AdvanTIG-211: A Randomized, Double-blind, Placebo-controlled, Phase II Study Evaluating the Efficacy and Safety of Ociperlimab (WCD118) Combined With Tislelizumab (VDT482) Plus Chemotherapy Versus Placebo Combined With Pembrolizumab Plus Chemotherapy as First-line Therapy for Participants With Advanced Triple Negative Breast Cancer (TNBC)

The primary scientific question of interest of this study is whether the combination of ociperlimab, tislelizumab and chemotherapy improves progression-free survival (PFS) compared to the combination of placebo, pembrolizumab and chemotherapy as first-line therapy for adult men and women with advanced triple negative breast cancer (TNBC) whose tumors express programmed death ligand 1 (PD - L1) [combined positive score (CPS) ≥10], regardless of study treatment discontinuation or start of new anti-neoplastic therapy.

开始日期2023-09-15

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT05791097 / Withdrawn临床3期

AdvanTIG-306: A Randomized, Double-blind, Placebo-controlled, Phase III Study Evaluating the Efficacy and Safety of Ociperlimab (WCD118/BGB-A1217) Combined With Tislelizumab (VDT482/BGB-A317) Plus Platinum-based Doublet Chemotherapy Versus Placebo Combined With Pembrolizumab Plus Platinum-based Doublet Chemotherapy as First-line Therapy for Participants With Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC)

The primary scientific question of interest is whether the addition of ociperlimab to platinum-based chemotherapy and tislelizumab improve progression-free survival (PFS) or overall survival (OS) compared to pembrolizumab and platinum-based chemotherapy as first-line therapy for participants with locally advanced or metastatic squamous or non-squamous NSCLC with PD-L1 expression of ≥1%.

开始日期2023-07-28

申办/合作机构

Novartis Pharmaceuticals Corp.

CTR20222760 / Recruiting临床2期

一项评价替雷利珠单抗单药治疗和多种含替雷利珠单抗的免疫治疗组合联合或不联合化疗用于可切除的II期至IIIA期非小细胞肺癌中国患者的新辅助治疗的初步有效性、安全性和药效学的2期、随机、开放性、多中心、伞式研究

有效性目的：基于盲态独立病理学审查（BIPR）结果评估接受试验用药物作为新辅助治疗的患者的主要病理学缓解（MPR）率，病理学完全缓解（pCR）率及其他相关生存相关的终点，包括：无事件生存期（EFS）、总生存期（OS）、无病生存期（DFS）和相应的里程碑终点。安全性目的；评估试验用药物作为新辅助治疗的安全性和耐受性，评估接受试验用药物作为新辅助治疗的患者中手术可行性。药效学目的：评估试验用药物作为新辅助治疗时肿瘤内、血液和引流淋巴结中的药效学、预后生物标志物，以及缓解或耐药相关的生物标志物，评估表征试验用药物的药代动力学，评估试验用蛋白治疗药物的个体免疫原性

开始日期2023-03-09

申办/合作机构

百济神州(上海)生物科技有限公司

100 项与欧司珀利单抗相关的临床结果

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100 项与欧司珀利单抗相关的转化医学

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100 项与欧司珀利单抗相关的专利（医药）

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项与欧司珀利单抗相关的文献（医药）

2023-10-01·Journal for immunotherapy of cancer

AdvanTIG-105: a phase I dose escalation study of the anti-TIGIT monoclonal antibody ociperlimab in combination with tislelizumab in patients with advanced solid tumors.

Article

作者: Sophia Frentzas ; Steven Kao ; Rang Gao ; Hao Zheng ; Ahsan Rizwan ; Nageshwar Budha ; Luz de la Hoz Pedroza ; Wei Tan ; Tarek Meniawy

BACKGROUND:

Ociperlimab, a novel, humanized monoclonal antibody (mAb), binds to T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) with high affinity and specificity. Tislelizumab is an anti-programmed cell death protein 1 mAb. We report results from a phase I, first-in-human, dose escalation study evaluating the safety, pharmacokinetics (PK), and preliminary antitumor activity of ociperlimab plus tislelizumab in patients with advanced solid tumors.

METHODS:

Eligible patients previously treated with standard systemic therapy, or for whom treatment was not available or tolerated, received ociperlimab intravenously on Cycle (C) 1 Day (D) 1 and tislelizumab 200 mg intravenously on C1 D8. If tolerated, patients received ociperlimab plus tislelizumab 200 mg sequentially on D29 and every 3 weeks (Q3W) thereafter until discontinuation. Dose escalation for ociperlimab was planned with four dose levels (50 mg, 150 mg, 450 mg, and 900 mg) according to a 3+3 design. An additional dose level of ociperlimab 1800 mg was also assessed. Primary endpoints were safety, determination of the maximum tolerated (or administered) dose, and the recommended phase II dose (RP2D). Secondary endpoints included overall response rate (ORR), duration of response (DoR), disease control rate (DCR) (Response Evaluation Criteria in Solid Tumors version 1.1), PK, and biomarker analysis.

RESULTS:

At data cut-off (September 29, 2022), 32 patients had received ≥1 dose of ociperlimab plus tislelizumab 200 mg Q3W. The maximum administered dose was ociperlimab 1800 mg plus tislelizumab 200 mg Q3W. The median age of enrolled patients was 59.5 years (range: 31-79). Most patients (96.9%) experienced ≥1 treatment-emergent adverse event (TEAE); 62.5% of patients experienced ≥grade 3 TEAEs and 50.0% of patients experienced serious TEAEs. No dose limiting toxicity events were reported. The maximum tolerated dose was not reached. The RP2D was ociperlimab 900 mg plus tislelizumab 200 mg Q3W. Overall, ORR was 10.0%, median DoR was 3.6 months, and DCR was 50.0%.

CONCLUSIONS:

Ociperlimab plus tislelizumab was well tolerated in patients with advanced solid tumors, and preliminary antitumor activity was observed with 450 mg, 900 mg, and 1800 mg ociperlimab. Phase II/III trials of ociperlimab 900 mg plus tislelizumab 200 mg Q3W are underway in a range of solid tumors.

TRIAL REGISTRATION NUMBER:

NCT04047862.

