Fedratinib Hydrochloride

编者按：“让天下没有难做的药，难治的病”，是初心，更是愿景。二十五年来，药明康德步履不停：从一间实验室，到覆盖亚洲、欧洲和北美的全球网络。从早期的化学合成服务，到贯穿研究（R）、开发（D）和生产（M）的一体化平台。从第一位客户，到全球三十多个国家的数千合作伙伴。不断发展的，是规模与能力；始终坚守的，是梦想与承诺。 致敬来时路，共谱新篇章！在二十五周年之际，我们以“逐梦者”视角，回顾药明康德成长发展的峥嵘岁月，回望赋能客户创新的并肩往事，更以独特的“药明精神”展望未来新篇章。 那个下午本来再普通不过，直到电话响起，约翰·胡德（John Hood）博士接到噩耗：他所熟知的一位患者离世了。 一款名为fedratinib的在研药物曾经控制住了她的病情。这是约翰早年在TargeGen担任研发负责人时带领团队开发的强效JAK2抑制剂。在临床试验中，这款药给不少患者带来了明显的改善。但意外出现的不良事件，让临床试验被迫暂停。原本依赖药物维持病情的患者被迫停药，重新寻找替代方案。那位患者最终没能等到新的治疗希望。 对约翰来说，这不仅令人心碎，更是一种召唤。 “那一天，我意识到，我必须把这款药带回来。”他说。 他很快创立了Impact Biomedicines，目标只有一个：重新推动fedratinib的临床开发，让它真正回到患者手中。 但要做到这一点并不简单，必须以惊人的速度弥补化学、生产、监管等众多准备工作。而一家公司，尤其是初创公司，很难独自撑起这一切。 约翰第一时间就想到一个名字：曾帮助他“以不可思议的速度”推进研发的合作伙伴：药明康德。 当“速度”决定了承诺能否兑现 时间倒回十年前。TargeGen刚刚起步，资源有限，而约翰追寻的，是当时看来相当激进的构想：靶向骨髓纤维化中的突变酶JAK2。当时，患者几乎没有治疗选择，大多数确诊后只能存活几年。 团队最终发现了fedratinib，这是一款有望显著改变疾病进程的高选择性JAK2抑制剂。然而从科学突破走到临床候选药物之间，还有无数繁琐而关键的环节：标准化生产、分析方法、监管要求……样样都不能出差错。 药明康德依托其一体化的新药研发赋能平台与TargeGen合作，将科研团队的早期发现转化为高质量的临床材料，并建立了稳定的工艺和生产体系。从发现先导化合物到首次概念验证，仅用了一年时间。 “当时，这样的速度是前所未闻的。”约翰回忆道。 试验结果令人鼓舞。Fedratinib给许多患者带来了新的转机。即便意外不良事件的出现一度阻碍其上市进程，约翰对它的信心从未动摇，也从未忘记曾并肩加速其研发进展的合作伙伴。 当Impact重新拿回药物开发权时，他们设定了一个看似“不可能”的目标：在十四个月内完成三批注册级别fedratinib的生产。 项目时间紧、任务重，直接关系到药品的上市速度。药明康德接下了这个挑战，并最终将药物提前交付给Impact公司。 “在规模、质量和速度三方面能同时做到最好，这不是每家公司都做得到的。”约翰说。 2019年，fedratinib终于获得美国FDA的批准。这不仅是约翰职业生涯的高光时刻，更是承诺的兑现： 那些曾经无助等待的患者，终于等到了属于他们的药物。 逆转“不可逆” 在让fedratinib“起死回生”之后，约翰并没有停下脚步。 他成立了Endeavor Biomedicines，把目光投向特发性肺纤维化（IPF）。这种疾病会让肺逐渐失去弹性，最终使患者无法呼吸。现有疗法只能延缓病情恶化，却无法逆转肺部损伤。 Endeavor的研发策略，瞄准了在组织修复中至关重要的Hedgehog信号通路。 在一项2a期临床试验中，其候选药物展现出前所未有的结果：患者肺部纤维化状况出现了逆转。 “在那么短的12周内看到肺功能改善，让我们意识到IPF也许并不是绝症。”约翰说。 不久前，这款在研疗法成为首个获欧洲药品管理局（EMA）授予PRIME认定的IPF疗法。 推动这一进展的过程同样是一场与时间的赛跑。 Endeavor从另一家药企获得这款疗法的开发权益时，从先前许可方获得的原料即将过期，临床试验进度面临危机。 药明康德与Endeavor再次携手，并肩设计了全新的并行合成工艺，不仅顺利保障了药物供应的连续性，还提升了产率和纯度，确保临床试验按时启动。 “在我们这个行业，时间就是生命。”约翰感叹道，“而他们永远能在关键节点给出高质量、准时的交付。” 如今，这款新药的后续开发工作，正在四大洲、十余个国家与地区推进。 对那些每一天都感到呼吸在流失的患者来说，每争取一周，都意义重大。 合作驱动精准创新 在聚焦于逆转肺纤维化的同时，Endeavor的另一个项目是一款抗癌的抗体偶联药物（ADC），靶向一种比HER2表达更为广泛的受体，可能为缺乏治疗选择的癌症带来全新方案。 但ADC的制造本身就像在走钢丝。几十道工艺环环相扣，任何效率上的差一点，都可能让本来可行的药变得不可及。 图片来源：123RF 药明康德与Endeavor重新设计了关键合成步骤，将整体产率提升了10%以上，同时提高纯度和稳定性。 “这不是小优化。”约翰说，“它直接改变了整个项目的可行性。” 在他看来，这正体现了药明康德的核心能力。“他们不仅执行力强，而且不断创新。无论面对什么样的挑战，总能迅速给出高质量解决方案。” 很多人会说，在药物开发中，“速度、质量、成本，三者只能取其二。” 约翰笑了笑：“药明康德打破了这条规则。他们持续稳定地做到三者兼得。而这就是我为何不断回来与他们合作的原因。” “始终是那个可靠的伙伴” 如今，Endeavor正在推进IPF项目的2b期临床试验，并不断扩展其肿瘤学管线。 当被问到与药明康德二十年的合作意味着什么时，约翰没有犹豫： “每一次新药成功获批，都是我们职业生涯中最重要的时刻。药明康德从骨髓纤维化到IPF、再到癌症项目，都站在我们身边。他们始终是那个可靠的伙伴。” “在复杂的全球试验推进过程中，有太多不确定性，但CMC从来不是我们需要担心的部分。” 他说着停顿了一下，语气放轻，却格外坚定： “我很幸运，在职业生涯的早期就选择与他们合作。每当我有不同的尝试，我都会再次意识到，最初的选择是对的。” “我很难想象，会选择其他伙伴。” 药物研发是一场漫长的接力，有些人奔跑，是为了兑现一句承诺。有些公司陪跑，是为了让承诺抵达现实。 A Promise Fulfilled: Dr. John Hood and the Two-Decade Partnership with WuXi AppTec Editor’s Note: “Every drug can be made and every disease can be treated”. Over the past 25 years, from a single laboratory to a global network spanning Asia, Europe, and North America; from early chemical synthesis services to an integrated platform that connects Research (R), Development (D), and Manufacturing (M); from its very first customer to thousands of partners across more than 30 countries, WuXi AppTec has never stopped moving forward to realize its enduring vision.  