Vibostolimab

氨基观察-创新药组原创出品 作者 | 武月 肿瘤免疫研发的狂热与理性之殇，在TIGIT身上暴露无遗。 被视为“下一代PD-1”的TIGIT靶点，在吞噬药企十几亿美元首付款和数十亿研发资金后，终成肿瘤免疫领域又一大“研发黑洞”。 尽管仍有一些项目在推进临床，但在业内看来，随着今年上半年iTeos的TIGIT+PD-1联合疗法临床失败，罗氏TIGIT终止全部三期临床，TIGIT单药或联合用药全军覆没，TIGIT这一靶点基本宣告“剧终”。 药物研发失败并不奇怪，这本就是一项成本高昂、风险高的业务。在药物最终上市之前，谁也无法预测最终的结果，即便是身经百战的大药企们。 然而，多个临床表现与预期之间产生的不可弥合的背离，一次次失利烧掉百亿，TIGIT的大溃败仍是让我们再次见识到热门靶点的“杀伤力”，以及免疫系统的复杂性。 更重要的是，TIGIT之后，下一场豪赌早已开场。如何避免重蹈覆辙，或许是所有入局者要考虑的。 / 01 / TIGIT的沉没成本 2020年，TIGIT靶点顶着“下一个PD-1”的名头横空出世。 罗氏的TIGIT单抗Tiragolumab在当年ASCO大会上惊艳亮相后，吉利德、BMS、GSK、诺华等大药企开始争相入场，疯抢全球TIGIT在研临床管线，相关交易首付款超14亿美元。 其中，吉利德、GSK出手最为大方，前者为了引进Arcus管线，除了支付1.75亿美元首付款（多靶点），2.75亿美元行权费（TIGIT靶点），还通过7.4亿美元股权投资（均价27.58美元/股），而Arcus股价现已跌破 10美元。 GSK为了引进iTeos的管线，仅首付款就高达6.25亿美元。随着今年5月双方因TIGIT+PD-1联合疗法临床失败而终止合作，GSK当初的首付款也打了水漂。 这是我们能看到的成本。 考虑到全球有超80条TIGIT管线，大药企曾先后启动大规模三期临床，以及一些biotech也借此完成了融资，整个行业在TIGIT靶点上的投入，远不止这些。 首先是与BD交易相关的里程碑款超 50亿美元，但因项目终止，绝大多数未被支付。 大头则是研发成本。对于罗氏等大药企来说，TIGIT的成本隐含在推进候选药物的巨额研发预算中，我们无法得知具体投入，但通过一些合作管线的投入，仍可以窥得一二。 以GSK与iTeos的合作为例，GSK承诺为后者的TIGIT药物全球开发计划投入9亿美元，实际因2期失败可能仅支出小部分。但这一数字，可以为大型后期临床的投入量级提供一定参考。 由于对创新免疫疗法的迫切渴望，大药企在TIGIT管线的投入规模与推进速度层面，可以说不遗余力。 罗氏的tiragolumab在10项三期研究中，招募目标是近4600名患者； 默沙东的vibostolimab在5项三期研究中，招募目标是超4600名患者； 吉利德、Arcus等合作的3项三期研究，招募了近3000名患者。 如果参照GSK与iTeos的合作投入，罗氏、吉利德、默沙东在TIGIT资产的中后期临床试验中，可能合计已经消耗掉数十亿美元。 另外，iTeos的资金消耗速度，也能为我们提供一个角度。2021年以来，其通过融资及与GSK的交易，募集了超11亿美元，随着管线失败公司计划解散运营，现金储备仅剩 6.24亿美元，也就是说超5亿美元融资化为iTeos研发损耗。 总之，尽管仍有一些项目在推进临床，但是随着越来越多临床失败、药企的撤退，意味着短短几年间，行业已为TIGIT投入了数十亿美元的沉没成本。 / 02 / 溃败背后 正如前文所说，TIGIT靶点之所以成为研发热点，很大一部分原因与PD-1有关。 当时市场都在寻找下一个PD-1，而TIGIT在免疫抑制的机制上与之有一定的相似性，但作用的细胞类型和具体环节存在差异，二者联用有可能产生协同的免疫激活效果。 然而，理论与现实，总是有巨大的鸿沟。在实际临床试验中，这种联合治疗的优势并没有充分体现，单药治疗效果与PD-(L)1单药治疗相比也相差甚远。 以前文提及的iTeos为例，尽管其TIGIT与PD-1联合疗法曾在非小细胞癌中取得突破，主要终点客观缓解率（ORR）达到60%以上，对照组PD-1单药仅28.1%，但今年5月其更新的数据显示，与PD-1单药治疗相比，联合疗法队列中未达到无进展生存期的既定标准。 先驱罗氏则在二季度中，彻底移除了Tiragolumab。尽管TIGIT联合疗法在肝癌二期中持续更新积极数据，但二季度，其将TIGIT联合PD-L1抗体的不可切除的非小细胞肺癌，TIGIT、PD-L1抗体和贝伐珠一线肝癌的三联疗法的两项三期临床移除管线，Tiragolumab自此完全消失在罗氏管线中。 从预期一路走高，到TIGIT几经失败，预期不断翻转再翻转，当初那批顶着质疑与压力的药企，终究没能等来好消息。 这背后有一点不可忽视，当行业疯狂涌向一个热门靶点之际，科学理性容易被抛诸脑后。TIGIT至今未能成药，可能是其在肿瘤免疫调节中的作用从一开始就被高估，也可能是由于联合疗法的方案还有待优化。 而在业内人士看来，针对TIGIT靶点的研发，在多个临床表现与预期之间产生了不小的差距，本质上，这体现了我们对该靶点的认知程度不足，先前基于这一靶点的一些预测可能是错误的。 这也提醒我们，不要轻易对一个靶点的未来，极度乐观或悲观。 不只是TIGIT，过往肿瘤学押注失败的历史不再少数，典型高投入失败案例IL-2、CD47等，成功者总是少数。 / 03 / 新的赌局轮回 一个不争的事实是，创新药研发从来不是直线前进的旅程。虽然已有成功先例，但我们对免疫系统的认知依然有限，肿瘤免疫抑制微环境的复杂性和异质性，是阻碍免疫治疗前进的重要原因。 加上创新药研发本就是一项成本高昂、风险高的业务。在药物最终上市之前，谁也无法预测最终的结果，即便是身经百战的大药企们。 然而，如同TIGIT这样的惨痛教训也再次为我们带来启示。未来肿瘤免疫治疗，需要不断探索新的未知数，也需要更扎实的靶点与机制研究、更精准的患者分层又或是更创新的组合策略。与此同时，药企也需要在靶点验证严谨性与临床开发节奏间寻求一种平衡，避免上百亿学费重蹈覆辙。 因为，资本可以在“靶点风口”间逐浪狂时，科学却需要匍匐于机制验证的荆棘之路。 对整个行业来说，当旧靶点退场，新赌局早已开始。 包括默沙东、GSK、罗氏等大药企先后放弃TIGIT的原因，还在于新的免疫治疗靶点和技术如双抗、ADC等不断涌现，尤其是PD-(L)1/VEGF双抗的崛起，让TIGIT的临床意义逐渐弱化。 大药企也很难保证创新药的成功率，而它们更懂得战略性的撤退，为下一代突破性药物腾出资源与空间。以PD-(L)1/VEGF双抗为例，先驱康方生物已经让人看到了希望，并不断提高相关资产的价值。 仅计算国产PD-(L)1/VEGF双抗的BD规模，首付款及收购款已经超过30亿美元，若达所有里程碑，总交易额将超150亿美元。如果算上BMS与BioNTech的百亿美元交易，总交易额已经接近300亿美元，更不要提还有正在观望的艾伯维等大药企，贡献新的交易额。 在大药企的抢位与竞争下，已经有海外媒体发出了警示，一旦失败，PD-(L)1/VEGF双抗的灾难规模将令TIGIT风波相形见绌。 面对新的科学博弈与研发对赌，所有入局者都需要在创新激情与科学严谨的钢丝上保持平衡。因为，真正的突破永远来自对未知的敬畏，而非对风口的贪婪。 当然，每一次理性的撤退，也都是对下一次进击的蓄力。 PS：欢迎扫描下方二维码，添加氨基君微信号交流。