2022-01-01·Frontiers in immunology2区 · 医学

An Fc-Competent Anti-Human TIGIT Blocking Antibody Ociperlimab (BGB-A1217) Elicits Strong Immune Responses and Potent Anti-Tumor Efficacy in Pre-Clinical Models.

2区 · 医学

ArticleOA

作者: Xin Chen ; Liu Xue ; Xiao Ding ; Jing Zhang ; Lei Jiang ; Sha Liu ; Hongjia Hou ; Bin Jiang ; Liang Cheng ; Qing Zhu ; Lijie Zhang ; Xiaosui Zhou ; Jie Ma ; Qi Liu ; Yucheng Li ; Zhiying Ren ; Beibei Jiang ; Xiaomin Song ; Jing Song ; Wei Jin ; Min Wei ; Zhirong Shen ; Xuesong Liu ; Lai Wang ; Kang Li ; Tong Zhang

TIGIT (T-cell immunoglobulin and ITIM domain) has emerged as a promising target in cancer immunotherapy. It is an immune "checkpoint" inhibitor primarily expressed on activated T cells, NK cells and Tregs. Engagement of TIGIT to its ligands PVR and PVR-L2 leads to inhibitory signaling in T cells, promoting functional exhaustion of tumor-infiltrating T lymphocytes. Here, we described the pre-clinical characterization of Ociperlimab (BGB-A1217), a novel humanized IgG1 anti-TIGIT antibody (mAb), and systemically evaluated the contribution of Fc functions in the TIGIT mAb-mediated anti-tumor activities. BGB-A1217 binds to the extracellular domain of human TIGIT with high affinity (K_D = 0.135 nM) and specificity, and efficiently blocks the interaction between TIGIT and its ligands PVR or PVR-L2. Cell-based assays show that BGB-A1217 significantly enhances T-cell functions. In addition, BGB-A1217 induces antibody dependent cellular cytotoxicity (ADCC) against Treg cells, activates NK cells and monocytes, and removes TIGIT from T cell surfaces in an Fc-dependent manner, In vivo, BGB-A1217, either alone or in combination with an anti-PD-1 mAb elicits strong immune responses and potent anti-tumor efficacy in pre-clinical models. Moreover, the Fc effector function is critical for the anti-tumor activity of BGB-A1217 in a syngeneic human TIGIT-knock-in mouse model. The observed anti-tumor efficacy is associated with a pharmacodynamic change of TIGIT down-regulation and Treg reduction. These data support the selection of BGB-A1217 with an effector function competent Fc region for clinical development for the treatment of human cancers.

Cancer control : journal of the Moffitt Cancer Center

Tislelizumab: A Modified Anti-tumor Programmed Death Receptor 1 Antibody.

Article

作者: Lin Zhang ; Zhihua Geng ; Bo Hao ; Qing Geng

Tislelizumab is an anti-programmed death receptor 1 (PD-1) monoclonal immunoglobulin G 4 antibody developed by BeiGene. The structure of tislelizumab has been modified to maximally inhibit the binding of PD-1 to programmed death ligand 1 (PD-L1) and minimize the binding of tislelizumab to Fcγ receptors. In clinical studies, tislelizumab has shown preliminary anti-tumor effects in various solid tumors, such as Hodgkin's lymphoma, urothelial carcinoma, lung cancer, gastric and esophageal cancer, liver cancer, nasopharyngeal carcinoma, colorectal cancer, and microsatellite instability-high/mismatch repair-deficient tumors. In addition, it also showed new promise in solid tumor treatment in combination with ociperlimab. Due to its satisfactory anti-tumor effects, tislelizumab has received approvals in China for the treatment of classical Hodgkin's lymphoma, urothelial carcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and hepatocellular carcinoma, and it is now under investigation for a new indication in microsatellite instability-high/mismatch repair-deficient tumors. Moreover, it has been granted orphan designations in hepatocellular carcinoma, esophageal cancer, and gastric cancer, including cancer of the gastroesophageal junction, by the US Food and Drug Administration. Tislelizumab has an acceptable safety profile; the most common adverse effects include fatigue, anemia, and decreased neutrophil count, while the most fatal events have been related to respiratory infection or failure, and hepatic injury. Tislelizumab has an economic advantage compared with other well-studied PD-1/PD-L1 inhibitors; thus, the introduction of it could provide clinical oncologists with an effective weapon against tumors and may alleviate the burden of cancer patients.

