Sabatolimab

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.

关注并星标CPHI制药在线       TIM3（T 淋巴细胞免疫球蛋白黏蛋白-3）是TIM家族的一个受体蛋白，在T细胞、Treg细胞（T调控细胞）、先天免疫细胞表面表达。TIM3是一类负调控免疫检查点，其作用机制为通过抑制T辅助细胞（Th1和Th7）、诱导CD8+T细胞耗竭、促进Treg细胞成为免疫抑制的细胞群等途径发挥免疫抑制作用。       TIM-3是继PD-1、CTLA-4后，研究较多的免疫治疗靶点之一。研究发现，对于抗PD-1单抗治疗无反应或者产生耐药性的患者往往与TIM-3 的表达高度相关，这一高表达可导致免疫逃逸。因此，针对TIM3和PD1通路的联合用药研究具有广阔前景。       虽然TIM-3是目前研究最多的免疫治疗靶点之一，但目前国内外尚无药物获批上市，国内外研发进度靠前的产品如下。       诺华：Sabatolimab（MBG453）Sabatolimab（MBG453）是诺华开发的一款直接靶向于TIM-3的人源化IgG4k抗体，用于治疗骨髓增生异常综合征（MDS）和急性髓性白血病（AML），可以创新性地同时靶向髓系白血病细胞和免疫细胞，不但能杀伤癌细胞，而且可能增强免疫细胞的活力，曾被诺华寄予厚望。       不过，今年1月底，诺华在财报中宣布，Sabatolimab联合治疗中度、高或极高风险MDS或慢性粒单核细胞白血病-2（CMML-2）的III期研究未达到总生存期（OS）的主要终点。基于此，诺华已决定终止该药物的临床研发，并从公司研发管线中剔除。       GSK：TSR-022TSR-022是由Tesaro公司（被GSK收购）研发的一款人源化抗TIM-3 IgG4抗体，其适应症聚焦于非小细胞肺癌（NSCLC）、肝细胞癌、黑色素瘤等实体瘤。       在TSR-022进行单药治疗的临床试验中，31例肿瘤患者达到了疾病稳定（SD），1例平滑肌肉瘤患者出现部分反应（PR），并且未观察到剂量限制毒性。       这些数据为TSR-022与PD-1抗体联合治疗奠定了基础。这一推测也在临床试验中得到了验证，在202例PD-1/PD-L1抗体难治的NSCLC患者中，与固定剂量的TSR-042（一种PD-1抗体）联合使用的情况下，随着TSR-022的剂量增加其显示出的临床活性也在增加，且未观察到剂量限制毒性。       这说明TSR-022可与 PD-1/PD-L1等抗体起到协同作用，用于治疗PD-1/PD-L1耐药的患者。       罗氏：RO7121661罗氏研发的RO7121661是一种TIM-3/PD-1双特异性抗体，可靶向TIM3和PD-1双靶点。目前正在进行一项针对晚期转移性实体瘤患者的 II期研究。       恒瑞：SHR-1702SHR-1702是恒瑞研发的一款抗TIM-3单抗，早在2019年，恒瑞就开展了SHR-1702单药或联合PD-1抗体（卡瑞利珠单抗）治疗晚期实体瘤的I期研究，旨在确定SHR-1702单药或联合卡瑞利珠单抗在晚期实体瘤受试者中的剂量限制性毒性与最大耐受剂量等，不过目前该药仍处于I期临床阶段。       正大天晴：TQB2618TQB2618是正大天晴研发的一款靶向TIM-3受体的人源化单抗。针对该产品，正大天晴开展了多项临床研究，包括：联合去甲基化药物在复发难治性急性髓系白血病、骨髓增生异常综合征受试者中的I期临床试验；联合抗PD-L1单抗贝莫苏拜单抗（正大天晴研发）在晚期实体瘤患者中的Ib期临床试验；联合贝莫苏拜单抗一线标准治疗失败后的复发广泛期小细胞肺癌患者的Ib/II期临床试验；联合派安普利单抗(正大天晴和康方生物联合研发的一款抗PD-1抗体)治疗复发/转移性鼻咽癌患者的II期临床研究等。       百济神州：surzebiclimabsurzebiclimab是百济神州研发的一款抗TIM-3人源化IgG1单克隆抗体，目前正在进行与替雷利珠单抗联用治疗晚期实体瘤的研究。       作为免疫检查点的后起之秀，目前开发TIM-3靶点的公司并不多。据不完全统计，目前处于在研阶段的TIM3药物约33款，大部分处于临床前阶段。由于选择性激活TIM-3从而导致免疫逃逸是PD-1抗体免疫治疗过程中发生耐药的主要机制，可见TIM-3抗体应用前景巨大。对TIM-3抗体及其应用的研究还需要进一步探索，目前国内外研发进展相差不大，国内公司或可大有所为。       主要参考资料：       1、Romero, Diana. "PD1 says goodbye, TIM3 says hello." Nature Reviews Clinical Oncology 13.4 (2016): 202-203.       2、Ngiow, Shin Foong, et al. "Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors." Cancer research (2011).       3、https://stke.sciencemag.org/content/14/687/eaba0717.     4、BlockingTIM-3 in Treatment-Refractory Advanced Solid Tumors: A Phase Ia/b Study ofLY3321367 with or without an Anti-PD-L1 Antibody.ClinCancer Res2021 Jan 29;clincanres.4405.2020.【智药研习社课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~