iStock/ Afry Harvy TIGIT-targeting therapies have largely disappointed in recent months, with failed studies, terminated partnerships and shuttered businesses. Here are five biopharma players staying alive with differentiated candidates against the once promising immuno-oncology target. When GSK turned its back on development partner iTeos Therapeutics in May, a terminal countdown began for the Massachusetts-based biotech. Weeks later, time ran out and iTeos was forced to shutter operations. The biotech is only the latest casualty in a therapeutic space that is turning into a drug development wasteland. The asset that led to iTeos’ ultimate demise was belrestotug, an anti-TIGIT therapy that was being assessed for multiple solid tumors, including non-small cell lung and head and neck cancer. Though the partners did not reveal specific data, iTeos noted in May that even when used with GSK’s PD-1 blocker Jemperli, belrestotug was unable to improve progression-free survival in patients with NSCLC versus Jemperli alone. Findings in patients with head and neck cancer were likewise disappointing. Belrestotug is just one therapy in the long line of TIGIT assets that have run into insurmountable clinical roadblocks. Found in certain cells of the immune system, TIGIT —which stands for T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domain—is a receptor with immunosuppressive effects. Under healthy circumstances, TIGIT helps regulate the release of cytokines, in turn suppressing the activity of T cells. TIGIT is overexpressed in many cancers , allowing tumor cells to inhibit the immune system’s anti-cancer response. Many biopharma players have seized on this mode of action, identifying molecules that can block TIGIT in cancers in hopes of boosting the body’s antitumor activity. But none have been successful so far, and the experience of GSK and iTeos has become the unfortunate standard. In July 2024, Roche’s tiragolumab failed to improve survival in patients with NSCLC in the closely watched SKYSCRAPER-06 trial . A few months later, another study of tiragolumab, SKYSCRAPER-01, flopped . Merck has also been stymied by TIGIT. In May 2024, the pharma scrapped a late-stage study for its anti-TIGIT antibody vibostolimab due to treatment toxicity that led to a high rate of study dropouts. Safety concerns also led to the demise of another Phase III study later that same year, this time in extensive-stage small-cell lung cancer. A key reason behind these failures, according to Padmanee Sharma, a professor in the department of Genitourinary Medical Oncology at MD Anderson Cancer Center, is that much remains unknown about how this pathway specifically works. Other proteins may also be involved in the overall TIGIT mechanism, she told BioSpace in an email, or TIGIT itself may have a role to play in other cellular functions. “TIGIT is a complex biologic target,” Sharma said. “The exact mechanism is not clear.” Still, many persist in developing a TIGIT therapy, largely because its signals of efficacy are encouraging. “Pre-clinical data indicate that TIGIT is a relevant pathway to pursue,” Sharma said, particularly for antibodies, which in lab studies have shown “anti-tumor responses.” But a more complete picture of the TIGIT pathway, including the biological pathways that regulate TIGIT, are required to set the field up for success. Here, BioSpace looks at four companies that claim differentiated approaches. Will they succeed where their peers have failed? AstraZeneca’s Sprawling Development Program for Rilvegostomig AstraZeneca’s TIGIT rilvegostomig is enrolled in an extensive late-stage development program, with 10 Phase III studies underway in NSCLC, gastric cancer, biliary tract cancer and other solid tumors, Shubh Goel, the company’s global franchise head of oncology, told BioSpace in an email. AstraZeneca is also leveraging its partnership with Daiichi Sankyo to test combinations of the TIGIT with the antibody-drug conjugate Datroway for specific subtypes of NSCLC. The goal of such a broad development push, Goel explained, is to establish rilvegostomig as a “best-in-class [immuno-oncology