192

项与欧司珀利单抗相关的新闻（医药）

2024-04-01

·药时代

打破临床科研壁垒，发展新质生产力，这家创新药企出了本书……

正文共：3106 字预计阅读时间：10 分钟“作为一个生物学家，我深知生物统计在试验设计、数据分析等方面发挥着重要作用。同样，对于广大医学工作者来说，统计学的应用在医学研究中也是至关重要的。”——百济神州联合创始人王晓东（《统心协力》序）前言2024年的春天，对于中国创新药来说，是变革之春。创新药首度被纳入《政府工作报告》[1]：报告中对2024年政府工作任务作出部署，第一点即提出，大力推进现代化产业体系建设，加快发展新质生产力。具体包括积极培育新兴产业和未来产业。实施产业创新工程，完善产业生态，拓展应用场景，促进战略性新兴产业融合集群发展。巩固扩大智能网联新能源汽车等产业领先优势，加快前沿新兴氢能、新材料、创新药等产业发展，积极打造生物制造、商业航天、低空经济等新增长引擎。而想要让创新药的研发实力得到淬炼，还需要临床科研能力建设助推，克服目前临床科研转化的结构性问题。在真实世界中，临床科研通过研究疾病的发生机制、病理生理变化、患者群体特征等，为药物研发提供明确的靶点和治疗方向。创新药研发之所以高投入、高风险、长周期，与严谨复杂的药物疗效求证过程直接相关。据统计，超70%的药物研发投入是花费在临床试验之上[2]。因此，中国创新药想要成功“闯出来”，迫切需要提升行业整体的临床研究设计水平，培养出充分的临床研究管理能力。即便在药物上市后，还会通过临床科研继续收集真实世界的数据，进行药物的长期疗效和安全性监测评价。来自临床的信息可以反馈到药物研发中，进一步优化药物的使用方案或促使药物迭代升级。2024年元旦前夕，百济神州自著新书《统心协力：医学统计常用方法实操》低调发售，仅仅一个季度，该书就已销售过万册。这是一本介绍医学统计常用方法实操的书籍，受众面向医院和临床研究机构的研究者。新书共18章，每章后面配的讲解视频累计近14个小时，内容扎实。左右滑动查看封面与章节目录专业书籍短时间内能有如此惊人的销量，印证了一个现实问题：国内为临床研究者量身定制的统计概念和统计方法的普及读物，存在巨大的“学习需求”缺口。书籍本身值得深入探索的内容有很多，但我们更希望讨论的是书本以外的话题，或许可以通过这本书一窥背后的行业逻辑，以及来自行业龙头企业的解题思路。打穿科学与商业的墙2023年7月17日，《统心协力》发售前5个月，国家卫生健康委印发《国家卫生健康委关于推动临床专科能力建设的指导意见》文件，再次强调了要引领公立医院高质量发展，与 2021年9月国务院印发的《公立医院高质量发展促进行动（2021-2025年）》中提及的政策精神存在延续性。两份文件侧重点有所不同，但对于公立医院高质量发展的具体举措方面，都强调了要提升临床科研能力，一改过去“药企研发，医生应用”的习惯，其背后的逻辑十分清晰。提升临床科研能力可以促进基础医学研究和临床治疗之间的有效转化，将基础研究与实际临床需求紧密结合，实现实验室研究成果快速转化为临床和公共卫生防治新方法，提高医疗总体水平。常年与患者打交道的医生，能够真正充分地了解临床需求，因此，从临床角度出发开展的科研项目，可以更精准地做到“以患者为中心”。用任正非的话说，这便是让“听得见炮声的人做决策”，是让“听得到患者声音的人，决定下一步的科研方向”。当然，我们都知道，这是极具挑战的。医改20年，很大程度上改善了看病难、看病贵的问题，然而医疗资源供给不足、发展不均衡的挑战依然存在。据国家卫生健康委发布的《2022年我国卫生健康事业发展统计公报》，2022年末，中国执业（助理）医师共计443.5万人，每千人口执业（助理）医师仅有3.15人。对大多数临床医生而言，难以兼顾临床诊疗和科学研究，缺少参与创新疗法临床实践的机会——这在一定程度上制约了科学创新的临床转化。此外，医院科研通常是基于学科的，而不同学科之间的交叉融合却并不够。这限制了科研的创新性和突破性，使得许多跨学科的研究项目难以得到有效的支持和开展。即便医生在百忙之中开展了科研工作，但由于医院科研与产业界的交流不够充分，缺乏有效的成果转化机制和渠道，使得许多科研成果往往难以转化为实际的临床应用。临床科研，难；转化医学，难上加难。但从产业出发，问题似乎并非不可解决。对药企而言，发现优秀的分子，开发高质量的药物只是万里长征的第一步，药品正式上市后仍有大量的科研工作需要开展。在真实世界里，患者的基础疾病、交叉用药、经济状况等等诸多条件，都会制约患者的药物选择，这比临床试验阶段面临的情况要复杂得多。让更多临床医生了解同类药物的不同特点、让医生根据患者个体情况选择适配性最好的药物、探索药物更多的使用场景或限制、提升药物可及性……都是药企的商业化团队所需要面对的问题。从转化医学的角度出发，新药研发到临床应用之间的壁垒——这是矗立在医生面前的“临床与科研”之墙，同样也是药企所面临的“科学与商业”之墙。产业界对于打穿这堵墙的意愿，丝毫不弱于医界——创新穿墙惠及临床，进而反哺商业，让企业有源源不断的动力持续创新。成熟药企拥有的资源以及对资源的整合能力是临床端所不具备的，这也提供了从产业界出发，解决转化医学难题的基础。谁能当此破壁人理解了“坚壁高墙”从何起，再来讨论谁能当此“破壁人”？在推动药物上市的过程中，审批环节至关重要，临床数据分析可能影响一个药物能否成功按计划上市，甚至在后续的市场销售中起到决定性作用，这样的案例屡见不鲜。2023年末，全球首款杜氏肌营养不良症（DMD）基因疗法Elevidys Ⅲ期确证性试验未达到主要终点。在正常情况下，这就意味着试验的失败乃至药物未来的终结。