Topotecan Hydrochloride

Improved overall survival (OS), progression-free survival (PFS) and confirmed objective response rate (ORR) were observed in the China subpopulation treated with TIVDAK compared to chemotherapy, consistent with those in the global population The safety profile of TIVDAK among the China subpopulation was manageable and consistent with that observed in the global population Zai Lab intends to submit a New Drug Application (NDA) to China’s National Medical Products Administration (NMPA) in the first quarter of 2025 Zai Lab will leverage its commercial footprint of ZEJULA in women’s cancer to bring the medicine to patients in China if approved SHANGHAI & CAMBRIDGE, Mass.--(BUSINESS WIRE)--Jan. 15, 2025-- Zai Lab Limited (NASDAQ: ZLAB; HKEX: 9688) today announced positive topline results from the China subpopulation of the global Phase 3 innovaTV 301 study, demonstrating a clinically meaningful improvement in overall survival with TIVDAK treatment for patients with previously treated recurrent or metastatic cervical cancer compared to chemotherapy. The China subpopulation results were consistent with those in the global population: TIVDAK demonstrated a 45% reduction in the risk of death compared to chemotherapy (HR: 0.55 [95% CI: 0.27-1.15] in the China subpopulation who had received prior standard systemic therapies, with more than half of this Chinese population having received prior anti-PD(L)1 therapy. Median OS for patients treated with TIVDAK was not reached versus chemotherapy 10.7 months [95% CI: 6.0-not reached] with a median follow-up of 11.5 months. Secondary endpoints of PFS and confirmed ORR also favored treatment with TIVDAK compared to chemotherapy. The safety profile of TIVDAK in the China subpopulation was manageable and consistent with the global profile. “Recurrent or metastatic cervical cancer remains a significant challenge for patients, highlighting a critical unmet need for effective treatments that extend survival after relapse,” said Dr. Rafael Amado, M.D., President, Head of Global Research and Development at Zai Lab. “The consistent and positive results in the China subpopulation of the global Phase 3 study reinforce the potential for TIVDAK, the only ADC therapy in this disease setting, to increase options in this therapeutically unmet clinical setting. If approved, we expect TIVDAK to add to ZEJULA and augment our commercial franchise in women’s tumors.” “There are approximately 150,000 new cases of cervical cancer annually in China1, and patients face limited treatment options once their cancer recurs or spreads after initial treatment,” said Dr. Lingying Wu, Professor of the Department of Gynecologic Oncology of National Cancer Center / Cancer Hospital Chinese Academy of Medical Sciences. “While the recent adoption of immunotherapy as a first-line treatment in China represents progress, there is a lack of effective options for patients following relapse. The promising results from TIVDAK, which demonstrated superior survival extension in patients whose disease progressed after initial treatments, including prior anti-PD(L)1 treatment, offer hope for addressing this critical unmet need.” In April 2024, the U.S. Food and Drug Administration (FDA) approved the supplemental Biologics License Application (sBLA) granting full approval for TIVDAK® (tisotumab vedotin-tftv) for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. The approval was based on results from the global, randomized, Phase 3 innovaTV 301 clinical trial (NCT04697628), which met its primary endpoint, demonstrating overall survival (OS) benefit in adult patients with previously treated recurrent or metastatic cervical cancer treated with TIVDAK compared to chemotherapy. TIVDAK demonstrated a 30% reduction in the risk of death compared to chemotherapy (hazard ratio [HR]: 0.70 [95% CI: 0.54-0.89], two-sided p=0.0038)2. Median OS for patients treated with TIVDAK was 11.5 months [95% CI: 9.8-14.9] versus chemotherapy 9.5 months [95% CI: 7.9-10.7]. PFS and confirmed ORR were also significantly improved compared to chemotherapy. The safety profile of TIVDAK was consistent with its known safety profile as presented in the U.S. prescribing information, and no new safety signals were observed. Based on these encouraging results, Zai Lab intends to submit an NDA for TIVDAK to China’s National Medical Products Administration (NMPA) in the first quarter of 2025. The full China subpopulation data will be presented at a future medical conference in 2025. About innovaTV 301 Trial Design The innovaTV 301 trial (NCT04697628) is a global, 1:1 randomized, open-label Phase 3 trial evaluating TIVDAK® (tisotumab vedotin) versus investigator’s