An Open-Label, Single-Arm, Phase II Study of Pembrolizumab, Plinabulin Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer

Monoclonal antibodies against programmed death 1 (PD-1) and its ligand PD-L1 have shown efficacy in patients with ES-SCLC in the monotherapy and combination therapy settings. Up to now, Atezolizumab and Durvalumab has been approved for first line treatment for ES-SCLC in China combined with EP or EC. Besides, KEYNOTE-604 study revealed that adding pembrolizumab to standard first-line EP significantly improves PFS in patients with ES-SCLC and is associated with durable responses in a subset of patients. 12-m PFS rate were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. The statistical threshold for declaring significant prolongation of OS was narrowly missed. Considering sicker pts was enrolled and the interim analysis was quite often, even though the investigators narrowly missed the OS endpoint, longer numerical OS data was observed. The latest version of NCCN SCLC guidelines still recommended pembrolizumab as an option for ES-SCLC patients.
Plinabulin received breakthrough designation from both US and China FDA for CIN (Chemotherapy Induced Neutropenia) prevention indication. As a "pipeline in a drug," plinabulin is being broadly studied in combination with various immuno-oncology agents that could boost the effects of the PD-1/PD-L1 antibodies and re-sensitize PD-1/PD-L1 antibody resistant patients. In a poster released at 2021 ASCO conference, a phase I trial of Plinabulin in combination with nivolumab and ipilimumab in patients with relapsed small cell lung cancer: Big Ten Center Research Consortium (BTCRC-LUN17-127) study. Plinabulin in combination with nivolumab and ipilimumab was safe and well tolerated with promising efficacy signal of 46% ORR.
From above, Pembrolizumab, Plinabulin plus Etoposide and Platinum as First-Line Therapy for ES-SCLC should be a promising combination therapy, as the investigators expect increased efficacy and reduced toxicity with the addition of Plinabulin. In this proof of concept phase II study, the investigators will investigate that the efficacy and safety of Pembrolizumab, Plinabulin plus Etoposide and Platinum as First-Line Therapy for ES-SCLC.

开始日期2023-11-01

申办/合作机构-

NCT05599789 / Recruiting临床2期IIT

A Phase 2 Study of Pembrolizumab in Combination With Plinabulin and Docetaxel in Previously Treated Patients With Metastatic Non-Small Cell Lung Cancer and Progressive Disease (PD) After Immunotherapy (Anti-PD-1/PD-L1 Inhibitor) Alone or in Combination With Platinum-doublet Chemotherapy (KeyPemls-004)

A Phase 2 Study of Pembrolizumab in Combination with Plinabulin and Docetaxel in previously treated Patients with Metastatic Non-Small Cell Lung Cancer and progressive disease (PD) after immunotherapy (Anti-PD-1/PD-L1 inhibitor) alone or in combination with Platinum-doublet Chemotherapy.

开始日期2023-02-01

申办/合作机构

北京协和医院

[+2]

NCT05130827 / Active, not recruiting临床2期IIT

Pilot Trial of Plinabulin and Pegfilgrastim to Reduce the Duration of Absolute Neutropenia After Autologous Hematopoietic Cell Transplantation for Patients With Multiple Myeloma

This study will see how long it takes for white blood cell counts to return to normal in people with multiple myeloma (MM) who receive plinabulin and pegfilgrastim after undergoing an autologous hematopoietic stem cell transplant (AHCT).

开始日期2021-12-21

申办/合作机构

Memorial Sloan Kettering Cancer Center

[+1]

100 项与普那布林相关的临床结果

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100 项与普那布林相关的转化医学

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100 项与普那布林相关的专利（医药）

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项与普那布林相关的文献（医药）

2023-09-01·Chemical biology & drug design

Conformation and energy investigation of microtubule longitudinal dynamic instability induced by natural products

Article

作者: Li, Wenbao ; Chu, Yanyan ; Tian, Zhenhua ; Yang, Mengke

Abstract:

The natural products plinabulin, docetaxel, and vinblastine are microtubule targeting agents (MTAs). They have been used alone or in combination in cancer treatment. However, the exact nature of their effects on microtubule (MT) polymerization dynamics is poorly understood. To elucidate the longitudinal conformational and energetic changes during MT dynamics, a total of 140 ns molecular dynamic simulations combined with binding free energy calculations were performed on seven tubulin models. The results indicated that the drugs disrupted MT polymerization by altering both MT conformation and binding free energy of the neighboring tubulin subunits. The combination of plinabulin and docetaxel destabilized MT polymerization due to bending MT and weakening the polarity of tubulin polymerization. The new combination of docetaxel and vinblastine synergistically enhanced MT depolymerization and bending, while plinabulin and vinblastine had no synergistic inhibitory effects. The results were verified by the tubulin assembly assay. Our study obtained a comprehensive understanding of the action mechanisms of three natural drugs and their combinations on MT dynamic, provided theoretical guidance for new MTA combinations, and would promote the optimal use of MTA and contribute to developing new MTAs as anticancer agents.

2023-07-15·Bioorganic & medicinal chemistry letters

Design, synthesis and anti-tumor evaluation of plinabulin derivatives as potential agents targeting β-tubulin.

