Rilvegostomig

点击蓝字关注我们本期看点在康方股价大涨丨阿斯利康退英赴美上市关键期，缘何传出高价BD依沃西单抗消息一文中曾经说过，看不懂系列之BD传言引发股价暴涨传奇故事增加了新的素材。做药还是要脚踏实地，热钱现在应该已经逐步撤退，但带来了炒作的不好风气。阿斯利康本身有PD-1/TIGIT双抗押注肺癌一线，且在寻求撤出英国股市，赴美上市的关键时刻，按照第三方媒体平台透露的150亿美元的总价BD在美上市待商榷的依沃西单抗（PD-1/VEGF双抗），总感觉时机并不成熟。周一，summit股价回落，投行也开始放风：要真正提振投资者热情，合作方至少应支付：77亿美元前期现金，约100亿美元“生物资产”对价。本文将就各种关键事件进行梳理，以期不断打磨Biotech前瞻团队理性冷静分析各种热点投资相关的新闻事件。 本期内容01Summit/阿斯利康丨合作传闻回顾02水涨船高的首付款预期03一线肺癌治疗，竞争加剧04监管差异与未来展望 【01 依沃西单抗有望达成高价BD？】上周，彭博社报道称，阿斯利康正与 Summit Therapeutics 洽谈其创新双特异性抗体 ivonescimab（依沃西单抗，PD-1/VEGF双抗） 的全球许可合作，交易总价值或高达 150 亿美元，其中包含数十亿美元的前期付款及多项业绩里程碑支付。消息发布后，Summit 股价周四应声上涨 8.5%，但本周一几乎回吐全部涨幅，反映出市场对合作细节尚存疑虑。疑虑一、阿斯利康是否愿意高价BD？阿斯利康在肿瘤领域拥有丰富的内部研发管线和组合用药能力，从Summit 角度上来说，阿斯利康是最理想的合作伙伴之一。但需要注意的一点，阿斯利康鉴于本身的产品管线，开始布局CAR-T、ADC热门赛道，且已在 PD‑1 检查点双抗领域布局，包括 PD‑1×CTLA‑4 的 volrustomig 和 PD‑1×TIGIT 的 rilvegostomig。因此，有观点认为，阿斯利康已在其他双抗项目上投入巨大，若再加码 PD‑1×VEGF 赛道，需谨慎评估整体投入产出。疑虑二、Rilvegostomig加速布局非小细胞肺癌，适应症重叠阿斯利康对于 rilvegostomig更是押注多项III期研究。阿斯利康在clinical trials网站上，还登记了一项一项PD-1/TIGIT双抗药物Rilvegostomig，在PD-L1高表达的一线非小细胞肺癌患者中，启动一项与Keytruda头对头对比的三期临床试验ARTEMIDE-Lung04（NCT06868277）。该临床预计于2025年4月启动，入组人数为830例，该项临床的首要临床终点为PFS和OS。早在2024年10月，阿斯利康即在clinical trials网站上公布了Rilvegostomig联合化疗头对头对比帕博利珠单抗联合化疗一线治疗PD-L1阳性（TC≥1%）的非鳞状非小细胞患者的三期临床试验（NCT06627647），计划入组人数为878例。除非是在研究中提前发现了rilvegostomig效果不及预期，急于寻找当下已经验证成药性的PD-1/VEGF双抗。否则，大概率不会出现左右手互搏的现象。疑虑三、FDA会否批准依沃西单抗上市今年五月，Summit 发布了 ivonescimab 首个全球 III 期试验（HARMONi）的早期结果：在既往接受过治疗的 EGFR 突变非鳞 NSCLC 患者中，该药显著降低了疾病进展或死亡风险。但由于总体生存（OS）尚未达统计学显著性，Summit 正在重新评估向 FDA 提交注册申请的最佳时机。02 水涨船高的首付款预期 业内普遍认为，ivonescimab 若想保持先发优势，必须依靠强有力的资金和合作伙伴来加速后续临床及商业化进程。毕竟当下的竞争十分激烈。多家大型药企—默沙东、BMS、辉瑞—纷纷将 PD‑(L)1×VEGF 双抗资产纳入自家组合，计划与已有药物配合使用。相比之下，Summit 缺乏配套管线与资金实力，若无法加速推进 ivonescimab 的临床试验，或将被市场边缘化。投行 Leerink Partners 的分析师团队指出，要真正提振市场信心，合作方至少需支付约 77 亿美元的前期现金，再加上 100 亿美元左右的“生物资产”对价。这个“77+100” 的估值参考了百时美施贵宝（BMS）与 BioNTech 就其类似产品 BNT327（PD‑L1×VEGF）达成的 110 亿美元合作案：BMS 向 BioNTech 支付了 15 亿美元前期款，以及直到 2028 年累计 20 亿美元的无条件续约款。与 BioNTech 拥有多款自研管线可作联合测试不同，Summit 除 ivonescimab 外暂无其他项目作支撑，因此在谈判中处于相对弱势。【03 一线肺癌治疗，竞争加剧】Summit积极推进依沃西单抗在一线NSCLC的开发：目前在研的HARMONi-3（联合化疗vs. Keytruda+化疗）和HARMONi-7（单抗vs. Keytruda单抗）均为头对头III期设计。此前，中国HARMONi-2研究中，依沃西单抗单药作为一线治疗显著延长了PD-L1阳性NSCLC患者的PFS：中位PFS为11.14个月，对照组Keytruda仅为5.80个月（HR=0.51，p<0.0001）；且在几乎所有患者亚组中均观察到获益。中国监管部门已基于此PFS数据批准了依沃西单抗一线适应症，这一经验或为Summit在全球一线适应症开发提供重要参考。随着HARMONi-3/7结果的陆续到来，依沃西单抗在一线免疫联合疗法领域的竞争力有望进一步被检验。除了面对其他在研PD-(L)1/VEGF双抗的竞争以外，O药和K药正在联合LAG3单抗试图破局。详情见：康方双抗肺癌一线适应症获批，O药和K药分别联合LAG3单抗破局！04 监管差异与未来展望当然，除了BD以外，还有一种破局方式，summit自己做海外市场。但这一点要建立在依沃西单抗在美获批上市确定无疑之后。但需要指出的是，中美监管对OS和PFS数据的权重存在差异：美国FDA在重大适应症审批中更加注重OS是否显著改善，而中国NMPA在近年来多次基于优势PFS数据批准了创新疗法。因此，本轮市场反应也反映出投资者对两地监管逻辑的担忧：若FDA坚持OS显著门槛，Summit确实面临更严格的审批挑战。未来需关注完整OS数据的进一步更新，以及中美监管机构对双特异性抗体创新疗法的态度演变。 ★

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.