. Nobelpharma licensed Y-mAbs' Danyelza for neuroblastoma in Japan. DRI Healthcare acquired global royalty rights for KalVista's sebetralstat for HAE. Nxera and Antiverse are collaborating on AI-based GPCR antibodies. Aditum Bio and Leads Biolabs formed Oblenio Bio for a tri-specific T-cell engager. Santen gained rights to Arctic Vision’s ARVN-001 for eye conditions in China. Zhida Pharma secured an option for Vivesto’s Apealea in Greater China. PharmaEngine to distribute Shanghai RMX Biopharma’s LIPORAXEL in China Nov 4, 2024 – PharmaEngine and Shanghai RMX Biopharma (a subsidiary of Haihe Biopharma) entered into an exclusive distribution agreement for LIPORAXEL (paclitaxel oral solution) in the Taiwan market. Novo Nordisk to use Ascendis Pharma' TransCon Technology to develop, manufacture and commercialize therapeutics including Semaglutide for metabolic diseases and cardiovascular diseases worldwide Nov 4, 2024 – Novo Nordisk entered into an exclusive worldwide research and development collaboration and license agreement with Ascendis Pharma for TransCon technology to develop, manufacture and commercialize therapeutics including semaglutide , by reducing their dosing frequency for the treatment of metabolic diseases and a product-by-product exclusive license in cardiovascular diseases. Royalty Pharma to acquire royalty rights of Syndax's Niktimvo against GVHD in the US Nov 4, 2024 –Royalty Pharma entered into a synthetic royalty funding agreement for Syndax Pharmaceuticals ' Niktimvo (axatilimab) against chronic graft-versus-host disease (GVHD) in the United States. Nobelpharma to commercialize Y mAbs Therapeutics' Danyelza for relapsed/refractory high risk neuroblastoma in Japan Nov 4, 2024 –Nobelpharma entered into an exclusive license and distribution agreement with Y-mAbs Therapeutics to commercialize Danyelza for the treatment of relapsed/refractory high risk neuroblastoma in Japan. DRI Healthcare to acquire royalty rights of KalVista's sebetralstat against HAE worldwide Nov 4, 2024 – DRI Healthcare signed a synthetic royalty financing agreement to acquire rights of KalVista Pharmaceuticals ' sebetralstat against hereditary angioedema (HAE) worldwide. Nxera and Antiverse to design and globally commercialize AI based antibodies for GPCRs Nov 5, 2024 – Nxera agreed with Antiverse to design and globally commercialize AI based antibodies for G-protein coupled receptors (GPCRs). Aditum Bio and Leads Biolabs