Mazisotine

（来源：一度医药）转自：一度医药2025年10月30日，生物医药行业迎来特殊的“管线调整日”。百时美施贵宝（BMS）、礼来（Eli Lilly）、武田（Takeda）三大跨国药企同步宣布终止6项临床阶段项目，覆盖肿瘤、慢性疼痛、神经疾病等热门治疗领域。这场集中“砍线”不仅是企业对研发管线的动态优化，更折射出当前医药行业在靶点攻坚、成本控制与资产整合中的深层挑战。BMS此次调整涉及两项关键战略资产，均与此前大额投资布局相关。其中，SOS1抑制剂MRTX0902是2023年BMS以58亿美元收购Mirati Therapeutics时纳入的核心资产，原本被寄予实体瘤治疗厚望，处于1/2期临床阶段，原计划2026年中公布核心试验数据，同时探索单药及与已获批药物Adagrasib的联合疗法。另一项终止的EXS4318则源自BMS与Exscientia（现已与Recursion合并）的合作，作为具有“first-in-class”潜力的PKC-theta抑制剂，主打免疫炎症疾病治疗，2023年已启动人体临床试验，BMS当初以12亿美元“里程碑付款+授权费”模式获得其开发权。BMS在2025年Q3财报中仅提及终止原因是“基于试验阶段与药物作用机制评估”，未披露更多细节。值得关注的是，此次调整正值BMS推进“年末前节省15亿美元”的成本削减计划，研发资源重新分配或为重要考量，不过BMS并未完全放弃Mirati的资产，针对MTAP缺失实体瘤的MRTX1719仍在1期临床开发中。礼来的管线调整聚焦疼痛领域，宣布终止P2X7抑制剂LY3857210的2期临床开发。该药物并非礼来自研，而是2021年从日本旭化成制药授权引进，当时旭化成获得2000万美元预付款，且已完成1期临床。LY3857210原本被纳入礼来“慢性疼痛主协议研究”，针对骨关节炎、糖尿病周围神经病变、慢性背痛三大适应症，但礼来发言人明确表示，该药物的P2X7相关试验数据未达到公司内部设定的高成功标准。不过礼来强调与旭化成的licensing 协议仍有效，目前正评估该药物用于其他适应症的可能性。这并非礼来近期砍掉的首个疼痛药物，上一季度其已终止2019年以4750万美元从Centrexion Therapeutics引进的非阿片类疼痛候选药mazisotine。但礼来在疼痛领域的布局并未停滞，通过收购SiteOne Therapeutics纳入NaV1.8抑制剂STC-004，同时推进从Confo Therapeutics授权的AT2R拮抗剂、抗epiregulin抗体fepixnebart，以及明星口服GLP-1候选药orforglipron的疼痛相关临床试验。值得注意的是，P2X7靶点此前已多次折戟，GSK、阿斯利康等企业均曾因数据或疗效问题终止相关项目。武田的管线调整涉及三项资产，核心是与阿斯利康联合开发的神经疾病药物TAK-341（阿斯利康代号MEDI1341）。作为一款α-突触核蛋白抗体，TAK-341针对罕见神经疾病多系统萎缩（MSA）开展全球2期研究，共入组159名患者，每4周静脉输注一次，核心目标是治疗52周时通过“改良统一多系统萎缩评分量表”证明药物获益，但最终试验未达到主要及次要终点，武田明确表示“不足以支持继续开发MSA适应症”。根据最初协议，TAK-341同时布局MSA和帕金森病适应症，目前武田已将其移出管线，但阿斯利康仍保留该药物的2期研究状态，后续开发方向待定。此外，武田还以“战略原因”终止两项1期项目：一是2021年收购GammaDelta Therapeutics时获得的异基因γδT细胞疗法TAK-012-1501，此前用于急性髓系白血病（AML）的1/2期临床开发，这也是武田“全面收缩细胞疗法领域布局”的重要举措；二是食欲素2受体激动剂TAK-925（通用名danavorexton）的发作性睡病适应症，该药物目前仍在2期临床用于呼吸疾病治疗，而其阻塞性睡眠呼吸暂停适应症的2期试验已于一年前因入组缓慢终止。单日三家巨头集中优化管线，并非偶然，而是生物医药行业发展的必然趋势。首先，临床价值优先成为硬标准，药企对研发项目的评估更趋严格，对于既往多次失败的靶点和难治性疾病，不再盲目投入。其次，并购后资产整合进入“深水区”，BMS对Mirati资产的取舍、武田对收购所得细胞疗法的收缩，体现出海药企在大额并购后，更注重根据临床进展和战略匹配度进行精准筛选，形成“并购-评估-优化”的闭环。最后，成本控制驱动资源聚焦，BMS的15亿美元成本削减计划、武田收缩非核心领域，本质上都是通过砍掉前景不明的项目，将研发资源集中于高潜力核心管线，以提升研发效率。这场管线调整既是行业洗牌的缩影，也预示着生物医药研发将更趋理性与聚焦。参考：fierce biotech

Tucked into its latest earnings report, Eli Lilly disclosed that it has removed from its research pipeline an experimental drug for pain.The drug, which Lilly in-licensed several years ago, works by inhibiting a protein called P2X7. This protein helps regulate molecules that trigger inflammation and amplify pain signals. Blocking P2X7, Lilly had hoped, would be an effective way to treat conditions like osteoarthritis, chronic lower back pain and the nerve pain that often accompanies diabetes.However, data from mid-stage tests did not meet our high internal bar for success, according to Lilly spokesperson Ashley Hennessey. While the company is assessing next steps for the program, including possible additional indications, for now, the drug is out of its pain pipeline.Its at least the second Lilly pain program to get axed this year. A drug named mazisotine, designed to boost a pain-relieving protein known as SSTR4, was shelved this summer.These cuts underscore just how incredibly difficult pain drug research continues to be, even for deep-pocketed companies with extensive experience studying the nervous system. Lillys biggest rival in pain, Vertex Pharmaceuticals, lost billions of dollars in market value a few months ago, after reporting a potential successor to its pioneering pain medicine Journavx had failed a key mid-stage trial.Alongside that disclosure, Vertex said it would not start a late-stage study of Journavx in a form of sciatica, derailing plans to expand use of the drug into peripheral neuropathic pain.Despite such setbacks, the immense number of people suffering from pain has encouraged some companies to keep pushing forward. Lilly, for one, has gradually deepened its investments over the past few years. In May, it wagered up to $1 billion on an acquisition of SiteOne Therapeutics, a private biotechnology company working on new, non-opioid pain medicines that may one day compete with Journavx.Lilly has had a persistent interest in pain in recent years ... but with little tangible success, Carter Gould, an analyst at the investment firm Cantor Fitzgerald, wrote in a note to clients shortly after the acquisition was announced. Given the deal terms and the clear strategic interest, this seems like a reasonable move, even with the outstanding commercial and clinical questions for the class of drugs SiteOne specializes in.That deal handed Lilly a drug which had already gone through Phase 1 testing and, like Vertexs molecule, targets a type of cellular signaling channel known as Nav1.8.Beyond that program, Lilly has a another non-opioid, early-stage candidate targeting a protein, AT2R, tied to neuropathic pain.And on the more advanced end, Lilly is evaluating whether an antibody that impedes the epiregulin protein can be a treatment for chronic pain. The company is also seeing if two of its most closely watched experimental therapies for diabetes and weight loss orforglipron and retatrutide could also be useful against osteoarthritis or chronic lower back pain. '