Zinpentraxin alfa

编者按：2023 Q1，多家药企接连终止在研管线，例如，GSK结束对细胞基因疗法领域的投入、诺华削减10%非核心管线、武田放弃AAV基因疗法和罕见血液学领域……当然，也有例外，例如诺和诺德。在糖尿病与肥胖领域，其司美格鲁肽很有可能成为今年“药王”的有力竞争者。关于诺和诺德的研发之道，药时代有幸采访到了诺和诺德全球药物发现负责人，相信对致力于研发FIC药物的企业们会有帮助。百年药企诺和诺德如何「以慢制快」？对话诺和诺德全球药物发现高级副总裁 Karin Conde-Knape博士药时代对强生、礼来、艾伯维、罗氏、阿斯利康、辉瑞、BMS、赛诺菲、安进、再生元、拜耳、第一三共、渤健、GSK的四十多条终止管线进行了汇总梳理，在此与大家分享。小分子药物被砍掉最多小分子药物是被砍掉最多的类型，有20条管线。辉瑞一共终止了6条管线，其中5条为小分子药物，分别是：用于急性心力衰竭的APD418、用于血管阻塞的Temanogre、用于治疗雷诺氏综合征的Temanogrel、用于掌跖脓疱病和化脓性汗腺炎两种适应症的RIST4721。（图源：辉瑞官网）拜耳的4项终止均为小分子药物，分别为：用于糖尿病神经性疼痛的BDKRB1 受体拮抗剂、用于慢性肾病的Runcaciguat、用于子宫内膜异位症的BAY 2395840和P2X4拮抗剂。礼来终止TRPA1 拮抗剂在镇痛领域的研究；艾伯维终止ABBV-154在囊性纤维化上的研究；阿斯利康终止ALXN1840在威尔逊病领域的研究；BMS终止iberdomide在淋巴瘤上的研究；赛诺菲终止Tolebrutinib和atuzabrutinib在自身免疫病相关研究；渤健终止BIIB093在脑挫伤和大脑半球梗塞领域的研究，及BIIB131在急性缺血性中风上的研究；GSK停止了Zejula在乳腺癌领域的研究。（图源：Lilly官网）（图源：百时美施贵宝官网）单抗类药物次于小分子药物，被砍掉逾10条管线。罗氏一共终止了3条单抗类药物管线，均为Tecentrig组合药物，分别为：用于一线转移性尿路上皮癌的Tecentrig+chemo、用于二线非小细胞肺癌的Tecentriq+Cabometyx、用于二线her2阳性、PD-L1阳性转移性乳腺癌的Tecentriq +Kadcyla。赛诺菲和再生元均分别终止了Dupixent的一条管线，分别为过敏性真菌性鼻炎和无鼻息肉慢性鼻窦炎、慢性寒冷引起的荨麻疹。阿斯利康终止了用于实体瘤的AZD8853和用于一线转移性非小细胞肺癌的Imfinzi。礼来终止用于阿尔兹海默症的solanezumab；辉瑞终止用于溃疡性结肠炎的PF-06480605；BMS终止用于黑色素瘤的nivolumab +rHuPH20；第一三共终止用于进行性骨化性纤维发育不良的DS-6016。疫苗终止了两条管线，均为强生的药物，分别是成人RSV疫苗和HIV疫苗。反义寡核苷酸类药物共有两个，分别是第一三共用于杜氏进行性肌营养不良的DS-5141和渤健用于脊髓小脑性共济失调3型的BIIB132。融合蛋白类有两个，分别为礼来和安进用于系统性红斑狼疮的Rezpegaldesleukin和efavaleukin alfa。剩下的为阿斯利康用于NASH领域的合成多肽类药物cotadutide、罗氏用于骨髓纤维化的重组蛋白类药物zinpentraxin alfa、安进用于系统性红斑狼疮的双特异性抗体药物Rozibafusp alfa。免疫和肿瘤领域依然占大头被砍掉的自免型疾病管线占大头，有11条。其次是肿瘤类管线，有8条。再就是罕见病领域，有4条管线被终止。渤健终止的几条管线均为脑血管疾病领域。II期项目“夭折”最多根据统计，除去部分临床阶段不明的管线，在II期被终止的管线有19条：在III期被终止的管线有11条：在I期被终止的管线有6条：II期试验也称为疗效试验或临床效能试验。主要目的是评估新药在特定疾病人群中的治疗效果和安全性。如果在这个阶段没有足够的证据表明新药对疾病有明显的疗效，或者新药的效果与已有治疗方案相比没有显著优势，试验可能会被终止。同时，临床II期试验是在相对较大规模的患者群体中进行的，这时候药物的潜在安全性问题更容易被发现。如果药物出现了严重的安全问题，试验可能会被终止以保护患者安全。而III期实验的终止，可能是因为前两期的实验过程出现了问题，而导致潜在安全问题没有被发现。且即使是到了申报上市的阶段，也有可能管线被终止，而无法上市。只过了2个月，就从「即将获批」变成了「管线终止」......这款药，是从一开始就做错了吗？封面图来源：123rf2023年1月1日至今，~20笔中国新药出海交易横空出世，总金额高达上百亿美元！一时间，喜讯频传，令行业、企业和每一位同药振奋！曾经提出“百靶竞技，百炼创新，百家上市，百药争先”的药时代团队再一次真切感受到：中国新药研发正当时！中国新药出海正当时！中国新药BD正当时！在这个BD如火如的好时代里，企业对于BD的要求不断提高，如何与时俱进，学习最新BD知识，掌握最新BD技能，成为摆在每一位BD同药面前的一个实际而迫切的问题。为了帮助企业培养优秀的BD高级人才，为了帮助BD人才成长进步，药时代学苑全力打造创新药BD高级研讨会，致力于成为中国制药界ZUI有实力和活力的学习平台。点击这里，报名参加，一起快乐学习！

Roche used an update to reveal the disappearance of a geographic atrophy program from its pipeline. Roche no longer sees the magic in MAGE-A4. The Swiss drugmaker signaled a retreat from the TCR T-cell target in its first quarter results by putting a pair of phase 1 solid tumor programs out to pasture along with hopes of recouping the $490 million paid out for the assets. Genentech, a subsidiary of Roche, put down $100 million in upfront and near-term milestone payments to co-develop one of the candidates with Immunocore in 2018. The drug candidate, a bispecific T-cell