Announce the Formation of Oblenio Bio to Develop a Tri-Specific T-Cell Engager for Autoimmune Disorders Nov 7, 2024 – Aditum Bio and Leads Biolabs today announced the formation of Oblenio Bio, which is being formed in conjunction with an exclusive option and license agreement to develop LBL-051, a first-in-class CD19xBCMAxCD3 tri-specific T-cell engager antibody for autoimmune diseases. Aditum Bio will fund Oblenio Bio and the parties will collaborate to rapidly bring LBL-051 into clinical studies. Santen to commercialize Arctic Vision' ARVN-001 for UME and other ophthalmic indications in China excluding Taiwan, Hong Kong and Macau Nov 7, 2024 – Santen signed an agreement with Arctic Vision to commercialize ARVN-001 for uveitic macular edema (UME) and certain other ophthalmic indications in China excluding Taiwan, Hong Kong and Macau. Zhida Pharma to sign an option to develop and commercialize Vivesto’s Apealea for ovarian cancer in China, Hong Kong, Macau and Taiwan Nov 7, 2024 –Zhejiang Zhida Pharmaceutical signed an exclusive license option agreement with Vivesto to develop and commercialize anticancer product Apealea (paclitaxel micellar) for ovarian cancer in China, Hong Kong, Macau and Taiwan. References： 1.https://www.carsgen.com/en/news/carsgen-to-present-zevor-cel-ct071-and-ct0590-at-ash-2024-annual-congress/ 2.https://www.hengrui.com/media/detail-665.html

引言 2024年10月，维克托·安布罗斯（Victor Ambros）和加里·鲁夫肯（Gary Ruvkun）因发现微小RNA（miRNA）在基因表达中的核心作用而荣获诺贝尔生理学或医学奖。这一发现自1993年揭示了miRNA通过与靶mRNA结合并抑制其翻译的方式调节基因表达。自此，miRNA在细胞分化、增殖和生存等多条基因表达通路中的重要作用逐渐得到认识。然而，尽管miRNA的生物学功能已得到充分研究，但将miRNA应用于临床治疗的道路依然漫长且充满挑战。（11月4日 Nature Biotechnology “What will it take to get miRNA therapies to market?” ） miRNA：从基础研究到临床应用的跨越 miRNA作为一种短小的非编码RNA，其作用机制在许多重要的生物学过程中起着至关重要的作用。早期的研究发现，miRNA通过与靶mRNA的3'非编码区结合，抑制其翻译或促进其降解，从而在基因表达的调控中扮演重要角色。miRNA的发现为我们提供了新的视角去理解基因调控的复杂性，并为疾病治疗开辟了潜在的治疗方向，特别是在癌症、心血管疾病和代谢性疾病等领域。 然而，尽管miRNA在基础研究中展现了巨大潜力，但将其转化为有效的临床治疗手段仍面临诸多挑战。miRNA治疗的前景尚未能够超越现有的治疗方法，且要想克服这些挑战，仍需在多个领域取得突破。 miRNA治疗的两大类型：模拟miRNA和抗miRNA 目前，miRNA治疗主要有两种形式：miRNA模拟物（miRNA mimics）和抗miRNA（antimiRs）。miRNA模拟物通常模仿内源性miRNA的功能，恢复或增强在疾病中丧失或下调的miRNA的功能。抗miRNA则通过与过度表达的内源性miRNA结合并沉默其功能，起到逆向作用。 miRNA模拟物和抗miRNA治疗可以同时作用于多个基因，放大特定信号通路的激活或抑制，因此在治疗复杂疾病（如癌症、纤维化等）时具有潜在优势。然而，这种广泛的作用特性也带来了一个不可避免的问题：脱靶效应（off-target effects）。由于miRNA具有较低的靶向特异性，其可能与多个不相关的基因结合，从而导致不良反应或毒性效应。 临床试验的挑战：从临床前到临床试验的难题 尽管已有一些miRNA疗法进入了临床试验，但迄今为止，没有任何miRNA治疗药物进入了III期临床试验，也没有获得美国FDA的批准。2013年，MRX34（一个miR-34a模拟物）成为第一个进入I期临床试验的miRNA癌症治疗药物。