In tribute to the journey and in celebration of new beginnings, we look back through the eyes of our “dream-makers”: revisiting the stories of partnership that empowered global innovation, and the unique spirit that continues to guide us toward the next chapter. The call came on an otherwise ordinary afternoon. A patient, one Dr. John Hood had met personally, was gone. She died because the illness progressed after she lost access to the experimental drug that had been keeping it in check. The medicine was fedratinib, a potent JAK2 inhibitor Hood had helped bring into existence years earlier at TargeGen. The compound was real, the data compelling, but development had stalled, and the molecule sat in limbo. For Hood, the news wasn’t just a heartbreak. It was a summons. “That day,” he later recalls, “I decided I had to bring the drug back.” Within months he founded Impact Biomedicines, assembling a small team with a single purpose: to resurrect fedratinib and carry it all the way to patients. To do that, he needed chemistry, manufacturing, and regulatory readiness faster than any young biotech could build alone. He turned instinctively to the same collaborator that had once helped him compress discovery timelines to record speed: WuXi AppTec. When Speed Became the Difference Between Promise and Reality About a decade earlier, in the early days of TargeGen, John Hood was chasing an idea that few believed possible: targeting a single mutant enzyme, JAK2, that drives myelofibrosis, a rare and devastating blood cancer. At that time, patients faced limited options, and most succumbed within a few years of diagnosis. For a young biotech with limited resources, turning a concept into a clinic-ready drug seemed like a distant goal. Hood’s team led the scientific discovery, identifying fedratinib as a highly selective JAK2 inhibitor with the potential to change the course of the disease. But transforming that molecule into a therapy required scale, precision, and speed. WuXi AppTec, serving as an integrated CRDMO platform, stepped in to enable what would become a record-setting advance. Its chemists translated TargeGen’s early discovery into high-quality clinical material, establishing the analytical and manufacturing foundations that allowed the company to move from lead identification to first-in-human studies in just one year, an extraordinary pace in the mid-2000s. “That speed was unheard of back then,” Hood recalls. Fedratinib went on to achieve impressive response rates in myelofibrosis, offering new hope to patients who had failed previous treatments. When regulatory uncertainty temporarily halted its progress, Hood never lost faith in the science or in the partner who had helped him realize it the first time. At Impact Biomedicines, the situation was urgent, and the stakes were high. The company had an ambitious goal: manufacture three registration-grade lots of fedratinib