Sabatolimab

近日，一个大靶点的代表性管线有了新的核心进展。2025年6月16日，艾伯维宣布Bcl-2抑制剂维奈克拉+阿扎胞苷联合一线治疗高危骨髓增生异常综合征（HR-MDS）的三期临床VERONA没有达到OS主要终点，HR为0.908，p值为0.3772。维奈克拉拓展适应症，宣告失败。Bcl-2靶点的first in class在HR-MDS上的失败，会不会影响国内管线的整体布局，该适应症的市场，又有几何？01Bcl-2发家要了解Bcl-2抑制剂，首先先详细对Bcl-2本身进行了解。Bcl-2是Bcl-2调节蛋白家族的创始成员，在该家族之中，一些成员抑制细胞凋亡，而另一些成员则促进细胞死亡。恰好Bcl-2蛋白属于抑制细胞凋亡的类型。如图所示，BCL-2及其他拮抗凋亡蛋白通过直接结合BAX和BAK起抑制凋亡作用。从这个逻辑去推，Bcl-2如果异常高表达的话，那么细胞就没办法正常凋亡了。于是，如果细胞内这种蛋白质调高，没办法正常凋亡了呢？这就是问题所在了，没办法正常凋亡而堆积如山的细胞，就成了癌细胞。拮抗和促进细胞凋亡的BCL-2家族蛋白之间的相互作用和动态平衡决定着细胞的生死，细胞是否开始凋亡过程取决于细胞内各种促进和拮抗凋亡信号的整合，正常情况下细胞凋亡过程被严格调控，而这一过程在很多血液系统恶性肿瘤中被破坏。因此，得想办法抑制Bcl-2的表达。根据文献《BCL-2抑制剂在血液系统恶性肿瘤中的研究进展》，BCL-2的功能可被BH3-only蛋白抑制，BH3-only蛋白结合BCL-2位点同时也是BAX与BCL-2的结合位点，因此一个合理的抗癌药物设计思路便是设计BH3类似物。而维奈克拉，是第一个BCL-2选择性BH3类似物。维奈克拉破坏了其与促凋亡蛋白（如BAX、BAK和BIM）的相互作用，使这些蛋白能够诱导线粒体外膜通透性，从而导致细胞色素c的释放、胱天蛋白酶的激活和细胞凋亡。2011年，维奈克拉开始了一系列的临床试验，而它的宿敌为慢性淋巴细胞白血病（CLL）与急性髓性白血病（AML）。其代号为VIALE的临床试验，随后拉开了序幕。VIALE-A为阿扎胞苷和维奈克拉联用在一线治疗AML。主要终点上，阿扎胞苷-维奈克拉组的中位总生存期为14.7个月，对照组（化疗组）为9.6个月，HR值为0.66。安全性上，阿扎胞苷-维奈克拉组235例患者（83%）和对照组105例患者（73%）发生严重不良事件。这个严重不良反应发生率还是有些高的。此外，还有一项AML适应症的三期临床——VIALE-C。这一临床试验上，该试验专为无法接受强化诱导治疗的新诊断AML患者而设计。旨在评估维奈克拉和阿糖胞苷的组合是否比安慰剂和阿糖胞苷联合使用更能改善OS。最后mOS的HR为0.75，P=0.11，没能达到临床试验终点。但后来经过6个月的额外随访，经过调整后的mOS的HR为0.7，p=0.04。慢性淋巴细胞白血病的一线治疗呢？根据文章《First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia》，其设计的三期临床非常复杂，1：1：1：1分为了四组，分别接受四种治疗方案去治疗，分别为化学免疫疗法，维奈克拉-利妥昔单抗治疗，维奈克拉-奥比妥珠单抗治疗，接受维奈克拉-奥比妥珠单抗-伊布替尼治疗。最后结果上，经过中位随访期38.8 个月后，mPFS的中期分析显示，维奈克拉-奥比妥珠单抗-伊布替尼联合治疗优于化学免疫治疗，HR为0.32；P<0.001。尽管维奈克拉-奥比妥珠单抗在无进展生存期方面优于化学免疫疗法（HR，0.42；P<0.001），但维奈克拉-利妥昔单抗组与化学免疫疗法组之间无显著差异（HR，0.79；P=0.18）。维奈克拉目前公认的情况来看，单药治疗的疗效是有限的，这是事实，因此目前开的临床基本许多是靠联用。但不能否认的是维奈克拉确实开创了Bcl-2的整整一个时代，获批了CLL、AML等适应症。2024年，其销售额达到了25.83亿美金。02HR-MDS——确实不好出结果本次临床试验上，治疗适应症为高危骨髓增生异常综合征（HR-MDS）。MDS是一组异质性克隆性造血干细胞恶性肿瘤，其特征是骨髓衰竭、转化为急性髓系白血病 (AML) 的风险以及总体生存期 (OS) 缩短。在一线治疗中，化疗药物HMA例如阿扎胞苷(AZA)、地西他滨和口服地西他滨/西达尿苷仍然是标准治疗。在它之上临床试验折戟的药物并不少，如图所示。Eprenetapopt是一种小分子p53稳定剂，与阿扎胞苷联用共同诱导肿瘤细胞死亡。它主要针对的是TP53突变型MDS，约占MDS人群总数的20%。临床II期结果上，MDS 患者中，73%（n=29）的患者有缓解，其中50%（n=20）达到CR。但该药后续就没了下文，因为和阿扎胞苷对比，它的联用并没有表现出很明显的优效性。再之后，它没有再开三期临床。sabatolimab是诺华的TIM-3单抗，其治疗HR-MDS的II期临床试验为STIMULUS-MDS1，最后结果上，mPFS为11.1个月:8.5个月，HR为0.75，p＞0.1，没做出统计学差异。之后它也没有再开三期临床。Magrolimab，这个熟了，吉利德的CD47单抗。本来是二期临床完之后开了三期临床，2023年7月21日，吉利德宣布终止CD47单抗Magrolimab联合阿扎胞苷治疗高风险骨髓增生异常综合征（MDS）的3期临床Enhance研究，原因是疗效不佳。由此我们可以看到，维奈克拉的失败，真的不能只怪维奈克拉，这个适应症本身，现在都还没有在它上面做出不错对比疗效的新药，啃不下来，不足为奇。03下一代管线谁与争锋但HR-MDS仍是不可小觑的适应症。其在中老年患者高发，尤其在60岁以上的老年人群体，大部分因身体条件问题对化疗不耐受，仅通过替换受损的造血干细胞来恢复正常的血液功能（供体有限&配型不合），从而改善MDS症状或实现治愈，未满足临床需求巨大。HR-MDS市场潜力同样不可小觑，数据显示：国内MDS发病率在1.5人/10万人，美国每年MDS新发患者在2-4万人，其中仅高危MDS预期市场规模就在10-20亿美元。维奈克拉折戟后，国内外不少玩家也瞄准了这个潜力市场。国内最为知名的Bcl-2抑制剂研发biotech就是亚盛医药了，它的APG-2575在FDA获得了5个孤儿药资格认定，分别为华氏巨球蛋白血症、慢性淋巴细胞白血病、多发性骨髓瘤、急性髓系白血病和滤泡性淋巴瘤。都是非常经典的骨髓白血病，也是比较对照化疗比较容易做出结果的适应症。不过，它也在啃HR-MDS这块硬骨头。根据2024年ASH大会上的数据，HR-MDS患者的ORR为50%（1/2），样本量太小，目前还不太好下结论，不过它目前已经在准备三期临床了，其名为GLOR-A-4，已获国家药品监督管理局药物审评中心临床试验许可，预计在2029年达到临床主要终点。此外，还有别的靶点在这个适应症上深耕，比较典型的是康方的AK117。