miR-34a作为肿瘤抑制因子，能够靶向p53蛋白，并在许多癌症中被下调。然而，由于严重的免疫介导的毒性反应和患者死亡，Mirna Therapeutics在三年后暂停了该试验。 此外，Viridian Therapeutics（前身为miRagen Therapeutics）开发的miRNA-29b模拟物，最初被认为是治疗纤维化的有前景药物，但在二期临床试验后也被终止。2022年，Regulus Therapeutics公司为治疗阿尔波特综合征开发的miR-21抗miRNA的二期试验也提前终止。再如，针对丙型肝炎的miR-122抗miRNA的临床试验也未能取得预期的成功，最终被停用。 这些失败的例子表明，miRNA治疗在临床开发过程中面临着严重的挑战，尤其是在安全性和疗效方面。与小干扰RNA（siRNA）相比，miRNA治疗的临床进展明显滞后，尽管siRNA在多个领域（如遗传疾病、癌症等）取得了显著的临床成果，FDA至今已批准了六种siRNA药物。 miRNA治疗面临的主要挑战 靶点选择与验证的难度 miRNA治疗的第一个挑战是靶点的选择与验证。由于miRNA通常可以同时靶向多个基因，这使得准确识别其作用机制变得极为复杂。目前，尽管已有了更为先进的算法、广泛的序列数据以及MiRBase数据库等工具，可以帮助预测miRNA与mRNA的结合位点，但多数miRNA的功能仍不明晰，且无法在所有生物学背景下进行验证。 在临床应用中，miRNA模拟物主要用于替代缺失或低表达的miRNA，这时，靶点特异性并不是主要问题，关键是如何找到能够直接影响目标通路的miRNA，并证明其恢复活动能够缓解疾病表型。然而，肿瘤等疾病中的miRNA表达高度异质，且受肿瘤微环境的影响，这使得找到一个统一的、能够在多种肿瘤中发挥作用的miRNA变得更加困难。 脱靶效应与安全性 由于miRNA具有多靶点的特性，治疗过程中可能发生脱靶效应，导致对非目标基因的抑制或激活，从而引发不良反应。例如，抗miRNA治疗可能会靶向某些肿瘤抑制基因或参与正常细胞稳态的基因，这可能会干扰细胞的基本功能。此外，miRNA治疗可能与其他非编码RNA发生交互作用，进一步增加了治疗的复杂性。 递送与毒性问题 与所有RNA治疗方法一样，miRNA治疗的另一个重大挑战是递送问题。有效的递送载体不仅需要将miRNA有效地送达目标细胞，还需要避免引发免疫反应或毒性反应。尽管脂质纳米粒子（LNP）和其他递送系统在siRNA和mRNA疫苗中取得了一定的成功，但miRNA治疗仍面临更大的递送难题。早期的miRNA临床试验中，尽管使用了脂质纳米粒子进行递送，效果却并不理想。当前，研究人员正在研究如何实现更为精确的靶向递送，尤其是肿瘤靶向递送。 miRNA的未来：诊断工具和治疗前景 尽管miRNA治疗在临床上的应用还面临诸多挑战，但其作为诊断工具的潜力已逐渐展现。miRNA能够通过外泌体（exosome）从细胞中释放并进入体液，这使得miRNA可以作为血液、尿液等体液中的生物标志物，进行疾病的早期诊断。例如，通过对血液中miRNA表达的分析，可以识别特定的miRNA，这些miRNA可能在癌症或其他疾病中具有更高的表达或与治疗反应相关。实际上，已经有一些miRNA面板的诊断工具进入临床使用，并取得了初步成果。 尽管miRNA治疗面临众多挑战，但它在疾病诊断中的应用前景依然光明。随着对miRNA生物学作用的深入理解，以及递送技术和靶向技术的进步，miRNA有望在未来的治疗中占据一席之地。然而，要真正实现miRNA治疗的临床成功，仍需解决脱靶效应、递送和安全性等问题。当前，siRNA和mRNA治疗方法在临床上的领先地位依然稳固，但miRNA作为新兴疗法，仍有潜力成为未来基因治疗领域的重要组成部分。 参考文献 What will it take to get miRNA therapies to market? Nat Biotechnol. 2024 Nov 4. doi: 10.1038/s41587-024-02480-0. Epub ahead of print. PMID: 39496928. Jones, D. Nat. Biotech. https://doi.org/10.1038/nbt1018-909 (2018). Hong, D. S. et al. Br. J. Cancer https://doi.org/10.1038/s41416-020-0802-1 (2020). Gallant-Behm, C. L. et al. J. Invest. Dermatol. https://doi.org/10.1016/j.jid.2018.11.007 (2019). Rupaimoole, R. & Slack, F. J. Nat. Rev. Drug Discov. https://doi.org/10.1038/nrd.2016.246 (2017). Fromm, B. et al. RNA https://doi.org/10.1261/rna.079098.122 (2022). Orellana, E. A. et al. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aam9327 (2017). Orellana, E. A. et al. Mol. Ther. Nucleic Acids https://doi.org/10.1016/j.omtn.2019.04.003 (2019). 责编|探索君 排版|探索君 转载请注明来源于【生物探索】 End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell 综述