Article

作者: Tang, Yu ; Bi, Shijie ; Li, Yannan ; Tian, Shuai ; Wang, Shixiao ; Qiu, Peiju ; Fang, Shiyuan ; Xu, Huixin ; Fu, Lei

Plinabulin is a promising microtubule destabilizing agent in phase 3 clinical stage for treating non-small cell lung cancer. However, the high toxicity and the poor water solubility of plinabulin limited its use and more plinabulin derivatives need to be explored. Here, two series of 29 plinabulin derivatives were designed, synthesized and evaluated for their anti-tumor effect against three types of cancer cell lines. Most of derivatives exerted obvious inhibition to the proliferation of the cell lines tested. Among them, compound 11c exerted stronger efficiency than plinabulin, and the reason might be the additional hydrogen bond between the nitrogen atom of the indole ring in compound 11c and Gln134 of β-tubulin. Immunofluorescence assay showed that compound 11c at 10 nM significantly disrupted tubulin structure. Compound 11c also significantly induced G2/M cell cycle arrest and apoptosis in dose dependent manner. These results suggest that compound 11c might be a potential candidate for cancer treatment as antimicrotubule agent.

2023-07-01·Current opinion in oncology

The impact of new and emerging agents on outcomes for febrile neutropenia: addressing clinical gaps.

Review

作者: Oswalt, Cameron ; Crawford, Jeffrey

PURPOSE OF REVIEW:

While chemotherapy treatment options for patients with solid and hematologic malignancies have dramatically improved over recent years, chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) remain major barriers to delivering treatment at full doses and optimal timing. Despite concurrent advances in granulocyte colony-stimulating factor (G-CSF) administration, multiple barriers to the administration of and disparities in the access to these agents remain. The introduction of new, emerging agents, including biosimilars and novel therapies show promise in improving outcomes for CIN.

RECENT FINDINGS:

The introduction of biosimilar filgrastim products has improved access to G-CSF administration by driving marketplace competition and has reduced costs for both patients and healthcare systems without sacrificing efficacy. Emerging therapies to address similar issues include long-acting G-CSF products, efbemalenograstim alfa and eflapegrastin-xnst, as well as agents with novel mechanisms of action, plinabulin and trilaciclib. These agents have shown efficacy and cost-saving benefits in certain populations and disease groups.

SUMMARY:

Multiple emerging agents show promise in decreasing the burden of CIN. Use of these therapies will reduce access disparities and will improve outcomes for patients with cancer receiving cytotoxic chemotherapy. Many ongoing trials are underway to evaluate the roles of these agents for more widespread use.

