Tislelizumab

“People went for Fc-competent [TIGITs] because it worked best in mice,” said Leerink Partners analyst Daina Graybosch, Ph.D. “They couldn\'t help themselves.\"\n Once hailed as the future of immuno-oncology, it’s been a tough few months for any remaining fans of anti-TIGIT antibodies.In April, BeOne Medicines, formerly known as BeiGene, announced it was scrapping ociperlimab over a disappointing phase 3 outlook two years after Novartis handed back the asset. Specifically, the study’s independent data monitoring committee deemed the trial unlikely to show that a combination of ociperlimab and BeOne’s own PD-1 inhibitor Tevimbra would beat Keytruda in patients with PD-L1-high non-small cell lung cancer (NSCLC).The following month brought more tough times for TIGITs, as GSK halted development of its own candidate belrestotug after deciding the iTeos Therapeutics-partnered drug in combination with anti-PD-1 inhibitor Jemperli wouldn’t score a phase 2 win in a similar NSCLC population.Even executives at Roche, whose tiragolumab appeared to buck the trend with a caveated phase 3 win in esophageal cancer in 2024, reaffirmed to Fierce Biotech earlier this year that “we stopped all of the tiragolumab trials that we could stop, and those that couldn\'t be stopped are just running out.”With Big Pharma having pumped $6 billion into this modality, what went so wrong for TIGITs?Daina Graybosch, Ph.D., a senior research analyst at Leerink Partners who covers immuno-oncology, traces the problems back to the exuberant reaction to Roche’s impressive phase 2 tiragolumab data that read out across 2020 and 2021. The Cityscape trial demonstrated that the TIGIT drug in combination with Roche’s own PD-L1 blocker Tecentriq shrank tumors in 31% of patients with metastatic lung cancer—twice as many patients as Tecentriq alone.“That\'s probably the biggest point where the field went wrong, in that they looked at this massive benefit in the small phase 2, and everybody ran after it in a parallel and broad way,” Graybosch told Fierce in an interview.“We had randomized phase 2 data from Roche, from Arcus-Gilead, from iTeos-GSK, and they all consistently showed benefit in response rate and in [progression-free survival],” she added.“I think the challenge ultimately was: How much benefit is there really? Is it enough benefit to be clinically meaningful? And are we developing the drugs in the right way, in the right format, to optimize and bring that benefit to patients?”The industry’s “overenthusiasm” for the potential of TIGITs led to a “simplistic approach” to how other companies planned to develop their own candidates, according to Graybosch.If pharmas had anticipated a “more realistic demonstration of benefit,” as seen in the failed Skyscraper-01 phase 3 study in NSCLC, “I think everybody would have developed [TIGITs] differently,” she suggested.Companies swimming in the TIGIT space have broadly fallen into two camps. Roche’s tiragolumab, along with Merck & Co.’s vibostolimab, GSK and iTeos’ EOS-448, and BeOne’s ociperlimab, are all Fc-enabled. These antibodies retain a fully functional Fc region, meaning they can bind to Fc receptors found on the cell surface and contribute to the protective antitumor functions of the immune system.The theory behind Fc-enabled anti-TIGIT antibodies is that they have enhanced tumor-killing effects. However, the risk is that they could possibly also eliminate certain regulatory T cells and therefore lead to unwanted immune responses.In fact, side effects did cast a shadow over some of the Fc-enabled TIGIT trials, with Merck halting a phase 3 trial of vibostolimab due to a higher than expected rate of discontinuations blamed on “immune-mediated adverse experiences.”“Toxicity that may lead patients to discontinue I think ended up being a contributing factor across the Fc-enabled TIGITs that are all now dead,” Graybosch said.The last TIGITs still standing—Arcus Biosciences and Gilead’s domvanalimab, as well as AstraZeneca’s TIGIT/PD-1 bispecific antibody rilvegostomig—have mutated out the Fc function. This should mean they are less toxic for patients.“People went for Fc-competent because it worked best in mice,” Graybosch explained. “They couldn\'t help themselves, even though they knew there was some risk of depleting T effector cells that are actually what you need to fight your tumor.” Focusing on \'modest benefit\'So, what would a more measured approach to the TIGIT gold rush have meant in practice?“I think you ultimately do what Astra is doing,” said Graybosch, referring to AstraZeneca’s ongoing phase 3 trials of its bispecific rilvegostomig in a range of phase 3 studies for NSCLC or stomach cancer, including in combination with its Daiichi Sankyo-partnered antibody-drug conjugates Enhertu or Datroway.“Astra is recognizing the modest benefit,” she explained. “Their bispecific is very safe because it\'s Fc silent. And in some ways, Astra can\'t lose because [rilvegostomig] doesn\'t need to work that much for a lot of their trials to be successful.”AstraZeneca’s Puja Sapra, Ph.D., senior vice president for biologics engineering and oncology target discovery, was also upbeat about rilvegostomig’s prospects when she spoke to Fierce back in April. She pointed to the fact that engineering the bispecific to reduce Fc effector functionality should reduce unwanted side effects, while blocking both PD-1 and TIGIT at the same time “should hopefully help us increase the response rate and durability.”“At least in preclinical studies, we see that a bispecific molecule has better responses than a combination of both agents alone,” Sapra said at the time. “The molecule is doing very well in the clinic so far, so we continue to believe in this molecule.”Gilead is also staying loyal to its TIGIT candidate, which is being evaluated in phase 3 trials for first-line NSCLC as well as for locally advanced unresectable or metastatic gastric, gastroesophageal junction and esophageal adenocarcinoma.The pharma’s chief medical officer Dietmar Berger, M.D., Ph.D., told Fierce earlier this month that the Arcus-partnered domvanalimab still has a chance, pointing to its Fc-silent character.“We believe there is differentiation but, of course, we need to see how those studies read out,” Berger said. “Any additional activities around that will be based on what we see in those studies.”With AstraZeneca and Gilead still holding a candle for their Fc-silent candidates, Leerink’s Graybosch doesn’t think “it\'s fair to completely write off TIGIT.”“But if you ask 99% of average investors, generalists or specialists and [key opinion leaders], I think they’ll tell you it\'s dead,” she added.Angus Liu contributed to this reporting.

