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在近两年以来的自免热潮中，TL1A无疑是最靓的仔，Merck以$10.8b收购Prometheus获得PRA-023、Roche以$7.25b从Roivant子公司收购RVT-3101的美日权利、Sanofi以$1.5b从Teva引进TEV-574的欧洲以外权利、Abbvie以$1.7b从明济生物引进FG-M701……MNC一顿风卷残云，将目前所有浮出水面的TL1A分子尽数收入囊中，仿佛攥住了制霸自免的希望。 那么问题来了，TL1A真的值这么多钱么？随着前三个管线陆续披露临床数据，笔者的这一困惑好像也并没有完全被解开…… 12月17日Sanofi和Teva公布了合作开发的Duvakitug（TEV-574）的Phase 2b初步结果，这是一项代号RELIEVE UCCD的试验（NCT05499130），共入组了UC和CD患者各约120例，按1:1:1分配到高低剂量组和安慰剂组。 https://s24.q4cdn.com/720828402/files/doc_presentations/2024/12/Teva-Duva-Ph2-TLR_Dec17-2024_vF.pdf 乍一看14周诱导期的主要临床终点，感觉确实非常炸裂：UC部分，高剂量组的临床缓解率居然高达47.8%，断崖式领先其他两个TL1A分子以及目前几乎所有能看到的UC临床试验数据；CD部分，高剂量组的内镜响应率也高达47.8%，同样是目前CD临床数据中最亮眼的。 于是联想起了TEV-574在临床前展现出BIC的活性和对DR3的高选择性（图中的TL1A#1/2大概率就是另外两个同靶点竞品，另将Spyre的对比作为旁证），仿佛一下子就与临床结果对得上了。 然而我们不难发现，RELIEVE UC试验的安慰剂组表现好像有点过于出挑了，印象中UC的临床试验里很少有安慰剂效应这么高的，于是做了一下cross-trial对比，可以看出本次安慰剂组20%+的临床缓解率远远超出了历史上所有其他试验的安慰剂组水平，使得高剂量组TEV-574的48%绝对值黯然失色，经安慰剂修正后就成了泯然众人的27%，就算在现有三个TL1A分子中也只略占上风，甚至就还比不上Infliximab和Upadacitinib了。 进一步地，TEV-574的短半衰期劣势十分明显，人体内t1/2约6-9天，而PRA-023和RVT-3101都在20天左右，所以前者Q2W、后两者Q4W；虽然TEV-574本次暂未披露具体剂量，但从一期临床的SAD和MAD剂量爬坡推测，有可能高低剂量组分别在1600mg和600mg Q2W，而PRA-023和RVT-3101的三期临床剂量则分别是500mg和450mg Q4W，TEV-574以明显更高的剂量和更短的给药间隔，却只获得略高一点的有效性边际优势，似乎就算不上是多么炸裂的表现了。 看来看去，这次TEV-574的有效性数据好像十分炸裂但又没有完全炸裂，安慰剂效应的高企十分离奇，使得经安慰剂修正的临床缓解率并不算惊艳，相比另两个TL1A临床在研管线只有少许提高、也并不能碾压此前的anti-TNFα和JAKi。 那么，为什么TL1A资产还会受到MNC如此重金追捧呢？ 附录：主要溃疡性结肠炎药物临床数据 1）诱导期 2）维持期

Teva and Sanofi announced positive mid-stage results ahead of schedule for their inflammatory bowel disease candidate as they look to keep pace in an anti-TL1A race with Merck and Roche. The duo’s duvakitug met the primary endpoints in a Phase 2b trial evaluating patients with ulcerative colitis and Crohn’s disease, two forms of IBD, Teva and Sanofi said Tuesday morning. In ulcerative colitis, 36.2% of patients taking a low dose of duvakitug and 47.8% of patients taking a high dose achieved clinical remission, compared to 20.45% of placebo patients at week 14. P-values came in at 0.05 and 0.003 for the low and high doses, respectively. In Crohn’s disease, 26.1% of low-dose duvakitug patients and 47.8% of high-dose patients saw an endoscopic response as measured by a scoring system for Crohn’s severity, compared to 13% on placebo (p-values were 0.058 for the low dose and <0.001 for the high dose). While 0.05 is typically considered the gold standard for assessing statistical significance, a Teva spokesperson said the Phase 2 study had a “one-sided test at a significance of 0.1.” The partners said duvakitug was “generally well-tolerated,” with similar rates of treatment-emergent adverse events occurring in the treatment and placebo arms. Sanofi put down €469 million ($500 million) upfront in a deal to co-develop and co-commercialize duvakitug with Teva in October 2023. The anti-TL1A contest also includes Roche, which put down $7.1 billion upfront in late 2023 to acquire Roivant’s subsidiary Telavant and RVT-3101. Merck is also a rival, following its acquisition of Prometheus Biosciences and its MK-7240 in a deal worth $10.8 billion. The duvakitug topline results came earlier than expected, due to “significant acceleration in patient recruitment,” Sanofi and Teva said back in July. As a result, they skipped an interim analysis which was originally planned for the second half of this year. Now, the partners said they plan to initiate a Phase 3 trial in 2025 in IBD “pending regulatory discussions.” A Teva spokesperson declined to share further specifics on the timing of Phase 3 initiation or the dose that will be taken forward. Each company will share the development costs globally, while Sanofi will lead Phase 3 development. Teva will lead commercialization in Europe, Israel and certain other countries, and Sanofi will take the commercial lead in North America, Japan and other parts of Asia, and the rest of the world. Editor’s Note: A correction has been made to reflect that Teva and Sanofi are studying duvakitug in inflammatory bowel disease, not irritable bowel disease.