therapy] and the preferred IO backbone for combination therapies.” Aside from these late-stage programs, AstraZeneca is also running multiple early studies of rilvegostomig “across different tumor settings and in combination with a range of standard of care and novel agents,” Goel said. AstraZeneca’s steep investment into rilvegostomig is underpinned by what Goel called a “differentiated” mechanism of action. The molecule’s bispecific structure “optimizes dual PD1/TIGIT check point control.” Rilvegostomig first anchors itself to TIGIT before targeting PD-1, in turn “leading to enhanced immune activation and improving anti-tumor responses,” Goel explained, as compared with dosing patients with separate PD-1 and TIGIT agents. Simultaneously, rilvegostomig minimizes the unwanted depletion of effector immune cells that also express TIGIT, which results in a cleaner safety profile. Aside from a differentiated molecule, AstraZeneca is also being deliberate with its trials, focusing on patients most likely to respond to PD-1/TIGIT co-inhibition, Goel said. So far, AstraZeneca’s strategy seems to be working, at least in NSCLC. At the American Society of Clinical Oncology meeting in May, the pharma presented Phase Ib data showing that rilvegostomig plus Datroway could elicit a 57.5% confirmed overall response rate (ORR) and a 95% disease control rate as a first-line treatment for patients with advanced or metastatic NSCLC. Gilead, Arcus Forge New TIGIT Path With ‘Silent’ Killer Joining AstraZeneca in the late-stage TIGIT field are Gilead and Arcus Biosciences, which are co-developing the monoclonal antibody domvanalimab for solid tumors. Unlike rilvegostomig, domvanalimab only targets TIGIT. To address a second immune checkpoint, the partners are co-administering it with Arcus’ zimberelimab, an investigational PD-1 inhibitor, plus chemotherapy. The companies are proposing this regimen as a first-line therapy for NSCLC and upper gastrointestinal cancer—both programs are in late-stage development —and for head and neck carcinoma, currently in mid-stage studies. What sets domvanalimab apart from the rest of the TIGIT field, according to Ashish Jhingan, program strategy leader of oncology at Gilead, is its Fc-silent properties. That is, the antibody tail—the part that isn’t involved in binding to its targets—has been rendered inert. Such an approach, which goes against the current trend in the TIGIT space, minimizes the likelihood of inadvertently killing cells other than the malignant target, according to Arcus’ website . “By binding to TIGIT with Fc-silent properties, domvanalimab is believed to work by freeing up immune-activating pathways and activate immune cells to attack and kill cancer cells without depleting the peripheral regulatory T cells important in avoiding immune-related toxicity,” Jhingan told BioSpace in an email. This silent approach has so far worked well for the partners. In November 2023, they released data from the Phase II EDGE-Gastric trial, demonstrating a 59% ORR in patients after treatment with the domvanalimab-based regimen. This effect was stronger in those with high PD-L1 expression level, hitting 80% ORR. Six-month progression-free survival (PFS) at the time was 77%. Follow-up results in June 2024 showed that the domvanalimab combo could maintain its efficacy through a median of 49.4 weeks on treatment. ORR dipped only slightly to 58.5% while 12-month progression-free survival (PFS) reached 57.6% in the overall study population. Gilead and Arcus have moved domvanalimab into late-stage development. The partners are running the STAR-221 study, which will test