精彩内容米内网数据显示，2024年中国零售药店终端（城市实体药店+网上药店）药品销售额超过3800亿元，其中化学药占比超过51%，中成药占比超过38%，生物药占比超过9%。29个化学药销售额超过10亿元，超50亿大品种领跑，10个品种涨逾10%；中成药TOP20中有16个超10亿元，独家品种霸屏，康恩贝、太极、扬子江上榜；生物药TOP20中有7个超10亿元，创新药“称王”，2个注射剂大涨。化学药：超50亿大品种领跑，10个品种涨逾10%近年来，中国零售药店终端化学药销售额逐年上涨，2024年突破2000亿元，占药品总销售额比重超过51%。TOP20一级集团中，阿斯利康以约4.7%的市场份额稳居首位，拜耳、华润医药依次位列第二、第三，市场份额约达4%。从销售额增速看，豪森药业涨超30%，辉瑞涨超20%，阿斯利康、正大制药、石药集团、远大健康、齐鲁制药等企业均涨超10%。从产品排名看，TOP29产品销售额均超过10亿元，其中，枸橼酸西地那非片以超50亿元领跑，位列第二、第三的维生素D滴剂、葡萄糖酸钙锌口服溶液均为营养素补充剂，分别属于维生素类、矿物质补充剂，销售额分别超过40亿元、30亿元。2024年中国零售药店终端销售额超10亿元的化学药注：标红为近5年来销售额持续正增长，标*为独家品种来源：米内网综合数据库从销售额增速看，19个品种呈正增长，甲磺酸阿美替尼片、达格列净片、沙库巴曲缬沙坦钠片涨幅均超过30%，其中甲磺酸阿美替尼片为29个超10亿品种中唯一一款独家品种；10个品种近5年来保持持续正增长，其中玻璃酸钠滴眼液销售额增速均达两位数。玻璃酸钠滴眼液是治疗干眼症的主要药物之一，目前已有50余家企业拥有该产品生产批文，其中46家已过评或视同过评。米内网数据显示，2023年玻璃酸钠滴眼液在中国零售药店终端的销售额突破10亿元，2024年进一步增长至超15亿元，在眼科化药产品排名中稳居首位。近年来中国零售药店终端玻璃酸钠滴眼液销售情况（单位：万元）来源：米内网格局数据库甲磺酸阿美替尼片是豪森药业自主研发的一款国产1类新药，目前已被纳入国家医保乙类目录，2023年在中国零售药店终端的销售额突破10亿元，同比增长38.86%；2024年进一步增长至超15亿元，同比增长39.14%。在抗肿瘤化药产品排名中，甲磺酸阿美替尼片近年来稳居第二位。近年来中国零售药店终端甲磺酸阿美替尼片销售情况（单位：万元）来源：米内网格局数据库中成药：11个独家品种霸屏，片仔癀、太极上榜2024年中国零售药店终端中成药销售额突破1500亿元，占药品总销售额比重超过38%。TOP20一级集团中，华润医药稳居首位，市场份额接近10%；国药集团、北京同仁堂、广药集团依次位列第二、第三、第四，市场份额均超过4%。从销售额增速看，真奥药业涨幅接近50%，华润医药、云南白药、仲景宛西制药等亦呈正增长。TOP20产品中有16个销售额超过10亿元，其中阿胶以超55亿元蝉联榜首，安宫牛黄丸以超47亿元紧接在后，感冒灵颗粒以超32亿元排位第三，独家品种片仔癀以超20亿元排位第四，2家企业在销的藿香正气口服液以超19亿元排位第五。2024年中国零售药店终端中成药TOP20产品注：标红为销售额增速超10%，标*为独家品种来源：米内网综合数据库阿胶近年来在中国零售药店终端的销售额有所波动，但始终稳居补气补血中成药销冠宝座。目前有40家企业的阿胶在销，从2024年厂家格局看，东阿阿胶以约49%的市场份额领跑，山东福牌阿胶以约25%的市场份额紧接其后，山东宏济堂制药以约13%的市场份额排位第三。此外，山东东滕阿胶表现亮眼，2024年销售额增速达135.45%。在2024年中国零售药店终端肝病中成药产品排名中，片仔癀药业的片仔癀稳居首位，市场份额超过46%，其另一款产品片仔癀胶囊排位第五。