但有趣的是，研发药企Sarepta通过对临床试验重新进行亚组分析，成功论证在4-5岁年龄的患者亚组中Elevidys取得了多个次要终点的明确改善[3]，不但免于撤市，还有望取得全面批准。长久以来，美国FDA被视为全球新药审评的风向标。能够取得FDA的认可，在相当程度上说明一家药企已经充分完成了上市前的一系列准备，印证其拥有过硬的临床科研能力。随着中国生物医药产业十多年来的蓬勃发展，越来越多中国的创新药企通过了FDA的考验，站上国际舞台。想从产业角度出发提升临床科研能力，研发与商业化两方面的力量缺一不可。因此，能够打破“临床与科研”之墙的，必然是两者兼备的药企。如果仅有研发导向而缺乏商业化的支持，会缺少产品落地后的临床反馈，出现闭门造车的情况；如果仅有销售导向而缺乏研发端的数据和经验积累，推动临床科研进步的想法无异于空中楼阁。从新药研发、新适应症拓展，到上市后评价，乃至不断优化用药方案，百济神州团队在与临床工作者长期紧密合作的过程中，积累了大量实际案例，也对临床科研工作中遇到的挑战有了深刻的理解。在此基础上，结合其统计和数据科学团队的专业知识和经验，著成了《统心协力》一书。研发方面，百济神州建立了广泛、多元化的药物管线和技术平台，已进入临床阶段的自研与合作产品管线就有13款之多，其中Sonrotoclax和欧司珀利单抗已处于3期临床阶段[4]，为其后续创新突破奠定了基础。而其商业转化、国际化成功的自研成果，毋庸置疑已成为业界样板。百济神州手握泽布替尼、替雷利珠单抗两款自主研发的重磅产品，凭借亮眼的临床数据立下国产创新药在海外获批的里程碑。2023年第65届ASH年会上，百济神州公布了泽布替尼全球3期ALPINE试验数据，在接受泽布替尼治疗超过三年以上的复发或难治性（R/R）慢性淋巴细胞白血病（CLL）患者中，泽布替尼对比伊布替尼展现出持续的PFS获益（HR: 0.68 [95% CI, 0.53-0.86] P=0.0011），在多个亚组中也观察到持续的PFS获益[5]。百济神州作为“后起之秀”也具备了与全球制药巨头“掰手腕”的能力。百济神州2023年财报显示，泽布替尼已在全球70个市场获批，并成为出海创新药中的首个“十亿美元分子”。过去一年，百济神州自研PD-1替雷利珠单抗在全球药政进展上捷报频传，再次验证其高质量的注册性研究和相关数据分析：2023年9月19日，替雷利珠单抗获得欧盟委员会批准，用于治疗既往含铂化疗后患有不可切除、局部晚期或转移性食管鳞状细胞癌（ESCC）的成年患者，成为首个成功出海的中国原研PD-1单抗；2024年3月15日，FDA批准替雷利珠单抗上市，用于治疗既往经系统治疗后不可切除、复发性局部晚期或转移性食管鳞状细胞癌（ESCC）患者。破壁“组合拳”作为企业，能跳出产业的维度，以一种更加宏观的视角审视创新药产业存在的临床研究问题实属难得。更值得一提的是，著书行动并非心血来潮，而是百济神州持续数年的战略计划之一。《统心协力》的书封右上角标有“百济·星计划”标识，据悉，这是一个早在2022年就已设立的创新专项，旨在为中国临床科研能力提升搭建行业赋能交流平台，具体分为三个模块：能力培训、学术交流、工具书开发。相当于针对临床科研各个环节存在的挑战，打出了一套“组合拳”。除《统心协力》以外，百济神州还推出“科研周四见”平台，从临床试验运营管理，IIT研究及统计学，SCI课题申请，转化医学等多个维度持续输出专业培训，帮助临床科研工作者持续学习和能力提升。百济神州总裁、首席运营官吴晓滨博士表示：“越来越多的临床医生做出了创新性的临床研究，推动了治疗方案的升级，解决了更多患者的实际问题。作为一家全球肿瘤创新公司，百济神州将继续支持更多研究者的创新想法落地，以医生、以患者为中心，为临床研究的高质量发展贡献力量。”结语客观来说，中国创新药产业成规模出现的时间不足20年，相对欧美发达国家而言根基尚浅，有些差距可以用经济投入抹平，有些则必须要通过时间积累，凭借多方持续推动才能奋起直追，临床科研能力的整体进步正是如此。想要完全发展新质生产力，将创新药提升至中国现代化产业体系建设的核心，需要从研发基础设施、人才团队、产业资本、科技人才与成果评价体系等多方面协调组织，上下游各环节通力合作。药时代也期待更多拥有行业号召力的企业参与和推动临床科研水平提升，打破科学与商业之间的高墙，让创新成果真正惠及患者。参考资料1.2024年《政府工作报告》https://www.gov.cn/zhengce/jiedu/tujie/202403/content_6937462.html2.《人民政协报》2024.03.26 第705期，为何要完善创新药产业发展生态环境？全国政协常委毕井泉点出关键http://dzb.rmzxb.com/rmzxbPaper/pc/att/202403/26/bfa56b14-e6ed-4017-9ea7-12b59c57ebeb.pdf3.Sarepta Therapeutics公司新闻稿，2023-06-22，https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-fda-approval-elevidys-first-gene4.百济神州官网，https://www.beigene.com/wp-content/uploads/2023/04/Pipeline_Slide_FY_2023_final_March-24.pdf5.百济神州官方微信，https://mp.weixin.qq.com/s/MCT7JkkFpaRiwv6BkUEobw