137

项与普那布林相关的新闻（医药）

2024-05-29

·药渡

被追逐的分子胶，还需要一个成功的故事

2023 年 12 月10日，FDA批准的基因编辑和基因治疗镰状细胞病疗法上市两天后，诺华的生物化学家 Pamela Ting 在美国血液学会年会上做了一份全体报告。Pamela Ting描述了一种表型筛选，该筛选产生的结果会导致胎儿血红蛋白激增，这种蛋白质与最近批准的基因编辑疗法经过改造后产生的蛋白质相同。但与售价 220 万美元的基因编辑疗法不同的是，诺华的化合物是小分子蛋白质降解剂，也就是分子胶，其生产和管理成本要低得多。3个月前，诺和诺德宣布了一笔潜在交易总额14.6亿美元的合作，加大其在分子胶领域的研发力度。2023年以来，包括BMS、罗氏、默沙东等大药企相继与海外biotech达成分子胶技术平台/项目合作，潜在交易总额超过百亿美元。分子胶，作为破解传统小分子药物耐药突变及不可成药难题的利器，又一次站上了风口。面对巨大的市场空间，国内药企同样不甘落后。诺诚健华、正大天晴、康朴生物、达歌生物、格博生物等药企纷纷布局……并且，过去一周，达歌生物牵手武田，嘉越医药与美国Erasca展开分子胶项目合作；因普那布林上市失败而陷入困境的万春医药，则因其子公司SEED的分子胶项目而股价大涨，自2月份以来涨幅超200%。新的竞速开始了，所有人都在等待着一个成功的故事。/ 01 /不可成药靶点的救赎近几十年来，随着结构生物学的发展，已经发现了数千种与疾病相关的蛋白结构，传统的药物研发通过调控这些蛋白结构和活性来治疗疾病。比如小分子抑制剂的经典作用模式是“占据驱动”，通过和蛋白的活性位点或变构位点结合，以废除该蛋白的功能。但传统的小分子抑制剂面临着耐药突变和难成药靶点两大挑战。根据2017年NRDD综述的统计，彼时FDA批准的1578个药物仅仅靶向了667种靶蛋白，其中小分子药物靶向了549种，大分子药物靶向了146种，仅占潜在靶点的1/3。大量潜在靶点受限于小分子药物的局限性难以开发药物。正是在这一背景下，靶向蛋白降解（TPD）技术成为了小分子药物研发的一种开创性策略。所谓蛋白降解，主要通过诱导致病靶蛋白的快速降解发挥治疗作用。理论上，致病靶点都消失了，不可成药和耐药性的问题自然迎刃而解。TPD分为PROTAC和分子胶两大类。《PROTAC，小分子药物的“百忧解”？》分子胶，顾名思义像胶水一样的小分子。其工作原理是通过与一种称为E3泛素连接酶的酶结合，改变其表面形状，使其能够与目标蛋白结合。一旦形成三者结合，E3连接酶就会在蛋白质中添加一条泛素分子链，从而触发细胞的蛋白质降解系统，将目标蛋白质分解。在传统的小分子药物中，药物与致病靶点结合占据了结合位点，使得致病靶点无法正常发挥作用，而对于不可成药靶点来说，由于没有结合位点，传统小分子药物则无法与其结合。在细胞内部，很多生理过程是需要靠300000多个蛋白与蛋白的相互作用完成，比如快速的修饰和调节，或是快速的合成和降解。分子胶正是利用了细胞内天然的过程，迫使原本不会相互结合的蛋白质与E3连接酶发生作用，从而实现对疾病相关蛋白质的降解。如此一来，就解决了药物靶点不可成药的难题；由于致病靶点被裂解，自然也不会存在耐药性的问题。这也是其与PROTAC技术最有吸引力的地方。而相比分子量较大的PROTAC，通常难以遵守类药五原则，提高生物利用度、实现口服给药往往存在较高的设计壁垒，分子胶的分子量较小，某种程度上简化了PROTAC降解剂的结构，具有更好的成药性，代表性药物如沙利度胺、来那度胺等。/ 02 /“赌”平台的MNC分子胶降解剂的故事与沙利度胺密切相关。尽管早在90年代分子胶的概念就被提出，但直到2013年，研究人员才阐明了沙利度胺类似物作为分子胶降解剂的作用机制，这才彻底打开了分子胶领域的大门。2014年之后，分子胶降解剂逐渐兴起，并逐步发展成为研发人员关注的小分子药物焦点；过去几年，全球医药圈掀起了一波研发热潮，大药企也相继入局。而与其他领域以引进管线为主不同的是，分子胶领域的交易则是以MNC合作开发/引进biotech技术平台为主。最大的交易来自BMS，其于2019年以740亿美元收购Celgene，并获得了三款“度胺”类上市产品（沙利度胺及其类似物来那度胺和泊马度胺），以及CC-92480、CC-99282、CC-220等在研管线，一举稳坐分子胶领域头把交椅。