engager targeting MAGE-A4, entered the clinic the following year, but both developers have walked away from the program since the release of phase 1 ovarian cancer data late last year. In February, Immunocore stopped funding the program, apart from the cost of winding down the phase 1 trial. The action left Roche’s Genentech with an exclusive worldwide license to the MAGE-A4 HLA-A02 soluble TCR bispecific therapeutic candidate compounds. It seems Roche doesn’t want the compounds, either. The Swiss drugmaker disclosed the axing of RG6290, a drug candidate based on Immunocore’s ImmTAC technology that is also known as IMC-C103C, alongside news of the removal of another MAGE-A4 asset from its pipeline. Roche took the other candidate, HLA-A2-MAGE-A4xCD3 bispecific antibody RG6129, into the clinic months after Immunocore began a phase 1 trial of IMC-C103C. Early this year, Roche said it had stopped enrolling patients in the study of RG6129, pulling the targeted completion date of the trial forward by more than two years in the process. The removal of the asset from the pipeline recasts the cessation of enrollment as the start of Roche’s retreat from the candidate. Roche invested in the programs in the belief a molecule that simultaneously binds to CD3 on cytotoxic T-lymphocytes and HLA-A2 MAGE-A4 on tumor cells could orchestrate an anti-cancer immune attack. As MAGE-A4 is overexpressed by a variety of cancer cell types, the mechanism is potentially applicable to a range of tumors. The attributes of MAGE-A4 have made it a popular target for TCR T-cell biotechs, with Immunocore and its sibling Adaptimmune among the companies to go after the protein. Adaptimmune is closing in (PDF) on a filing for FDA approval of its first-generation MAGE-A4 candidate. Roche disclosed the MAGE-A4 news as part of a pipeline update that saw it punt two other programs. The list of castoffs includes zinpentraxin alfa, also known as PRM-151 and RG6354. Roche previously stopped a phase 3 trial of the candidate in idiopathic pulmonary fibrosis early because the study looked on course to fail.  Now, the drugmaker has stopped work on myelofibrosis, too. Roche acquired the drug candidate in the 2019 takeover of Promedior, which cost it $390 million upfront. Removing the myelofibrosis program from the midphase pipeline leaves Roche without active clinical programs involving zinpentraxin alfa. Finally, Roche also used the update to disclose the removal of a geographic atrophy program RG6312 from its phase 1 pipeline. Since RG6312 entered the clinic in 2020, the Big Pharma has suffered setbacks in its pursuit of the eye indication, failing a phase 3 trial in 2017 and dropping galegenimab last year. But it still has two shots on goal, including a Lineage Cell Therapeutics candidate that recently entered phase 2.