它已经在HR-MDS上出了临床Ib期数据，根据临床Ib期数据，27例可评估患者中CR率为48.1%（不同剂量组下），在24例随访≥3个月的可评估患者中，CR率进一步升至54.2%。13例最初需要红细胞（RBC）输注的可评估患者中，8例（61.5%）最终不再依赖红细胞输注。而同靶点的知名管线则是宜明昂科的IMM01，也随后出了结果，51例疗效可评估患者中，ORR为64.7%，其中CR率为29.4%。目前的肩对肩比较来看，康方的同靶点数据更胜一筹。当然，国外也有公司有新的消息。Bexmarilimab为靶向Clever-1的抗体，机制上来说，通过阻断巨噬细胞上的Clever-1可以增强抗原呈递和T细胞活化。由于Clever-1在髓系白血病细胞上表达，Bexmarilimab因此具有抗白血病作用。该药已在MDS适应症上授予孤儿药认定，其二期临床已经达到了终点，Bexmarilimab联合阿扎胞苷治疗方案在R/R MDS患者中取得63%的ORR，在初治患者中达到76%的ORR。不过该适应症，最终还是需要三期临床对比阿扎胞苷单药的验证。无论何时都不能半场开香槟。结语：总的来说，维奈克拉凭借一己之力，单独为bcl-2开创了一个时代。不能因为它在一个大家都失败的适应症上折戟，就否认它的价值。接下来，该轮到下一波血液疾病管线梯队上了。识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！请注明：姓名+研究方向！本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

1.Theravance Biopharma: Yupelri (revfenacin)Indication: Chronic Obstructive Pulmonary Disease (COPD) Clinical Trials: Phase 4 On January 5th, Theravance Biopharma announced that the Phase IV PIFR-2 study of Yupelri (revefenacin) inhalation solution for the maintenance treatment of Chronic Obstructive Pulmonary Disease (COPD) did not meet the primary endpoint. Yupelri is the only once-daily nebulized long-acting muscarinic antagonist (LAMA) approved in the United States for the maintenance treatment of COPD. The PIFR-2 study aimed to evaluate the improvement in lung function of Yupelri as compared to tiotropium bromide (Spiriva, a dry powder inhaler) in patients with severe to very severe COPD. The study results showed that on day 85, there was no statistically significant difference in the primary endpoint of change from baseline in trough Forced Expiratory Volume in one second (FEV1) compared to the control group. The safety and tolerability profile of Yupelri was consistent with previous studies. 2. Novartis: LigelizumabIndication: peanut allergy Clinical Trials: Phase 3 On January 16th, the clinicaltrials.gov website indicated that Novartis has discontinued the Phase III clinical trial for the treatment of peanut allergy with the immunoglobulin E (IgE) monoclonal antibody Ligelizumab (study CQGE031G12301). This study was a multicenter, randomized, double-blind, placebo-controlled clinical trial, which initially aimed to enroll 486 patients medically diagnosed with IgE-mediated peanut allergy, to evaluate the efficacy and safety of Ligelizumab (120/240mg, once a month) compared to a placebo. As of the termination date of the trial, 211 patients had been enrolled. This termination marks the second setback encountered by Ligelizumab in the immunotherapy field. In September 2023, Novartis formally terminated the Phase III PEARL-PROVOKE study for the treatment of chronic inducible urticaria (CIU) with Ligelizumab, due to the drug not demonstrating a significant therapeutic advantage in two Phase III studies (PEARL 1 and PEARL 2) for the treatment of chronic spontaneous urticaria (CSU). Although Ligelizumab was more effective than a placebo, it was less effective than omalizumab. 