within fourteen months. WuXi AppTec took on the challenge and delivered ahead of schedule. “That reliability was the difference between success and failure,” Hood says. “They gave us quality and speed at a scale no one else could match.” In 2019, fedratinib won global approval. For Hood, the moment wasn’t just a professional triumph; it was the closure of a deeply personal circle. The patients who had once been left waiting now had a therapy in their hands. The Next Frontier: Reversing the Irreversible If fedratinib was about bringing back a lost medicine, Hood’s next venture is about rewriting what medicine itself can do. The company’s lead focus is idiopathic pulmonary fibrosis (IPF), a disease that scars the lungs until patients can no longer breathe. Current treatments can only slow the decline; none have yet reversed it. Endeavor’s approach is built around a molecule that targets the Hedgehog signaling pathway, which regulates cellular repair. In a Phase 2a study, the compound showed something unprecedented: measurable reversal of fibrosis in the lungs. “That hasn’t been seen before,” Hood says. “To watch lung function and architecture improve over twelve weeks, it gives us hope that IPF may not have to be a death sentence.” Recently, this drug candidate became the first investigational IPF therapy to receive PRIME designation from the European Medicines Agency. Behind that data was a quiet race against time. The material inherited from a prior license was nearing expiration, jeopardizing the trial schedule. WuXi AppTec and Endeavor’s teams worked side by side to design a new parallel synthesis process that not only replaced the old supply but improved yield and purity, allowing the Phase 2 trial to start on schedule. “Time is the biggest asset in our business,” Hood notes. “WuXi AppTec delivered drug product on time and at high quality. They’ve been a trusted partner for me going on two decades.” The global study now spans four continents and more than a dozen countries, reflecting the complexity of modern development and the necessity of reliable partners who can bridge geographies and regulatory systems seamlessly. For patients whose lungs are failing, every week gained matters. Engineering Precision Through Partnership While one arm of Endeavor Biomedicines focuses on reversing lung fibrosis, the other is pushing boundaries in oncology. Its antibody–drug conjugate (ADC) program targets a receptor more prevalent than HER2, offering new possibilities for cancers that remain resistant to existing therapies. Yet behind this scientific ambition lay a practical obstacle: cost and complexity. ADC manufacturing involves dozens of interdependent steps, and even small inefficiencies can make a promising therapy unfeasible. That’s where WuXi AppTec came in. Endeavor’s internal chemists worked closely with WuXi AppTec’s teams to redesign critical stages of the ADC synthesis. Together, they re-engineered the process to improve yield by more than 10 percent while simultaneously increasing purity and stability. “That