去年以来，默沙东、罗氏、诺和诺德先后入局，BMS更是再度加码。其中，默沙东以总额25.5亿美元与分子胶领头羊之一Proxygen达成合作，共同开发分子胶降解剂。后者开发了一种高度通用的分子胶降解剂发现引擎，可以推动新型分子胶降解剂的规模化开发，通过结合基因组学、蛋白质组学和药物化学等高度跨学科的方法发现和开发新型分子胶降解剂。默沙东之前，勃林格殷格翰、德国默克先后与Proxygen达成合作。罗氏也着手在分子胶领域布局，在不到一个月的时间宣布了两项关于分子胶技术平台的合作。拥有分子胶发现平台的biotech，正在成为大药企眼中的香饽饽。如果说，过去分子胶赛道的BD更多是发生在MNC与海外biotech之间，如今国内biotech也开始被发掘。过去一周，嘉越医药与美国Erasca就Pan-RAS(ON) 抑制剂JYP0015达成全球独家授权协议；达歌生物则牵手武田制药，利用其GlueXplorer平台，针对武田选定的特定疾病靶点发现、验证和优化分子胶降解剂，潜在交易总额最高可达12亿美元。MNC之所以不约而同地押注平台，本质是因为，分子胶虽然非常理想，但迄今为止发现的分子胶水降解剂仍寥寥可数，其发现过程具有很大的偶然性，缺乏一个系统的发现和设计策略。因此，大药企希望押注新的技术平台，甚至借助AI技术，加速分子胶的发现。由于巨大的不确定性，大药企也在这场赌局中保留着理性。比如，罗氏去年与分子胶领域明星公司Monte Rosa达成的总额超20亿美元合作，利用其Queen技术平台开发分子胶降解剂。其中，首付款只有5000万美元，占比仅2.5%。至于BD交易中的其它后续款项，则需要药企不断达到交易前设立的目标，才能够拿到手。/ 03 /需要一个成功的故事无论如何，近两年在小分子药物领域，分子胶几乎成为了最受追捧的赛道。但这个领域，还需要一个成功的故事。截至目前，全球已上市、颇具销售规模的分子胶药并不多，仍停留在三大“度胺”阶段。国内外企业虽在积极布局，但多数还处于临床阶段。而分子胶的临床研发并不顺利，此前Celgene和Biotheryx 的 GSPT1 降解剂已不再开发；诺华在1期试验后停止了其 IKZF2 降解剂。可以说，除了三大“度胺”，该领域仍在等待概念的临床验证。正如前文所说，尽管与PROTAC相比，分子胶体积通常更小，有更好的成药潜力，但其无法像PROTAC一样可以通过各组分大规模筛选获得，设计原理尚不明晰，研发仍存在不少技术难点。首先，分子胶通过诱导或稳定E3泛素连接酶和靶蛋白之间的蛋白相互作用，实现对靶蛋白的招募和降解，但是，这种三元复合物的复杂结构导致分子胶无法用化学方法直接设计；其次，分子胶需要特定化学构成完成对靶蛋白的选择性招募，所以缺乏定向设计的化合物文库会让分子胶药物无法进行精准筛选；最后，分子胶和靶蛋白的互作需要一系列复杂的体外和体内生物验证，而且分子胶的先导化合物优化，及其药效药理研究都没有大量数据积累，给药物的临床推进带来挑战。如何设计分子胶？如何筛选分子胶？如何寻找新的靶点？如何寻找新的E3？如何优化分子的特异性？都是有待解答的问题。当然，随着技术的不断发展，最近几年，分子胶药物设计方法正得以优化，分子胶化合物库也在不断丰富与扩大，关于分子胶的探索正逐步过渡到了理性药物设计阶段。比如前文提及的Proxygen。除此之外，AI技术的发展也为分子胶的突破带来了机遇。计算机辅助药物设计加快了小分子药物的开发进度，同样可以用于TPD领域的药物研发。典型如AI分子胶发现公司VantAI，虽然其成立至今无任何融资信息，也无产品管线，却先后获得了杨森、勃林格殷格翰、BMS等MNC的青睐。可以说，寻找新的E3，新类型的分子，是PROTAC和分子胶都要走的创新型路线。拿到高结合力、特异性高的分子，还是需要很多设计和筛选，敢于走这样路线的公司，要么有自己大量的小分子库，要么有自己的AI算法或是高通量筛选的方法，没有一定积累的药企很难突破这一关。缺乏足够的积累，缺少基础理论的支撑，缺少分子胶研发可以参考的规律，缺少更多成功的案例，缺少临床获批的候选化合物。如果说针对分子胶，我们还需要什么？毫无疑问，需要的很多。但这同样是所有入局者的机遇所在。文／武月点击下方“药渡“，关注更多精彩内容免责声明“药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！