一致性评价医药出海

2024-03-06

·BioSpace

BeiGene to Present Clinical and Preclinical Data from Broad Portfolio and Pipeline at AACR Annual Meeting 2024

Multiple trials underscore the potential of tislelizumab-containing immuno-oncology combinations in a variety of solid tumor settings Additional highlights include preclinical characterization data for an investigational BTK degrader, BGB-16673, currently in clinical development for B-cell malignancies, including mantle cell lymphoma BASEL, Switzerland & BEIJING & CAMBRIDGE, Mass.--(BUSINESS WIRE)-- BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global oncology company, today announced the presentation of emerging oncology pipeline data at the American Association for Cancer Research (AACR) Annual Meeting April 5-10 in San Diego. BeiGene has nine abstracts scheduled for poster presentations at AACR. “Our presentations at this year’s AACR showcase our ongoing development of tislelizumab combinations in solid tumors as we assess the clinical potential of multiple novel immuno-oncology candidates and make data-driven decisions for further development,” said Lai Wang, Ph.D., Global Head of Research & Development at BeiGene. “More broadly, they reflect our deep commitment to discovering innovative new medicines for cancer patients, including by pioneering novel mechanisms like targeted degradation.” BeiGene will present results from the AdvanTIG-204 Phase 2 study of tislelizumab (anti-PD1) plus ociperlimab (anti-TIGIT) in first-line limited-stage small cell lung cancer (SCLC) as well as results of a biomarker study of the same doublet in the setting of first-line non-small cell lung cancer (NSCLC). An ongoing, global Phase 3 trial of ociperlimab plus tislelizumab in stage IV, PD-L1 high NSCLC, AdvanTIG-302, will complete enrollment this month (NCT04746924). An additional clinical presentation includes the first data from a Phase 1a dose escalation study of BGB-10188, a phosphatidylinositol 3 kinase delta (PI3Kδ) inhibitor, plus tislelizumab in patients with solid tumors. BeiGene will also be presenting preclinical characterizations of several novel molecules from its internal discovery engine, including a CEA x 4-1BB bispecific antibody and a chimeric degradation activation compound (CDAC) targeting BTK, BGB-16673. Clinical data from an ongoing Phase 1 study of BGB-16673 in relapsed/refractory B-cell malignancies were presented at ASH 2023, demonstrating clinical responses and a tolerable safety pro heavily pre-treated patients with B-cell malignancies, including those with BTK inhibitor-resistant disease (NCT05006716). An additional preclinical presentation highlights the therapeutic potential of the triple-combination of tislelizumab with anti-LAG-3 (LBL-007) and anti-TIM-3 (surzebiclimab); this combination is being evaluated in an ongoing Phase 2 study in head and neck squamous cell carcinoma (NCT05909904). BeiGene Presentations During AACR 2024 Abstract Title Abstract # Presentation Time (PDT) Lead Author Preclinical Characterization of the correlation between BTK degradation and tumor growth inhibition of the BTK target protein degraders using PK/PD modeling 2110 Monday, April 8 9 a.m. – 12:30 p.m. Section 30 Board #1 Y. Wu BGB-B167, a first-in-class 4-1BB/CEACAM5 bispecific antibody, exhibits potent in vitro and in vivo anti-tumor activity and superior safety pro > in preclinical models 2371 Monday, April 8 9 a.m. – 12:30 p.m. Section 38 Board #17 Z. Li Translational assessment of triple combination with tislelizumab (anti-PD-1), LBL-007 (anti-LAG- 3) and surzebiclimab (anti-TIM-3) highlights its strong anti-tumor activity and clinical potential in solid tumors such as HNSCC 4041 Tuesday, April 9 9 a.m. – 12:30 p.m. Section 3 Board #17 H. Zhu Clinical Exploration of potential biomarkers correlated with efficacy of ociperlimab (anti-TIGIT) plus tislelizumab (anti-PD1) in 1L PD-L1+ non-small cell lung cancer (NSCLC) CT053 Monday, April 8 9 a.m. – 12:30 p.m. Section 48 Board #3 S. Kim A first in human, phase 1a, dose escalation study of BGB 10188, a phosphatidylinositol 3 kinase delta (PI3Kδ) inhibitor, + tislelizumab (anti-PD-1) in patients with solid tumors CT189 Tuesday, April 9 9 a.m. – 12:30 p.m. Section 48 Board #17 R. Cosman AdvanTIG-204: A phase 2, multicenter, randomized, 3-arm, open-label study investigating the preliminary efficacy and safety of ociperlimab (anti-TIGIT) + tislelizumab (anti-PD-1) + concurrent chemoradiotherapy (cCRT) in patients with untreated limited-stage small cell lung cancer (SCLC) CT255 Tuesday, April 9 1:30 p.m. – 5 p.m. Section 48 Board #14 Y. Gong BGB-A317-LBL-007-202 (NCT06010303): A phase 2, randomized, active-controlled, open- label study to evaluate the efficacy and safety of LBL 007 (anti-LAG-3) in combination with tislelizumab (TIS; anti-PD-1) plus chemotherapy (chemo) as first-line (1L) treatment in patients with unresectable locally advanced/metastatic esophageal squamous cell carcinoma (ESCC) CT274 Tuesday, April 9 1:30 p.m. – 5 p.m. Section 50 Board #4 S. Park Liberty-201 (NCT05609370): Maintenance fluoropyrimidine and bevacizumab with or without anti-lymphocyte activation gene-3 (LAG-3) antibody LBL-007 plus anti-programmed cell death protein-1 (PD-1) antibody tislelizumab (TIS) for patients (pts) with metastatic or unresectable microsatellite stable (MSS)/mismatch repair proficient (pMMR)colorectal cancer (CRC) CT276 Tuesday, April 9 1:30 p.m. – 5 p.m. Section 50 Board #6 H.-J. Lenz BGB-LC-201 (NCT05635708): A phase 2, open- label, multi-arm study of tislelizumab (TIS; anti- PD-1) in combination with investigational agents +/- chemotherapy as first-line treatment for patients with locally advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC) CT277 Tuesday, April 9 1:30 p.m. – 5 p.m. Section 50 Board #7 G. Blumenschein About Tislelizumab Tislelizumab is a uniquely designed humanized immunoglobulin G4 (IgG4) anti-programmed cell death protein 1 (PD‑1) monoclonal antibody with high affinity and binding specificity against PD‑1. It is designed to minimize binding to Fc-gamma (Fcγ) receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors. About BeiGene BeiGene is a global oncology company that is discovering and developing innovative treatments that are more affordable and accessible to cancer patients worldwide. With a broad portfolio, we are expediting development of our diverse pipeline of novel therapeutics through our internal capabilities and collaborations. We are committed to radically improving access to medicines for far more patients who need them. Our growing global team of more than 10,000 colleagues spans five continents, with administrative offices in Basel, Beijing, and Cambridge, U.S. To learn more about BeiGene, please visit and follow us on LinkedIn and X (formerly known as Twitter). Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws, including statements regarding BeiGene’s ability to discover innovative new medicines for cancer patients and pioneer novel mechanisms; the future development, regulatory filing and approval, and commercialization of tislelizumab, BGB-16673, and other novel molecules; and BeiGene’s plans, commitments, aspirations, and goals under the heading “About BeiGene.” Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including BeiGene's ability to demonstrate the efficacy and safety of its drug candidates; the clinical results for its drug candidates, which may not support further development or marketing approval; actions of regulatory agencies, which may affect the initiation, timing, and progress of clinical trials and marketing approval; BeiGene's ability to achieve commercial success for its marketed medicines and drug candidates, if approved; BeiGene's ability to obtain and maintain protection of intellectual property for its medicines and technology; BeiGene's reliance on third parties to conduct drug development, manufacturing, commercialization, and other services; BeiGene’s limited experience in obtaining regulatory approvals and commercializing pharmaceutical products; BeiGene’s ability to obtain additional funding for operations and to complete the development of its drug candidates and achieve and maintain profitability; and those risks more fully discussed in the section entitled “Risk Factors” in BeiGene’s most recent annual report on Form 10-K, as well as discussions of potential risks, uncertainties, and other important factors in BeiGene's subsequent filings with the U.S. Securities and Exchange Commission. All information in this press release is as of the date of this press release, and BeiGene undertakes no duty to update such information unless required by law. View source version on businesswire.com: Contacts Investor: Liza Heapes +1 857-302-5663 ir@beigene.com Media: Kyle Blankenship +1 667-351-5176 media@beigene.com Source: BeiGene, Ltd. View this news release online at:

临床2期临床1期免疫疗法临床3期

2024-03-04

·药智网

百济神州的福气，还在后头

自研产品获批之前，百济神州的收入靠License-in产品支撑，像一颗未“破土”的“竹笋”，隐埋于泥土之下。随着泽布替尼、替雷利珠单抗和帕米帕利的获批，百济神州这颗韧性十足的“常青竹”，进入“破土”成长阶段。从过去研发的“烧钱王”成为自研单品“挣钱王”，百济神州的福气还在后头。01“竹笋”破土,创下国内首款十亿美元分子近日，百济神州发布了2023年财务业绩，全年总收入24.59亿美元，同比增长73.65%，其中，产品收入21.90亿美元，同比增长75.54%，营收的大幅上涨，让其亏损进一步收窄，2023年净亏损8.82亿美元，减亏56.0%。这背后，是百济神州自我“造血”从无到有，快速成长的5年。因泽布替尼和替雷利珠单抗均在2019年底获批，仅有泽布替尼在当年贡献103.9万美元收入，虽相比2.23亿美元产品总收入是九牛一毛，但却是自研产品“造血”的开始。比营收持续增长更值得围观的是，百济神州自研产品让其营收结构发生了根本性且持续向好的改变，自研产品收入已由2020年占产品总收入的66.34%增长至2023年的83.74%，3款自研产品年度收入均持续增长。图1 百济神州2020年-2023年产品收入情况数据来源：百济神州2020年-2023年报尤其是泽布替尼，2023年全球销售额同比增长128.53%达到近13亿美元，成为国产创新药首个“十亿美元分子”，作为第二代BTK抑制剂，泽布替尼是首个且唯一一个有效性优于伊布替尼的BTK抑制剂。据头对头全球3期ALPINE试验数据显示，经IRC评估，泽布替尼用于治疗复发/难治性(R/R)慢性淋巴细胞白血病（CLL）的ORR为80.4%，而伊布替尼ORR为72.9%，最终PFS分析结果也显示，中位随访29.6个月，泽布替尼在R/R CLL患者中呈现出优于伊布替尼的PFS，且有更好心脏安全性，泽布替尼组因心脏疾病导致死亡率为0，而伊布替尼组为6例(0%vs1.9%)，房颤/房扑发生率也显著低于伊布替尼组(5.2%vs13.3%)。2023年12月，美国FDA批准泽布替尼进行说明书更新，纳入对比伊布替尼治疗R/R CLL优效性结果，2024年，“十亿美元分子”将向“二十亿美元分子”冲刺。PD-1海外进军再起航，路越走越宽。除了泽布替尼的海外进军，替雷利珠单抗也曾被视为有望闯关美国FDA的国产PD-1之一。2021年1月，诺华引进替雷利珠单抗的合作协议，是截至当时中国药物授权交易首付款和交易总金额最高的合作。然而，2022年7月，百济神州公告称，因新冠疫情相关旅行限制，美国FDA无法如期在中国完成现场核查工作，受理的替雷利珠单抗用于不可切除或转移性食管鳞状细胞癌（ESCC）患者二线（2L）治疗上市许可申请（BLA）的评审被延缓且至今未获批，2023年9月，诺华终止授权协议，加上PD-1的内卷升级，一度让外界对替雷利珠单抗的“出海”前景感到迷茫。前脚被弃，后脚反转，就在诺华与百济神州终止合作的当月，欧盟批准了替雷利珠单抗用于治疗既往接受过含铂化疗不可切除、局部晚期或转移性食管鳞状细胞癌（ESCC）成人患者。登美计划不变，且是重装归来。在美国FDA还未批准替雷利珠单抗用于二线治疗ESCC的上市申请之际，一线治疗不可切除局部晚期、复发或转移性ESCC患者BLA再获美国FDA受理。据全球3期RATIONALE 306研究数据显示，替雷利珠单抗联合化疗一线治疗ESCC患者总生存期（OS）显著改善，中位OS为17.2个月，而安慰剂联合化疗中位OS为10.6个月，此外，与安慰剂联合化疗相比，使患者死亡风险降低34%。随着替雷利珠单抗多个全球临床试验数据揭晓，闯关美国FDA的成功率也越来越高，就在前几日，美国FDA又受理了替雷利珠单抗联合含氟尿嘧啶类和铂类药物化疗治疗局部晚期不可切除或转移性胃或胃食管结合部（G/GEJ）腺癌患者BLA。值得一提的是，替雷利珠单抗单药一线治疗不可切除或转移性肝细胞癌（HCC）已在2024年1月获国家药监局批准，成为全球唯一单药获批HCC一线治疗及在中国获批适应症最多的PD-1单抗，而此前，美国FDA已授予替雷利珠单抗治疗1L HCC快速通道认定。此外，欧洲CHMP在2024年2月发布建议批准替雷利珠单抗用于治疗三项非小细胞肺癌（NSCLC）适应症的积极意见，替雷利珠单抗的“出海”路越走越宽。02正面硬刚1至3代BTK,福气还在后头截至目前，全球已经批准6款BTK抑制剂，分别为伊布替尼、阿可替尼、泽布替尼、Tirabrutinib、奥布替尼和Pirtobrutinib，其中，伊布替尼为第一代BTK，阿可替尼、泽布替尼、Tirabrutinib、奥布替尼为第二代BTK，Pirtobrutinib为第三代BTK。图2 全球已获批上市的BTK抑制剂图片来源：同写意公众号伊布替尼在第二代BTK的围剿下，特别是在CLL上被泽布替尼头对头击败后，市场表现已持续疲软。目前的BTK市场竞争只剩下二代“同门”相斗，以及三代能否后来居上。成为二代头牌？