improvement changed the economics of the project,” Hood says. “It turned something that might have been too expensive to pursue into a viable product candidate.” For Hood, this experience captures what sets WuXi AppTec apart. “It’s about execution and innovation,” he says. “No matter what challenge arises, they find a way to deliver high-quality solutions fast.” Source: 123RF He puts it plainly: most partners will tell you that in drug development, you can pick only two out of three—speed, quality, or cost. “WuXi AppTec breaks that rule,” Hood said. “They consistently deliver all three at once; it’s a big reason I keep coming back.” A Partnership Without Parallel As Endeavor pushes forward with its Phase 2b trials and begins scaling its oncology program, Hood remains characteristically focused on the work still ahead. Yet when asked what these twenty years of collaboration mean to him personally, his answer comes easily. “Any time you can get a new drug approved, that’s the pinnacle of a career,” he says. “WuXi AppTec supported us both in the discovery and registrational phases of fedratinib. Now they’re helping us pursue something just as meaningful in IPF and cancer. Throughout all this, they’ve been the one constant. With complex global trials, there’s plenty to worry about, but CMC isn’t one of them.” Then he pauses, the way someone does when reflecting on a truth that’s self-evident. “I was fortunate to partner with WuXi AppTec early in my career,” he says finally. “And every time I’ve looked elsewhere, I’ve been reminded why. I simply can’t imagine working with anyone else.” 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

► MPNs的定义与组成 骨髓增殖性肿瘤（MPNs）是一类克隆性血液疾病，严重威胁患者的骨髓健康，导致血细胞生成异常。这种疾病主要包括原发性血小板增多症（ET）、真性红细胞增多症（PV）和原发性骨髓纤维化（PMF），这些病症均有可能发展为骨髓纤维化（MF），从而带来严重的健康问题和不良预后。 ► JAK2在MPN中的作用 JAK2基因的突变或融合被认为是MPN发生和发展的关键因素。其中，JAK2 V617F突变最为常见，同时，TEL(ETV6)-JAK2融合也是主要类型之一。在真性红细胞增多症患者中，JAK2 V617F的检出率高达71.4%-96%，原发性血小板增多症患者中为30%-86%，原发性骨髓纤维化患者中则为40%-80%。这些数据显示，JAK2突变在MPN的发病机制中扮演着至关重要的角色，且携带突变的患者通常面临更为严峻的预后。 JAK2基因位于染色体9p24位置，其编码的JAK2蛋白是一种重要的细胞内酪氨酸激酶。在正常造血功能的维持过程中，JAK2与JAK2-STAT信号转导途径的调控起着核心作用。在野生型状态下，JAK2的激活需要细胞外配体，如EPO、TPO、GM-CSF和IL-3的刺激。然而，一旦JAK2发生突变或融合，其激活过程将不再依赖这些细胞外配体，导致JAK2-STAT等信号通路的持续激活，最终引发骨髓增殖性肿瘤的发生。 ► 已批准的JAK2抑制剂 针对骨髓纤维化（MF）的发病机制，JAK2已成为关键的治疗靶点。药企针对此开发了一系列JAK2选择性和非选择性的抑制剂，这些药物对于提高患者的存活率、改善疾病相关症状，如白细胞减少、红细胞比容升高、脾肿大以及骨髓纤维化等，均显示出积极的效果。JAK2抑制剂如 Jakafi（ruxolitinib）与 Inrebic（fedratinib）已经显著改善了骨髓纤维化患者的治疗方案。 2011年，诺华公司的JAK1/JAK2抑制剂Jakafi获得美国食品药品监督管理局（FDA）批准，成为首款专门治疗骨髓纤维化的JAK2药物。这一突破极大地改变了骨髓增殖性肿瘤的治疗格局。2019年，FDA再次批准新基制药的Inrebic，该药物针对中危-2和高危的原发性或继发性骨髓纤维化成人患者，显示出强大的JAK2抑制效果，甚至超越了对其他JAK家族成员的抑制。 ► 国内的JAK2抑制剂研发 在中国，多家企业正在积极推进JAK2抑制剂的创新药物研发。其中，泽璟生物的Jaktinib（JAK1/2抑制剂）已进入临床II期阶段，而正大天晴的选择性JAK2抑制剂TQ05105也已启动I期临床研究。这些进展展示了中国在JAK2抑制剂研发领域的实力和潜力。 ► 细胞筛选模型的建立 为了满足JAK2激酶抑制剂的开发需求，科佰生物开发了基于JAK2 V617F/BAF3等的细胞筛选模型。这一模型为筛选潜在的JAK2激酶抑制剂提供了强有力的支持。 ► 关键组合分析与实验 通过深入分析特定组合如JAK2 V617F/BaF3与CBP73246，我们获取了详尽的产品数据。这些数据为评估JAK2激酶抑制剂的效能和选择性提供了重要支持，进一步验证了我们之前的研究。此外，通过CTG增殖测定，我们还进一步探讨了这些组合在细胞增殖方面的具体表现。 这一系列的深入研究深化了我们对JAK2激酶抑制剂作用机制的理解，并为未来的药物筛选和开发提供了重要的数据支持。