蛋白降解靶向嵌合体基因疗法

2024-05-08

·生物制品圈

当恒瑞找到头绪

从去年开始的医疗反腐风暴导致传统的销售模式受限，出海与创新成为行业关键词。小船怕风浪，大船难转弯。但在医疗反腐之前，多年集采和国谈导致医疗环境巨变的铺垫，让传统药企们主动或者被动地做好了大船掉头的准备。在传统的药物销售模式巨变的情况下，一度不被看好的传统药企，从2023年业绩报告来看，却和想象的不一样。在医疗反腐高压的情况下，一些传统药企竟然营收和利润稳定增长，而且其中创新药收入的占比提高。2023年，恒瑞创新药实现收入106.37亿元，创新药收入占比达到46.6%，一年共达成了5项海外授权合作，总交易金额超40亿美元；中国生物制药紧随其后，2023年创新产品收入达到98.9亿元，占总收入的37.8%。翰森制药创新药与合作产品收入68.65亿元，占总收入比例提升至67.9%。恒瑞无疑是其中创新药收入最高的，但竟然也是二级市场投资者最不满意的。因为尽管经过两年调整，恒瑞在A股的市盈率(TTM)依然超过60。翰森、石药、中生制药等其他港股上市的传统药企，市盈率都不超过30。恒瑞估值高的主要原因在于，其所处的A股市场没有和恒瑞匹敌的头部传统药企，所以享受了行业龙头的溢价。某海外私募首席分析师认为“恒瑞如果在港股上市，估值估计要砍半”。恒瑞只能用时间换空间，通过盈利增长来降低PE，将投资回报拉回合理的水平。因此比起“稳健”，投资者们更想看到恒瑞以更高的成长性来消化高估值。恒瑞的自我调整意识极其明显，管线目标从me too创新药向BIC转换，并且对外多次强调“力争使 First-in-class 及 Best-in-class 的高质量、差异化产品成为未来研发主体”。在出海上，恒瑞有较大转变，不再紧攥管线——中国区的权益抓在自己手里，而管线的海外权益能卖则卖。相比中生制药走的抄底收购的路线，恒瑞依赖自研的路线略显保守。但这已经是恒瑞多次试错后寻找到的平衡状态。-01-从me too到best in class一位多年前在恒瑞工作过的研发人员透露，其实恒瑞很早布局siRNA、基因治疗等新兴疗法，国内都不知道mRNA是什么东西的时候，恒瑞已经在接触Moderna。但要等到其他药企做出临床效果，恒瑞才会开始fast follow。一位当年从外企到恒瑞做研发的人员回忆，恒瑞的效率让在外企工作的他叹为观止，一个团队手上同时进行多个项目，各部门配合非常快。恒瑞现在也是如此。PD-1单抗故事落地后，恒瑞开始重仓ADC和GLP-1领域。减重领域，恒瑞已有5款新药进入临床，除了利拉鲁肽me too药物诺利糖肽，长效胰岛素+GLP-1类似物复方制剂HR17031，还布局了两个双靶点新药HRS-9531和SHR-1816，以及一款口服GLP-1R新药HRS-7535。HER2 ADC赛道，恒瑞医药 SHR-A1811处于Ⅲ期试验阶段，已经落后于科伦博泰，并同时与复星医药FS-1502、石药集团DP303C、康宁杰瑞JSKN003、乐普生物MRG002竞争。但恒瑞同时准备了plan B——SHR-4602。SHR-4602已于2023年4月获批临床，其设计目标用于DS-8201或SHR-A1811耐药的后线治疗。这两个领域也是当下竞争最激烈的。如果不想重演PD-1内卷的故事，恒瑞在fast follow之后需要考虑如何在“Me-better”基础上做到同类最优。目前已经有一些管线表现出BIC潜质。一般来说恒瑞的小分子药受认可程度高于大分子药，JAK1抑制剂，EZH2抑制剂有望成为国产首款。此外，授权给跨国药企的Claudin 18.2 ADC/PARP1、TSLP单抗，也被看好。以前，恒瑞给人的感觉是很少涉及新靶点。但在2024年AACR上，恒瑞入选的壁报内容不同以往，不再只有老面孔，还有新靶点的早期研发阶段产品。因为目前披露的都是比较早的数据，所以没有引起太大水花。行业内有一个普遍的观点是，ADC的有效性和安全性要进入临床后才能看得出来。从BIC潜质到成为BIC，恒瑞有一条漫长的自证之路。这对公司的组织架构，管理层的思维有很大的挑战。就像翰森和先声，先恒瑞一步实现创新药收入过半的目标一样，以恒瑞的规模，从me too到BIC的过渡需要一段比较长的时间。-02-行不通的收并购众所周知，大药厂是靠并购起家的。大药企内部盘根错节，从内部打破重组很难实现，跨国药企的经验都是通过收并购biotech向外寻找新生的力量。另一家老牌药企中生制药，走的是并购之路。继30亿元入股科兴中维后，2022年6月，中生制药收购在美国上市的英国医药企业F-star，拿下一个双抗技术平台，3个其平台产生的双抗以及一款STING激动剂。中生BD更加活跃，2019年-2023年，先后从Octapharma AG、Abpro、Ambrx、Inventiva、盐野义制药等海外biotech引进创新药管线；还与康方生物、亿一生物（G-CSF药物）、鸿运华宁（ GIPR/GLP-1R 双重激动剂）、益方生物（KRAS G12C靶向药物）等本土新兴biotech达成合作。此外，中生掉头的方式是，先后抛售仿制药和商业流通资产，2023年10月，中生出售附属公司上海正大通用药业股份有限公司84.2%的股权，次月，出售苏州天晴55%股权、连云港正大天晴100%股权及浙江天晴55%股权。今年2月，中国生物制药继续出售正大青岛67%股权。中生制药敢于打破重组是因为在与科兴中维的合作中大赚一笔，给管理层继续收并购的信心。而且中生制药的二代掌舵人是商科背景，对资源整合比较重视。