the same regimen of domvanalimab plus zimberelimab and chemotherapy in locally advanced unresectable or metastatic HER2-negative gastric, gastroesophageal junction or esophageal adenocarcinoma. Enrollment began in June 2024 , with initial findings expected in 2026, according to Jhingan. Agenus Pushes Ahead After Losing Powerhouse Partner In May 2021, when the TIGIT space was still young, Bristol Myers Squibb sought to get ahead of its cancer competitors with a $200 million spot payment to Agenus , licensing the biotech’s anti-TIGIT therapy AGEN1777. The deal included up to $1.36 billion in development, regulatory and commercial milestone payments. But ultimately, BMS found the partnership to be more burdensome than beneficial. In August 2024, the company walked away from the pact and returned AGEN1777 to Agenus, a move that was attributed to the “broader strategic realignment of [BMS’] development pipeline,” according to an Aug. 2, 2024 SEC document from Agenus. The contract termination formally took effect on Jan. 26. According to the regulatory filing, under the partnership, Agenus and BMS were able to generate “significant safety data” in early studies, with “indications of clinical activity.” With these in hand, Agenus in August said it intends “to explore further development and/or relicensing” of AGEN1777, but has yet to provide concrete plans for the molecule. Among these development prospects is the possibility of combining the asset with Agenus’ other immuno-oncology therapies. It might take some time, however, before Agenus provides next steps for its TIGIT program, since the biotech is currently in the midst of a strategic realignment initiative aimed at lowering its cash burn to $100 million during the 2025 fiscal year. Mereo Seeks Strategic Sponsors for Etigilimab Rounding out this list is Mereo BioPharma and its troubled program etigilimab , an IgG1 monoclonal antibody designed to target TIGIT, in turn, potentially “improving the activation and effectiveness of T-cell and NK [natural killer] cell anti-tumor activity,” as per its website. Unlike Gilead and Arcus, Mereo has decided against silencing the Fc domain of etigilimab, instead deliberately giving the TIGIT therapy the added functionality of reducing regulatory T cells while also maintaining the levels of CD8-positive cytotoxic T cells. In turn, etigilimab retains the immune system’s cancer-killing action while also delivering a clean safety profile, the biotech claims . Early testing of the mechanism suggests promise in the clinic so far. Phase Ib/II data published in October 2023 demonstrated an ORR of 25% in 40 treated patients, including three who achieved a complete response and seven who saw a partial response. Eleven patients had stable disease beyond 120 days, while seven maintained clinical benefit for more than a year. Despite a promising mechanism and clinical profile, however, Mereo has struggled to rally the support it needs to take etigilimab forward. In June 2019—just months before it would be swallowed by BMS in a $74 billion acquisition—Celgene decided not to exercise an option to license etigilimab. This was despite Mereo advancing the antibody as part of a two-therapy combo with BMS’ PD-1 blocker nivolumab. Since then, and even through a mid-stage readout in 2023, the industry has continued to overlook etigilimab. In a 2024 year-end report, Mereo revealed that it has put TIGIT on the backburner . “We intend to out-license or sell etigilimab . . . to third parties for the further development, recognizing the need for greater resources to take [this asset] to market,” the company wrote.