3. Allakos: lirentelimabIndication: Chronic Spontaneous Urticaria Clinical Trials: Phase 2 On January 16th, Allakos announced that lirentelimab did not meet the primary endpoints in the Phase 2 clinical trial (ATLAS) for patients with atopic dermatitis and the Phase 2b clinical trial (MAVERICK) for patients with chronic spontaneous urticaria. The results of the Phase 2b clinical trial (ATLAS) for the treatment of atopic dermatitis patients with lirentelimab showed that, at the primary endpoint after treatment to achieve EASI-75, 23% of patients treated with lirentelimab reached EASI-75 compared to 18% of patients treated with placebo, which was not statistically significant. In the MAVERICK trial, for the primary endpoint on the reduction of the UAS7 score, patients treated with lirentelimab saw a 27% reduction in UAS7 compared to a 26% reduction in the placebo-treated group, which also lacked statistical significance. 4. Gilead: Trodelvy® (sacituzumab-govitecan-hziy; SG)Indication: non-small cell lung cancer (NSCLC) Clinical Trials: Phase 3 On January 22, Gilead announced that its Trop2 ADC (antibody-drug conjugate) new drug, Trodelvy, did not meet the primary OS (overall survival) endpoint in the Phase III clinical trial EVOKE-01 for the treatment of non-small cell lung cancer (NSCLC). EVOKE-01 is assessing the efficacy of the Trop2 ADC drug Trodelvy® (sacituzumab govitecan-hziy; SG) in combination with docetaxel in patients with metastatic or advanced NSCLC who have progressed during or after treatment with platinum-based chemotherapy and checkpoint inhibitors. Trodelvy is a Trop-2 targeting ADC monoclonal antibody drug. Trop-2 is a transmembrane glycoprotein whose high expression is associated with the occurrence of many tumors and poorer prognosis, making it a very popular target for ADC research, second only to HER2 in terms of interest. Currently, Gilead's Trop-2 ADC drug Trodelvy is the only one approved globally for the treatment of adult patients with metastatic triple-negative breast cancer (mTNBC) who have previously received at least two therapies, and for patients with locally advanced or metastatic urothelial carcinoma (UC). 5. BMS: OpdivoIndication: Second Time in Late-Stage Kidney Cancer Clinical Trials: Phase 3 On January 29, Bristol-Myers Squibb (BMS) announced the failure of its PD-1 inhibitor, Opdivo, in Part B of the Phase III CheckMate-914 study, as it did not provide a significant benefit in disease-free survival for patients at high risk of recurrence after local renal cell carcinoma surgery. CheckMate-914 is a randomized, double-blind, two-part trial. In Part B, the study compared monotherapy with Opdivo to a placebo. The trial was designed to assess its use as an adjuvant treatment for renal cell carcinoma (RCC) patients who have undergone complete or partial nephrectomy and are at intermediate or high risk of recurrence. After a median follow-up of 27 months, Opdivo failed to demonstrate a significant