恒瑞完全不同，论自研能力，去年入选“全球TOP25管线规模的制药公司”榜单，管线规模比肩强生、默沙东、诺华等MNC。但在收购上的尝试最终都不欢而散。恒瑞最广为人知的一次收购项目是万春医药。2021年，恒瑞与万春达成合作的时候，万春的普那布林还被认为是一款first in class药物，万春自称“30年来在CIN适应症治疗标准和临床获益上的第一个突破。”在授权合作之外，恒瑞原本准备出资1亿认购大连万春的股份。然而，双方达成协议四个月后，FDA否决了普那布林的上市申请，2023年初在国内的新药上市申请也被否。而此时，恒瑞医药已经支付2亿元首付款。恒瑞医药与万春医药闹到对簿公堂的地步，申请冻结大连万春2亿元。这一场戏到今年1月才大结局，以恒瑞医药相关诉讼请求被仲裁庭驳回告终。同样不欢而散的还有瑞石生物。瑞石生物作为恒瑞子公司，分担了恒瑞在自身免疫性疾病领域的开发。2022年底瑞石完成JAK1抑制剂SHR0302在特应性皮炎适应症的临床 III期国际多中心临床研究，试验达到研究预设的共同主要终点及所有关键次要终点。这原本是一次里程碑式节点，在恒瑞来看对瑞石的支持到达了极限。恒瑞就此决定退出瑞石，收回管线。不难理解恒瑞为何坚守自研路线，一方面收购来的项目需要太多投入，另一方面国际市场还没打开，没能将管线的价值发挥到最大。对于风险接受度低的恒瑞来说，自研显然就成为比收并购更稳妥的选择。按照这样的思维，恒瑞后续收并购动作可能会越来越小。不过，恒瑞也给未来留了一些可能性。恒瑞在2021年开启CVC（企业风险投资/战略投资）模式，砸下20亿设立的盛迪投资。目前投资了多个领域的项目，分别是体外诊断产品生产商新羿生物、纳米抗体研发洛启生物、小分子抗肿瘤创新药公司泰励生物和布局多肽偶联药物的同宜医药，基因治疗的瑞宏迪医药。CVC模式下，企业可以先投资再并购，将被投企业纳入业务版图，以弥补自身业务短板。一位投资人认为，恒瑞下场做CVC的时机是正确的，如果放在融资上市环境更好的前几年，biotech不一定乐于在早期投资阶段将未来对产品的优先权交给投资方。-03-和Biopharma的海外较量恒瑞在年报里列出了四家同行业可比公司，有中生制药、石药两家传统药企，以及百济神州、信达生物两家Biopharma。恒瑞一直在传统药企和Biopharma两种身份中切换，作为一家传统药企，其创新转型的进度、临床开发的能力是毫无疑问的。但在Biopharma赛道上，恒瑞从PD-1内卷时期就不存在压倒性优势，随着其他对手商业化团队建立，优势越来越不明显。当年的国产PD-1较量中，百济神州、君实和信达刚刚从Biotech升级为Biopharma，只有恒瑞占据大药企的销售优势。但恒瑞的优势相当短暂，市场份额的领先只维持到2021年。根据PDB数据，2022年恒瑞医药的卡瑞利珠市场份额首次出现缩水，并滑至第二的位置，取而代之的是百济神州的替雷利珠单抗。现在四家PD-1各凭本事闯荡海外市场。君实的PD-1以鼻咽癌小适应症为突破口，最先在FDA获批。经过BTK抑制剂的历练，百济已经具备独立开展国际大规模临床运营的能力和海外申报的能力。百济的PD-1抗体先是在欧盟获批3项肺癌适应症，后来基于RATIONALE 306研究结果在FDA获批食管鳞状细胞癌（ESCC）适应症。恒瑞换了一套打法，为了增加出海可能性，没有向FDA提交PD-1单药上市申请，而是力推卡瑞利珠单抗联合阿帕替尼片（“双艾”组合），开展一项国际多中心III期临床研究，通过美国的Elevar Therapeutics公司提交上市申请。这项研究有一些不确定性，因为83%的临床试验受试者都是亚洲人，白人占不足17%。而百济的RATIONALE 306研究共入组649例患者，其中55%来自中国大陆，25%来自欧美，20%来自日韩等其他国家和地区。上述私募分析师在三年前觉得恒瑞的海外临床能力跟百济差了5年以上，现在改变想法，认为两者之间差了10年。论出海能力，百济神州确实是独一家，大多数Biopharma都和恒瑞一样，采取借船出海的方式。借船出海也并非那么容易，如果不能独立出海，在与海外药企谈判时缺少议价能力，容易被折价。恒瑞去年交了一笔学费。恒瑞以支付首付款和近期里程碑总计2,500万美元的价格将TSLP单抗授权给美国One Bio公司。由于TSLP单抗当时处于一期临床阶段，这个交易在当时没有引起太多注意。没想到半年后，one bio凭借这唯一一条管线，被GSK以14亿美元交易额收购，被收购时TSLP单抗依然处于一期临床。一位资深BD表示很不解，既然翰森能够和GSK达成交易合作，恒瑞没理由联系不到GSK。这对于GSK和恒瑞双方BD人员来说都是一次失误。BD个人的能力很大程度上决定了一家药企BD的情况。在海外BD团队换血后，恒瑞和德国默克的授权交易就顺利多了。恒瑞的PARP1小分子抑制剂HRS-1167在Claudin 18.2 ADCSHR-A1904在海外权益授权给默克，首付款 1.6 亿欧元，潜在的付款总额可能高达14亿欧元。-04-未知的前路恒瑞也曾雄心万丈地在美国设立研发中心，一掷千金收购潜在BIC管线，但都不成功。摸索多年，恒瑞终于在激进和保守之间寻找到的一种平衡状态，这或许在目前是最适合恒瑞的。至于恒瑞的稳扎稳打，和百济神州的高举高打，哪一种能走得更远，谁也不会有答案。政策环境、国际环境在变，企业战略也在变，上述私募分析师直言“‘长期’在医药行业无从谈起”。药企的未来，在大环境的冲击下，更是一个未知数，只不过大船抗风浪能力还是强一些。识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

