Belrestotug

葛兰素史克（GSK）的cobolimab成为最新一款在关键肿瘤学试验中失败的抗TIM-3抗体。与此同时，这家英国制药公司还因抗TIGIT药物研发失败承受了超过6亿美元的损失。GSK一直在评估cobolimab——该药物是其2018年以51亿美元收购Tesaro时获得的，与其肿瘤药物Jemperli及化疗药物多西他赛的多种联合方案，用于一项针对750名非小细胞肺癌（NSCLC）患者的三期临床试验。该公司在7月30日发布的第二季度财报中透露，这项研究未能达到其主要终点，即在患者接受过前期免疫肿瘤治疗后，延长晚期非小细胞肺癌患者的总生存期。GSK在最新财报中表示：“所有治疗方案的耐受性良好，毒性与多西他赛和免疫检查点抑制剂已知的安全特征一致。这仍是一个具有挑战性的治疗领域，目前新型联合疗法尚未能改善大多数患者的预后。”尽管这一晚期试验失败，GSK对cobolimab的希望并未彻底破灭。该公司仍在一项针对多种儿童癌症的1/2期试验，以及一项针对晚期肝癌的中期试验中对该药物进行评估。01 罗氏、BMS、礼来、诺华、GSK接连折戟TIM-3抗体TIM-3在免疫效应细胞上表达，发挥免疫检查点的作用；同时也在白血病干细胞上表达。这使得多家大型制药公司将这一受体视为既能激活免疫系统、又能抑制癌细胞增殖的潜在靶点。然而，GSK的cobolimab未能在三期试验中取得成功或许并不意外。2024年初，当诺华的抗TIM-3候选药物在骨髓增生异常综合征或白血病患者的晚期试验中失败后，cobolimab便成为当时进展最快的抗TIM-3抗体。诺华的研究聚焦于血液肿瘤，而GSK及其他拥有TIM-3候选药物的巨头则主要关注实体瘤。在此之前，罗氏早在2022年已将一款PD-1×TIM-3双特异性抗体从研发管线中移除；百时美施贵宝也在2022年终止了其TIM-3候选药物BMS-986299的一期试验，理由是“业务目标”已发生变化；礼来和因赛特也已终止了各自的TIM-3药物研发。目前，阿斯利康似乎仍在抗TIM-3领域有所布局，其一款PD-1×TIM-3双特异性抗体的1/2期试验预计将于今年完成。02 GSK停止多项研发管线GSK公布2025上半年业绩，总营收155.02亿英镑（约201.57亿美元），同比增长5%。TIM-3并非GSK本季度在高风险癌症靶点领域唯一遭遇挫折的项目。该公司在同一份财报中透露，其决定终止抗TIGIT抗体belrestotug的研发，这导致了4.71亿英镑（约合6.29亿美元）的减值损失。四年前，GSK向iTeos公司支付了6.25亿美元的预付款，获得了belrestotug的相关权利。在belrestotug的二期试验失败后，iTeos公司最初计划停止运营，随后在本月初接受了Concentra Biosciences的收购要约。财报还显示，GSK已终止了一款处于二期阶段的疟疾佐剂重组蛋白疫苗（GSK3437949）的研发。该公司发言人称，此举是基于其最近宣布的向第二代多阶段疟疾疫苗领域推进的战略。此外，发言人表示，抗生素sanfetrinem的口服前药sanfetrinem cilexetil也已从公司的二期研发管线中移除，原因是“在早期研究中，其表现不如现有治疗方案以及GSK正在研发的其他结核病特异性候选药物”。基于目前的管线布局，GSK仍对2031年销售额超过400亿英镑充满信心。识别微信二维码，可添加药时空小编请注明：姓名+研究方向！

GSK may not have been surprised its anti-TIM-3 drug couldn’t secure a phase 3 win based on how its pharma peers have struggled.\n GSK’s cobolimab has become the latest anti-TIM-3 antibody to flunk a crucial oncology test, as the pharma absorbs a more than $600 million hit from its anti-TIGIT drug failure.The British Big Pharma had been evaluating cobolimab—which it acquired in the $5.1 billion Tesaro takeover in 2018—in various combinations with oncology med Jemperli and the chemotherapy docetaxel in a phase 3 study of 750 patients with non-small cell lung cancer (NSCLC).The company revealed in its second-quarter earnings this morning that the study didn’t reach its primary endpoint of improving overall survival in advanced NSCLC after prior immuno-oncology therapies.“All regimens were well-tolerated and toxicities were consistent with known safety profiles of docetaxel and immune checkpoint inhibitors,” GSK said in its July 30 earnings release (PDF). “This remains a challenging treatment setting where novel combinations have yet to improve outcomes for most patients.”The late-stage fail doesn\'t mark the end of GSK\'s hopes for cobolimab. The company is still evaluating the drug in a phase 1/2 trial in a range of pediatric cancer settings as well as in a midstage trial for advanced liver cancer.TIM-3 is expressed by immune effector cells, where it acts as an immune checkpoint, and leukemic stem cells, leading various Big Pharmas to identify the receptor as a way to simultaneously activate the immune system and suppress the proliferation of cancer cells.GSK may not have been surprised that cobolimab couldn’t secure a phase 3 win. The drug was the most advanced anti-TIM-3 antibody left standing after Novartis’ own candidate failed a late-stage study in patients with myelodysplastic syndrome or leukemia at the start of 2024.While Novartis focused on blood cancers, GSK and other big names with TIM-3 candidates had largely looked at solid tumors. Roche removed (PDF) a PD-1xTIM-3 bispecific from its pipeline in 2022, while Bristol Myers Squibb terminated a phase 1 trial of a TIM-3 candidate, BMS-986299, in 2022 because its “business objectives” had changed. Eli Lilly and Incyte have also axed their respective TIM-3 drugs. AstraZeneca appears to still have a foot in the anti-TIM-3 space, with a PD-1xTIM-3 bispecific that is due to complete a phase 1/2 study this year.TIM-3 wasn’t the only high-risk cancer target where GSK crashed and burned this quarter. The pharma revealed in the same earnings document that its decision to end development of the anti-TIGIT antibody belrestotug had resulted in a 471 million pound sterling ($629 million) impairment charge.GSK paid iTeos $625 million upfront for the rights to belrestotug four years ago. In the wake of belrestotug’s phase 2 failure, the biotech initially planned to wind down operations before accepting a buyout offer from Concentra Biosciences earlier this month.This morning’s release also revealed that GSK has discontinued a phase 2-stage adjuvanted recombinant protein vaccine for malaria dubbed GSK3437949. A spokesperson for the company put this move in the context of the pharma’s recently announced push into second-generation, multistage malaria vaccines.Meanwhile, sanfetrinem cilexetil—an oral prodrug of the antibiotic sanfetrinem—has been removed from the company’s phase 2 pipeline after having “not compared favourably in early studies to existing treatments and other tuberculosis-specific assets also in development at GSK,” the spokesperson said.