Centre Hospitalier Universitaire Amiens-Picardie

自安进公司斥资近20亿美元收购Five Prime公司及其针对FGFR2b的单克隆抗体（mAb）以来，已过去四年多。如今，贝马妥珠单抗（bemarituzumab）的新数据证明了安进公司这一决策的正确性。6月30日，安进公司公布了一项胃癌III期临床试验的主要结果，显示该单克隆抗体达到了主要生存终点。尽管这家制药公司未透露此次临床试验成功的具体细节，但承诺会在未来的医学会议上提供详细数据。这项名为FORTITUDE-101的III期临床试验共招募了547名患有不可切除、局部晚期或转移性非HER2阳性、FGFR2b过表达的胃癌或胃食管交界处（GEJ）癌的患者。参与者被随机分组，一组接受一线贝马妥珠单抗联合化疗（mFOLFOX6方案）治疗，另一组仅接受化疗。根据预先设定的中期分析结果，联合治疗组在总生存期（OS）方面相比单纯化疗组，取得了具有统计学意义和临床意义的显著改善，达到了试验的主要终点。安进公司负责研发的执行副总裁杰伊·布拉德纳（Jay Bradner）表示：“大多数胃癌患者在确诊时已处于晚期，预后较差，生存率低，且治疗选择有限。”他补充道，此次研究结果“标志着在开发有效胃癌靶向治疗药物方面取得了具有重大意义的进展”。此次结果也印证了II期临床试验的发现。在II期试验中，贝马妥珠单抗联合化疗相较于单纯化疗，显著延长了患者的无进展生存期和总生存期。II期试验也显示，接受贝马妥珠单抗治疗的患者角膜和口腔炎等不良事件（AEs）的发生率更高。实验药物组中至少出现3级不良事件的患者比例达82.9%，而安慰剂组为74%。此外，34.2%接受贝马妥珠单抗治疗的患者因不良事件而中断治疗，而安慰剂组仅为5.2%。在III期试验中，贝马妥珠单抗组眼部不良事件的发生“频率更高，严重程度也更高”。超过四分之一接受该单克隆抗体治疗的患者出现了视力下降、点状角膜炎、贫血、中性粒细胞减少、恶心、角膜上皮缺损或干眼等症状。FORTITUDE-101试验得到了再鼎医药的支持。2017年，再鼎医药从Five Prime公司独家获得了贝马妥珠单抗在中国大陆、香港、澳门和台湾地区的共同开发与商业化权利。此外，双方合作伙伴还在开展一项贝马妥珠单抗联合化疗及百时美施贵宝公司的纳武利尤单抗（Opdivo，商品名）作为胃癌一线治疗的III期试验，预计今年下半年公布数据。药事纵横投稿须知：稿费已上调，欢迎投稿

New data unveiled Monday showed that Merck’s Winrevair can significantly cut the risk of death, lung transplantation and hospitalization in patients with a rare form of high blood pressure in the lungs, potentially providing a boost to sales. The data come from a study that was stopped early for overwhelming efficacy in November . However, this early halt meant that a secondary endpoint looking at deaths alone faced a higher bar and did not meet statistical significance. It is now unclear whether Winrevair, which was approved for pulmonary arterial hypertension (PAH) around a year ago , will be able to get a specific mortality claim on its label as the company had previously hoped. What is clear is that the trial, named ZENITH, scored a huge success on its primary endpoint. Winrevair, an injected activin receptor fusion protein, reduced a composite of all-cause death, lung transplantation and hospitalization for PAH by 76% compared with placebo. Of those given Merck’s drug, 17.4% experienced one or more of these major morbidity and mortality events, versus 54.7% of those given placebo. ZENITH enrolled 172 adults with advanced PAH who were at high risk of mortality and were on maximum tolerated background therapy. This finding, presented at the American College of Cardiology’s Annual Scientific Sessions, is important because Winrevair’s approval was based on softer endpoints, including improving patients’ exercise capacity and symptoms. Evidence of a more concrete effect on patients’ health could extend the drug’s reach. “Four to five weeks after initiation of [Winrevair] there’s already a detectable difference in deaths, hospitalization and lung transplant between both groups,” Joerg Koglin, senior VP of global clinical development at Merck, told Endpoints News . “That’s an endpoint that was never tackled by any other PAH drug development program,” he added. However, the crucial secondary endpoint of overall survival was not met. There were seven deaths in the Winrevair arm compared with 13 in the placebo arm, but the statistical threshold here was set at a p-value of 0.0021, a harder bar to hit than the more usual 0.05. Koglin said that this tougher standard was a statistical necessity when interim analyses are used. The actual p-value for mortality at the interim point was 0.0313. “If we would’ve seen that p-value at the end of the study, of course that would’ve been significant,” he said. When examined individually, the other components of the composite endpoint also favored Merck’s drug, though again the company was unable to claim statistical significance. One Winrevair patient had a lung transplant compared with six in the placebo arm, and eight patients in the drug group were hospitalized for PAH versus 43 — half the patients — in the placebo group. Safety was consistent with earlier studies, such as the STELLAR trial which led to Winrevair’s approval. The group will submit the ZENITH data to the FDA and other agencies, and Koglin said that “one of the discussions with regulators would be if the survival benefit should be spelled out more clearly in the label.” Whether a mortality benefit is added to the label or not, sales could see an uptick. With Winrevair, Koglin said, “you see an impact on hard endpoints and there is no other program out there that ever has shown a similar effect. It will be a strong argument for a physician to consider [Winrevair] for a given patient.” Merck confirmed that it does not anticipate a price increase for Winrevair even if the drug does receive a label update. Winrevair was one of the two main products behind Merck’s $11.5 billion acquisition of Acceleron in 2021 . The drug had sales of $419 million last year. The other main reason for the Acceleron deal was the blood disorder therapy Reblozyl, which sold $371 million in 2024. Winrevair sales will have to grow if Merck is to make its money back.