阿可替尼作为首款二代BTK，实力最为强悍。泽布替尼要想在市场上“吃的开”，除了击败伊布替尼外，还需在众多二代“同门”中立足，实力最强的阿可替尼，自然成了其“攀比”对象。据百济神州在2023年第65届美国血液学会（ASH）年会上公布的一项泽布替尼治疗阿可替尼不耐受B细胞淋巴瘤患者2期研究结果显示，因阿可替尼不耐受转为泽布替尼治疗的B细胞恶性肿瘤患者，有63%没有重现任何此前不耐受的不良反应，且疾病控制率高达96%。此外，基于3期ALPINE和3期ASCEND试验数据，获得的泽布替尼对比阿可替尼治疗复发或难治性（R/R）慢性淋巴细胞白血病（CLL）患者有效性匹配调整间接比较（MAIC）结果显示，泽布替尼对比阿可替尼获得经研究者评估的无进展生存期改善，完全缓解比值比（OR）也优于阿可替尼，这一研究在刚刚结束的第28届血液学恶性肿瘤国际年会上得以展示。图3 泽布替尼对比阿可替尼用于R/R CLL的MAIC结果图片来源：百济神州官网从获批适应症来看，泽布替尼也是二代BTK中获批最多的，值得一提的是，2023年11月，欧盟批准泽布替尼联合奥妥珠单抗用于治疗既往接受过至少两线系统性治疗的复发或难治性（R/R）滤泡性淋巴瘤（FL）成人患者，成为首个获批用于该适应症的BTK抑制剂。来自三代BTK的压力还未出现。Pirtobrutinib是首个获批的第三代非共价BTK抑制剂，但目前仅获批用于治疗共价BTK抑制剂耐药后的MCL患者。前两代BTK耐药突变大多与C481突变有关，Pirtobrutinib因不与C481结合，才有了可治疗对前两代BTK耐药的优势。但纪念斯隆-凯特琳癌症中心发起的一项研究结果显示，55例接受Pirtobrutinib治疗的患者中，有12例2年左右发生疾病进展，且疾病进展相对伊布替尼较早，相关患者中存在多个非C481突变位点，且绝大多数突变位点仅影响Pirtobrutinib体外活性，而对伊布替尼影响较小。图4 Pirtobrutinib和伊布替尼治疗后突变位点对比情况图片来源：西南证券以上研究结果提示Pirtobrutinib治疗的患者或有可能更早发生耐药。03后续产品丰富,“竹笋”蝶变成“竹”除了已获批的3款自研产品外，百济神州已进入临床阶段的自研产品管线中，还有Sonrotoclax、欧司珀利单抗、BGB-A445、BGB-16673、BGB-21447、Surzebiclimab、BGB-15025/26808、BGB-30813、BGB-A3055、BGB-24714、BGB-10188和BGB-43395等13款产品，其中，Somrotoclax和欧司珀利单抗已处于3期临床阶段。图5 百济神州自研产品管线图片来源：百济神州公告Sonrotoclax是第二代BCL-2抑制剂,相比目前获批地域范围最广的BCL-2药物维奈克拉，Sonrotoclax对BCL-2的效力和选择性高于维奈克拉，并显示了攻克BCL-2常见耐药突变的潜力，已获美国FDA授予治疗AML、MM、WM和MCL孤儿药认定，Sonrotoclax的多项研究在2023年第65届美国血液学会（ASH）年会上展示。据一项1/2期研究数据显示，初治（TN）CLL/SLL患者接受Sonrotoclax联合泽布替尼治疗，耐受性良好，且未出现肿瘤溶解综合征（TLS）病例，缓解率达到100%，无患者出现疾病进展（PFS）。此外，Sonrotoclax单药治疗R/R边缘区淋巴瘤患者ORR为67%（n=8），其中4名患者(33%)达到完全缓解(CR)；640mg组ORR为78%(n=7)，其中4名患者(44%)达到CR；在先前接受BTK治疗时出现进展的所有4名患者中均观察到PR或更好缓解。欧司珀利单抗是一款针对TIGIT的人源化IgG1变体单抗，目前尚无抗TIGIT抗体获批，截至2023年底，欧司珀利单抗开发项目已入组超2000例患者，包括在肺癌、食管鳞状细胞癌和宫颈癌患者中进行的8项全球临床试验，其中已有4项研究在2023年欧洲肿瘤内科学会上得以展示。值得一提的是，百济神州在BTK领域又找到了下一个“现金流密码”，BGB-16673是一款新型口服靶向BTK的嵌合式降解激活化合物（CDAC），在临床前的野生型BTK模型和BTK抑制剂耐药性突变模型中显示出了抗肿瘤活性。据1期研究初步结果显示，在B细胞恶性肿瘤患者（包括患有BTK耐药性疾病患者）中具有可耐受的安全性和临床反应,还观察到外周血和肿瘤组织中BTK蛋白水平大幅降低，证明了强大的靶向作用。04结语付出终有回报，今天的百济神州，通过自研产品在市场上的迅猛表现，已由过去的研发“烧钱王”成为自研单品“挣钱王”，而后续的自研管线也将持续助力，让其脱胎换骨，成长为制药圈中韧性十足的“常青竹”。参考来源：1.西南证券2.百济神州官网、公告、年报声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 青色转载开白 | 马老师 18996384680（同微信）商务合作 | 王存星 19922864877（同微信）阅读原文，是受欢迎的文章哦