肝病用药是片仔癀药业的重点业务，2024年公司的肝病用药大卖超过53亿元，再创新高。2024年中国零售药店终端肝病中成药TOP5产品来源：米内网格局数据库TOP20产品中有11个为独家品种（含独家剂型），包括片仔癀（片仔癀药业）、京都念慈菴蜜炼川贝枇杷膏（京都念慈菴总厂）、复方阿胶浆（东阿阿胶）、肠炎宁片（康恩贝）、急支糖浆（太极集团）、蓝芩口服液（扬子江药业）、云南白药气雾剂（云南白药）、消痛贴膏（奇正藏药）、蒲地蓝消炎口服液（济川药业）等。生物药：创新药“称王”，2大注射剂涨逾50%近年来，中国零售药店终端生物药销售额均以两位数的增速持续上涨，2024年超过360亿元，占药品总销售额比重超过9%。TOP20一级集团中，诺和诺德稳居首位，销售额超过38亿元，占比突破10%；罗氏紧接其后，销售额超过23亿元；默沙东排位第三，销售额超过18亿元。从销售额增速看，正大制药涨超130%，诺和诺德、默沙东、诺华、强生、赛诺菲、信达生物、安进生物等均有两位数增长。TOP20产品中有7个年销超10亿元，其中人血白蛋白稳居首位，销售额超过28亿元；司美格鲁肽注射液以超20亿元紧接在后，同比增长约57%，较2023年提升1个位次；帕博利珠单抗注射液以超18亿元排位第三，同比增长约15%。2024年中国零售药店终端销售额生物药TOP20产品注：标红为销售额增速超10%，标*为独家品种来源：米内网综合数据库TOP20产品中有11个为独家品种（含独家剂型），其中有6个销售额增速均达两位数，分别为诺和诺德的司美格鲁肽注射液（+57%）、默沙东的帕博利珠单抗注射液（+15%）、诺华的司库奇尤单抗注射液（+28%）、赛诺菲的度普利尤单抗注射液（+35%）、强生的古塞奇尤单抗注射液（+88%）、信达生物的信迪利单抗注射液（+24%）。司美格鲁肽注射液是一款新型长效胰高糖素样肽-1(GLP-1)类似物，2021年4月获批进入中国市场，2023年在中国零售药店终端的销售额突破10亿元，2024年突破20亿元，市场潜力较大。目前国内已有超过20家企业在布局司美格鲁肽生物类似药，其中杭州九源基因、丽珠集团新北江制药、齐鲁制药、中美华东等企业的产品已报产在审。近年来中国零售药店终端司美格鲁肽注射液销售情况（单位：万元）来源：米内网格局数据库从药物类型看，20个产品中有14个为抗体药物，其中帕博利珠单抗注射液、度伐利尤单抗注射液、纳武利尤单抗注射液、替雷利珠单抗注射液、信迪利单抗注射液均属于PD-(L)1单抗，司库奇尤单抗注射液、度普利尤单抗注射液、古塞奇尤单抗注射液均为白细胞介素(IL)的“家庭成员”，卡度尼利单抗注射液为唯一一款双抗药物等。卡度尼利单抗注射液是康方生物开发的一款PD-1/CTLA-4双抗药物，首个适应症于2022年7月获批上市，目前已通过谈判纳入国家医保乙类目录，2023年在中国零售药店终端的销售额突破10亿元，2024年进一步增长至超11亿元。近年来中国零售药店终端卡度尼利单抗注射液销售情况（单位：万元）来源：米内网格局数据库注：米内网《中国城市实体药店药品终端竞争格局》，统计范围是：全国地级及以上城市实体药店，不含县乡村药店；《中国网上药店药品终端竞争格局》，统计范围是：全国网上药店所有药品数据，包括天猫、京东等第三方平台及私域平台上所有网上药店药品数据；上述销售额以产品在终端的平均零售价计算。免责声明：本文仅作医药信息传播分享，并不构成投资或决策建议。本文为原创稿件，转载文章或引用数据请注明来源和作者，否则将追究侵权责任。投稿及报料请发邮件到872470254@qq.com稿件要求详询米内微信首页菜单栏商务及内容合作可联系QQ：412539092【分享、点赞、在看】点一点不失联哦