并购基因疗法信使RNAsiRNA引进/卖出

2024-05-03

·GlobeNewswire-Health Care

BeyondSpring To Host Virtual R&D Day to Discuss New Plinabulin Development Strategy for Cancer and Updates for SEED Therapeutics

FLORHAM PARK, N.J., May 03, 2024 (GLOBE NEWSWIRE) -- BeyondSpring Inc. (NASDAQ: BYSI) (“BeyondSpring” or the “Company”), a clinical-stage global biopharmaceutical company focused on developing innovative cancer therapies, today announced it will host a Research and Development (R&D) Day to discuss the current unmet medical needs and the potential of Plinabulin as a novel immunochemotherapeutic in drug combinations and updates for SEED Therapeutics on Wednesday, May 15th, 2024 at 10:00 a.m. ET. The conference call and webinar will feature presentations by Key Opinion Leaders (KOLs) Trevor M. Feinstein, M.D. (Piedmont Cancer Institute), Alberto Chiappori, M.D. (Moffitt Cancer Center), and Steven Lin, M.D. (MD Anderson Cancer Center), who will discuss below topics: Plinabulin history and development strategy for cancerPlinabulin’s immunomodulatory activity as a DC maturation agentUnmet needs after immune-checkpoint-inhibitor failure Also featured will be a management discussion on technology platform and pipeline updates of SEED Therapeutics, BeyondSpring’s majority-owned molecular glue subsidiary. The dial in numbers for the conference call are 1-877-407-0779 (U.S.) or 1-201-389-0914 (international). To register for the webinar, please click here. An archived replay of the webinar will be available following the presentation on BeyondSpring’s website www.beyondspringpharma.com under “Events and Presentations” in the Investors section. Trevor M. Feinstein, M.D.Dr. Feinstein is board certified in medical oncology and hematology. He joined Piedmont Cancer Institute in 2011 and is the Director of Research at Piedmont Fayette Hospital. Dr. Feinstein is actively involved in clinical trials focused on improved therapies for various cancers. He is a member of Georgia CORE’s research committee along with Georgia Society for Clinical Oncology Clinical Practice Committee. He also chairs the Lung Disease Group for the entire OneOncology network. He is a co-investigator on several peer-reviewed research projects and has authored numerous publications and abstracts in Hematology and Oncology. Dr. Feinstein graduated from the University of Illinois medical school and completed his residence and fellowships at the University of Pittsburgh. Alberto Chiappori, M.D.Dr. Chiappori is board certified in medical oncology. He serves as senior member of oncology and medicine for the Thoracic Oncology Program at the H. Lee Moffitt Cancer Center and Research Institute in Tampa and Florida. Dr. Chiappori is an active member of the American Society of Clinical Oncology, the European Society of Medical Oncology, the American Association for Cancer Research, and the International Association for the Study of Lung Cancer (IASLC). Dr. Chiappori received his MD from the Universidad Peruana Cayetano Heredia in Lima, Peru, completed his residency at Southern Illinois University School of Medicine in Springfield, Illinois, and finished his fellowship and senior fellowship in medical oncology-hematology at Vanderbilt University School of Medicine in Nashville, Tennessee. Steven Lin, M.D., Ph.D.Dr. Lin is a Professor and Physician-Scientist at MD Anderson Cancer Center, with joint appointments in the Departments of Radiation Oncology and Experimental Radiation Oncology. Dr. Lin’s practice focuses on thoracic malignancies, and he oversees several clinical trials including the use of proton beam therapy for esophageal cancer and in the combination of immunotherapy with radiotherapy in lung and esophageal cancers. Dr. Lin runs a translational research team that evaluates biomarkers for treatment response and disease outcomes after cancer therapy. Dr. Lin acquired his M.D. and Ph.D. in the Medical Scientist Training Program at the University of California Irvine Medical School. He went on for residency training in Radiation Oncology at The Johns Hopkins Hospital. About BeyondSpringBeyondSpring is a global clinical-stage biopharmaceutical company focused on developing innovative therapies to improve clinical outcomes for patients with high unmet medical needs. The Company is advancing its first-in-class lead asset, Plinabulin, as a direct anti-cancer agent in various cancer indications and to prevent chemotherapy-induced neutropenia. BeyondSpring’s pipeline also includes three preclinical immuno-oncology assets. Additionally, BeyondSpring’s subsidiary, SEED Therapeutics, leverages a proprietary TPD drug discovery platform and has an initial R&D collaboration with Eli Lilly. Learn more by visiting https://beyondspringpharma.com. Cautionary Note Regarding Forward-Looking StatementsThis press release includes forward-looking statements that are not historical facts. Words such as “will,” “expect,” “anticipate,” “plan,” “believe,” “design,” “may,” “future,” “estimate,” “predict,” “objective,” “goal,” or variations thereof and variations of such words and similar expressions are intended to identify such forward-looking statements. Forward-looking statements are based on BeyondSpring’s current knowledge and its present beliefs and expectations regarding possible future events and are subject to risks, uncertainties, and assumptions. Actual results and the timing of events could differ materially from those anticipated in these forward-looking statements as a result of several factors including, but not limited to, our ability to continue as a going concern, difficulties raising the anticipated amount needed to finance the Company’s future operations on terms acceptable to the Company, if at all, unexpected results of clinical trials, delays or denial in regulatory approval process, results that do not meet the Company’s expectations regarding the potential safety, the ultimate efficacy or clinical utility of the Company’s product candidates, increased competition in the market, the Company’s ability to meet Nasdaq's continued listing requirements, and other risks described in BeyondSpring’s most recent Form 20-F on file with the U.S. Securities and Exchange Commission. All forward-looking statements made herein speak only as of the date of this release and BeyondSpring undertakes no obligation to update publicly such forward-looking statements to reflect subsequent events or circumstances, except as otherwise required by law. Investor Contact:IR@beyondspringpharma.com Media Contact:PR@beyondspringpharma.com