引进/卖出临床3期财报临床结果

100 项与欧司珀利单抗相关的药物交易

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研发状态

适应症	最高研发状态	国家/地区	公司
不可切除的非小细胞肺癌	临床3期	中国更多	BeiGene Ltd. 更多
晚期非小细胞肺癌	临床3期	美国更多	百济神州（广州）医药有限公司更多
转移性非小细胞肺癌	临床3期	美国更多	BeiGene Ltd. 更多
非小细胞肺癌	临床3期	中国更多	百济神州（广州）创新科技有限公司更多
复发性弥漫性大B细胞淋巴瘤	临床2期	中国更多	BeiGene Ltd. 更多

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04693234 (AdvanTIG-202, ESMO2023) 人工标引	临床2期	宫颈癌二线 PD-L1	178	Tislelizumab 200 mg + Ociperlimab 900 mg	(網鬱製簾壓觸獵膚製獵) = 廠餘齋鑰衊餘獵顧憲餘網顧觸衊選鹽夢醖廠廠 (願願積積願獵積觸構觸, 15.8 ~ 30.3) 更多	积极	2023-10-22
				Tislelizumab 200 mg + Ociperlimab 900 mg (PD-L1 +)	(網鬱製簾壓觸獵膚製獵) = 選鏇餘蓋糧憲廠蓋餘蓋網顧觸衊選鹽夢醖廠廠 (願願積積願獵積觸構觸, 17.2 ~ 36.9) 更多
NCT04952597 (AdvanTIG-204, AACR2024) 人工标引	临床2期	小细胞肺癌	126	ociperlimab 900 mg + tislelizumab 200 mg+ cCRT	(構醖夢鏇壓築積醖窪積) = 觸觸範觸遞繭鬱遞餘襯廠築獵鹽餘衊窪餘選獵 (艱憲積鹹糧夢鹽構壓鑰 ) 更多	积极	2024-04-05
				tislelizumab + cCRT	(構醖夢鏇壓築積醖窪積) = 壓鹽膚廠製遞膚獵選齋廠築獵鹽餘衊窪餘選獵 (艱憲積鹹糧夢鹽構壓鑰 ) 更多
NCT04047862 (AdvanTIG-105, ESMO2022) 人工标引	临床1期	转移性非鳞状非小细胞肺癌一线 EGFR/ALK/ROS-1 wild-type	84	ociperlimab+tislelizumab+paclitaxel/nab-paclitaxel+carboplatin	(鏇糧範憲選築艱範願憲) = 襯繭簾廠鹽窪壓鑰鏇鹽遞選壓襯襯廠淵鬱膚選 (製鑰餘糧積廠窪獵積繭, 30 ~ 60)	积极	2022-09-10
				ociperlimab+tislelizumab+pemetrexed+cisplatin/carboplatin	(鏇糧範憲選築艱範願憲) = 網壓鏇壓鬱膚鹹鹹鬱範遞選壓襯襯廠淵鬱膚選 (製鑰餘糧積廠窪獵積繭, 10 ~ 40)
NCT05023109 (ZSAB-TOP, ASCO_GI2024) 人工标引	临床2期	胆道肿瘤一线	45	tislelizumab + ociperlimab + gemcitabine + cisplatin	(遞壓壓簾膚襯艱襯蓋積) = 壓積膚構鹹廠顧積醖糧獵齋蓋願艱壓構選壓夢 (遞範鑰範鑰製遞廠積壓, 32.9 ~ 64.9) 更多	积极	2024-01-18
NCT04047862 (AdvanTIG-105, ESMO_IO2022) 人工标引	临床1期	广泛期小细胞肺癌	42	Chemotherapy+Ociperlimab+Tislelizumab	(簾壓積獵艱壓襯鹽遞襯) = 膚鏇襯繭鹹蓋鏇網網網繭鬱範糧築夢繭獵壓鬱 (選鬱夢膚廠積淵範網憲, 48.3 ~ 79.4) 更多	积极	2022-12-08
NCT04732494 (AdvanTIG-203, ESMO2023) 人工标引	临床2期	PD-L1阳性食管鳞状细胞癌二线	125	Ociperlimab (OCI) + Tislelizumab (TIS)	(襯糧齋憲鬱淵繭鏇蓋醖) = 鏇願襯醖壓廠淵構憲鹹糧衊壓簾鑰廠醖鹹鹽構 (膚鏇鏇選蓋繭製構憲鏇 ) 更多	不佳	2023-10-21
				Placebo + Tislelizumab (TIS)	(襯糧齋憲鬱淵繭鏇蓋醖) = 範構範獵夢窪淵獵鹽築糧衊壓簾鑰廠醖鹹鹽構 (膚鏇鏇選蓋繭製構憲鏇 ) 更多
NCT04047862 (AdvanTIG-105, CSCO2022)	临床1期	晚期恶性实体瘤	20	Ociperlimab	(鹽糧鏇範憲淵餘簾鏇繭) = 艱觸憲憲範簾鹽鹹選衊齋鹽憲糧願蓋壓繭鬱繭 (艱製餘鏇觸廠構膚範夢, 0.4, 64.1) 更多	-	2022-09-21
				Tislelizumab	(鹽糧鏇範憲淵餘簾鏇繭) = 製衊膚醖積顧構製鹹蓋齋鹽憲糧願蓋壓繭鬱繭 (艱製餘鏇觸廠構膚範夢, 21.2, 86.3)
NCT04047862 (AdvanTIG-105 \| BGB-900-105, ASCO2023) 人工标引	临床1期	胃腺癌 \| 胃食管交界处恶性肿瘤	60	Ociperlimab+Tislelizumab+chemotherapy	(築窪鹽壓範壓獵夢製網) = 觸簾獵築積鏇鬱醖夢願鹽獵構遞壓壓願顧淵糧 (衊觸積製鹽製蓋網鹹廠, 37.5 ~ 64.1) 更多	积极	2023-05-26
				Ociperlimab+Tislelizumab+chemotherapy (PD-L1 tumor area positivity (TAP) score ≥5%)	(築窪鹽壓範壓獵夢製網) = 構簾醖壓蓋顧觸簾壓繭鹽獵構遞壓壓願顧淵糧 (衊觸積製鹽製蓋網鹹廠, 38.8 ~ 77.6)
NCT04948697 (AdvanTIG-206, ESMO2023) 人工标引	临床2期	晚期肝细胞癌	94	Ociperlimab + Tislelizumab + BAT1706	(襯鏇憲襯襯醖膚餘製遞) = 繭鹹鬱鏇範鏇襯範願遞顧簾製齋壓網繭壓願鹹 (積鑰齋鏇餘範廠顧繭襯, 23.7 ~ 48.7) 更多	积极	2023-10-21
				Tislelizumab + BAT1706	(襯鏇憲襯襯醖膚餘製遞) = 膚製衊廠鏇鹽衊壓夢觸顧簾製齋壓網繭壓願鹹 (積鑰齋鏇餘範廠顧繭襯, 21.1 ~ 56.3) 更多
NCT04047862 (AdvanTIG-105, ESMO_IO2022) 人工标引	临床1期	非小细胞肺癌	26	ociperlimab+tislelizumab	(鹽構襯餘構鬱顧壓蓋蓋) = 廠艱夢獵醖積齋鏇簾觸遞獵範鑰築築鹹鬱膚顧 (窪觸鹽獵願蓋繭膚壓觸, 1.0 ~ 26.0) 更多	积极	2022-12-08