improvement in disease-free survival (DFS) as compared to placebo, with a hazard ratio of 0.87 and a p-value of 0.3952 based on an assessment by blinded independent central review (BICR). The 12-month DFS probability for the Opdivo group was 83.3%, compared with 78.2% for the placebo group. At 18 months, these estimates changed only slightly to 78.4% and 75.4%, respectively. At the time of analysis, the median DFS for both treatment groups had not been reached. 6. Laekna: afuresertibIndication: platinum-resistant ovarian cancer (PROC) Clinical Trials: Phase 2 On January 29, Laekna Pharma announced the top-line data from the PROFECTA-II study for the combination of afuresertib with paclitaxel in the treatment of platinum-resistant ovarian cancer (PROC). The PROFECTA-II study (NCT04374630) is a randomized, open-label, active-controlled phase II clinical trial evaluating the efficacy and safety of the combination of afuresertib and paclitaxel compared to paclitaxel alone in female patients with platinum-resistant ovarian cancer (PROC). The study enrolled 150 patients randomly across the United States and China into both the experimental and control groups. The primary endpoint was progression-free survival as assessed by the researchers, while secondary endpoints included overall survival, objective response rate, and duration of response. Trial results indicated that the combination treatment of afuresertib and paclitaxel reduced the risk of disease progression or death (progression-free survival, PFS), with an HR of 0.744 (95% CI: 0.502-1.102); however, the results were not statistically significant. 7. Novartis: sabatolimabIndication: intermediate, high, or very high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia-2 (CMML-2) Clinical Trials: Phase 3 On January 31, in its 2023 financial report, Novartis provided updates on its pipeline progress, revealing that the phase III STIMULUS MDS2 study of its TIM-3 monoclonal antibody, sabatolimab (MBG453), in combination therapy for intermediate, high, or very high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia-2 (CMML-2), did not meet its primary endpoint of overall survival (OS). As a result, Novartis has removed it from its pipeline. Moreover, Novartis has also decided to discontinue the development of the BTK inhibitor remibrutinib for the treatment of Sjögren’s syndrome. TIM-3 is a receptor protein belonging to the T cell immunoglobulin and mucin domain (TIM) family that is expressed on the surfaces of T cells, regulatory T cells (Tregs), and innate immune cells (including dendritic cells, natural killer cells, and monocytes). Previously, Novartis had posited that sabatolimab could act by inhibiting the function of the TIM-3 receptor, thereby targeting both myeloid leukemia cells and immune cells simultaneously. This inhibition was hoped not only to kill cancer cells but also potentially enhance the vigor of immune cells.