高管变更临床研究免疫疗法ASH会议

100 项与普那布林相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09655	普那布林	-	DB05992

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
中性粒细胞减少	申请上市	中国	BeyondSpring Pharmaceuticals, Inc.	2021-08-17
中性粒细胞减少	申请上市	中国	大连万春布林医药有限公司初创企业	2021-08-17
中性粒细胞减少	申请上市	中国	Pharmaceutics International, Inc.	2021-08-17
续存性动脉干	临床3期	中国	BeyondSpring Pharmaceuticals, Inc.	2019-10-23
续存性动脉干	临床3期	乌克兰	BeyondSpring Pharmaceuticals, Inc.	2019-10-23
乳腺癌	临床3期	美国	BeyondSpring Pharmaceuticals, Inc.	2019-10-15
乳腺癌	临床3期	美国	Pharmaceutics International, Inc.	2019-10-15
乳腺癌	临床3期	美国	大连万春布林医药有限公司初创企业	2019-10-15
乳腺癌	临床3期	中国	BeyondSpring Pharmaceuticals, Inc.	2019-10-15
乳腺癌	临床3期	中国	Pharmaceutics International, Inc.	2019-10-15

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04345900 (CTgov)	临床2期	化疗引起的发热性中性粒细胞减少症 \| 实体瘤	55	Pegfilgrastim+Docetaxel (Arm 1)	膚遞鹹蓋範鹽鹽壓壓選(襯繭衊簾糧鹽顧鬱壓醖) = 願鬱醖鹽鹹範製製鏇壓網艱遞夢積簾淵製襯衊 (餘糧夢獵顧鬱壓範製製, 鹽齋選鹹鬱製遞衊鏇憲 ~ 願衊範衊築襯淵獵製餘) 更多	-	2024-05-16
				Plinabulin+Docetaxel (Arm 2)	膚遞鹹蓋範鹽鹽壓壓選(襯繭衊簾糧鹽顧鬱壓醖) = 簾顧夢糧積襯夢憲膚鑰網艱遞夢積簾淵製襯衊 (餘糧夢獵顧鬱壓範製製, 鬱遞繭鑰淵繭憲襯鹹繭 ~ 蓋膚選壓壓廠夢願齋齋) 更多
EHA2024	N/A	-	-	Plinabulin	襯選廠糧淵鏇夢鬱願網(繭衊觸窪餘齋遞構壓艱) = 構積艱夢製蓋憲艱簾鹽齋憲範簾蓋鹽鹹願遞繭 (鹽齋選選選製觸選醖鬱 )	积极	2024-05-14
				Selumetinib	襯選廠糧淵鏇夢鬱願網(繭衊觸窪餘齋遞構壓艱) = 積衊遞遞遞觸蓋鹽齋鹽齋憲範簾蓋鹽鹹願遞繭 (鹽齋選選選製觸選醖鬱 )
IMS2023	N/A	多发性骨髓瘤	15	Plinabulin + pegfilgrastim	願醖網構膚鬱觸遞鑰夢(構鬱選構壓醖憲網餘鹽) = 糧範襯廠淵遞鬱遞鬱獵積遞壓襯鑰鏇製觸觸顧 (網壓範網壓鏇簾選膚壓 ) 更多	-	2023-09-26
NCT02504489 (ASCO2023) 人工标引	临床2/3期	非小细胞肺癌	-	Plinabulin+Docetaxel	構窪網襯醖鬱窪鬱餘築(構窪鬱鬱醖築窪範鬱壓) = With Plin, AE frequency of diarrhea was slightly higher (5.2% vs 1%; 1 Gr4 case with Plin), but was manageable, and so was hypertension (11.2% vs 1.7%; all Gr3 cases) vs Plac. Hypertension occurred around the time of infusion and was short-lasting (~2-4 hours) and typically self-limiting. Plin had less AEs of neutropenia (16.4% vs 50.3%) and leukopenia (15.5% vs 38.5%) vs Plac. 壓網鑰顧顧齋淵構襯簾 (壓衊簾夢齋遞鬱醖窪鬱 )	积极	2023-05-31
				Placebo+Docetaxel
NCT03102606 (PROTECTIVE-1, ESMO_ASIA2022)	临床2/3期	非小细胞肺癌	30	Plinabulin	願繭範選遞遞遞築範鏇(艱餘襯壓衊顧積鑰淵醖) = 鑰淵觸遞鬱構鹹艱齋築膚壓願艱觸選顧遞淵醖 (顧醖艱鏇顧積醖餘鏇範 )	积极	2022-12-03
NCT03294577 (PROTECTIVE-2, Corporate Publications) 人工标引	临床3期	中性粒细胞减少	115	Pegfilgrastim+Plinabulin	願蓋願鹹製艱壓鹹糧顧(艱構鹹憲鏇齋餘繭齋繭) = 鏇製選遞網鹽糧齋遞築糧網夢鬱糧鹹壓窪蓋簾 (衊獵鏇鏇襯蓋築簾餘蓋 )	积极	2022-10-21
				Pegfilgrastim	願蓋願鹹製艱壓鹹糧顧(艱構鹹憲鏇齋餘繭齋繭) = 獵齋壓醖齋獵蓋壓膚觸糧網夢鬱糧鹹壓窪蓋簾 (衊獵鏇鏇襯蓋築簾餘蓋 )
NCT03102606 \| NCT03294577 (PROTECTIVE-2, ESMO2022) 人工标引	临床2/3期	子宫颈发育不良	496	Plinabulin 20 mg/m2 / 40 mg	齋襯願鏇蓋膚醖構顧艱(窪築製製鑰廠鏇築鬱鏇) = 鬱衊遞網構願顧衊簾憲獵鏇築膚鑰製艱觸獵鬱 (簾窪獵淵夢範鹹憲餘廠 ) 更多	积极	2022-09-10
				Docetaxel 75 mg/m2 or Doxorubicin 50 mg/m2	齋襯願鏇蓋膚醖構顧艱(窪築製製鑰廠鏇築鬱鏇) = 憲艱糧膚鹹廠積醖鑰鹽獵鏇築膚鑰製艱觸獵鬱 (簾窪獵淵夢範鹹憲餘廠 ) 更多
NCT05130827 (Corporate Publications) 人工标引	临床2期	中性粒细胞减少 \| 多发性骨髓瘤	10	JZB-27+Plinabulin	鏇鬱簾構夢繭鏇觸鏇鹹(觸餘鏇艱觸廠範鹹簾願) = 遞餘簾蓋艱齋憲繭膚廠範製鹽廠網膚獵網齋鏇 (襯範淵衊獵廠遞艱夢網 ) 更多	积极	2022-08-29
NCT02504489 (BPI-2358-103, ASCO2022) 人工标引	临床3期	非小细胞肺癌二线 EGFR Wild-type	361	Docetaxel+Plinabulin	糧觸壓憲願網鬱夢獵獵(遞網醖鬱鹹願積淵繭遞) = 壓夢築糧願糧淵製顧鬱餘願製築範鬱簾鬱繭鏇 (衊蓋糧衊壓艱遞憲壓觸, 9.37 ~ 12.4) 更多	积极	2022-06-02
				Docetaxel+Placebo	糧觸壓憲願網鬱夢獵獵(遞網醖鬱鹹願積淵繭遞) = 願獵範艱積壓廠廠膚餘餘願製築範鬱簾鬱繭鏇 (衊蓋糧衊壓艱遞憲壓觸, 8.05 ~ 10.9) 更多
PROTECTIVE-2 (CSCO2021)	临床3期	中性粒细胞减少	221	普那布林40mg+培非格司亭6mg	糧網衊淵齋醖鹽夢鹹齋(夢簾積網淵築窪糧廠願) = 獵鏇遞齋選憲鑰醖鏇構製遞淵鬱餘獵願衊鹽遞 (艱窪鬱餘衊齋艱網糧憲 ) 更多	积极	2021-09-25
				培非格司亭6mg+安慰剂	糧網衊淵齋醖鹽夢鹹齋(夢簾積網淵築窪糧廠願) = 糧廠襯鹹鏇鬱艱蓋襯蓋製遞淵鬱餘獵願衊鹽遞 (艱窪鬱餘衊齋艱網糧憲 ) 更多