choice of single agent chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) with recurrent or metastatic cervical cancer who received chemotherapy. Patients with recurrent or metastatic cervical cancer with squamous cell, adenocarcinoma, or adenosquamous histology, and disease progression during or after treatment with chemotherapy doublet +/- bevacizumab and an anti-PD-(L)1 agent (if eligible) are included. The primary endpoint was overall survival. The main secondary outcomes were progression-free survival and objective response rate. The study was conducted by Seagen, which was acquired by Pfizer in December 2023, in collaboration with Genmab, European Network of Gynaecological Oncological Trial Groups (ENGOT, study number ENGOT cx-12) and the Gynecologic Oncology Group (GOG) Foundation (study number GOG 3057), as well as other global gynecological oncology cooperative groups. For more information about the Phase 3 innovaTV 301 clinical trial and other clinical trials with tisotumab vedotin, please visit www.clinicaltrials.gov. About Cervical Cancer in China Cervical cancer remains one of the leading causes of cancer death in women in China and globally. An estimated 150,000 new cases of cervical cancer occur annually in China1. Current treatment options are limited for patients with recurrent or metastatic cervical cancer with disease progression on or after systemic therapy. TIVDAK is well positioned to provide a new option for previously treated advanced cervical cancer patients who currently have limited treatment options and poor outcomes. About TIVDAK® (tisotumab vedotin) TIVDAK® (tisotumab vedotin) is an antibody-drug conjugate (ADC) composed of Genmab’s human monoclonal antibody directed to tissue factor (TF) and Pfizer’s ADC technology that utilizes a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody. Nonclinical data suggest that the anticancer activity of tisotumab vedotin is due to the binding of the ADC to TF-expressing cancer cells, followed by internalization of the ADC-TF complex, and release of MMAE via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. In vitro, tisotumab vedotin also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity. TIVDAK received accelerated approval from the FDA in September 2021 and full approval in April 2024 for adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Please see full prescribing information, including BOXED WARNING for TIVDAK here. Zai Lab has an exclusive license from Seagen Inc., a company later acquired by Pfizer, to develop and commercialize TIVDAK in Greater China (mainland China, Hong Kong, Macau, and Taiwan, collectively). About Zai Lab Zai Lab (NASDAQ: ZLAB; HKEX: 9688) is an innovative, research-based, commercial-stage biopharmaceutical company based in China and the United States. We are focused on discovering, developing, and commercializing innovative products that address medical conditions with significant unmet needs in the areas of oncology, immunology, neuroscience and infectious disease. Our goal is to leverage our competencies and resources to positively impact human health worldwide. For additional information about Zai Lab, please visit www.zailaboratory.com or follow us at www.twitter.com/ZaiLab_Global. Zai Lab Forward-Looking Statements This press release contains forward-looking statements relating to our future expectations, plans, and prospects, including, without limitation, statements relating to our prospects and plans for developing and commercializing TIVDAK in Greater China, the potential benefits of TIVDAK, and the potential treatment of cervical cancer. These forward-looking statements may contain words such as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “goal,” “intend,” “may,” “plan,” “possible,” “potential,” “will,” “would,” and other similar expressions. Such statements constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are not statements of historical fact or guarantees or assurances of future performance. Forward-looking statements are based on our expectations and assumptions as of the date of this press release and are subject to inherent uncertainties, risks, and changes in circumstances that may differ materially from those contemplated by the forward-looking statements. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including but not limited to (1) our ability to successfully commercialize and generate revenue from our approved products, (2) our ability to obtain funding for our operations and business decisions, (3) the results of our clinical and pre-clinical development of our product candidates, (4) the content and timing of decisions made by the relevant regulatory authorities regarding regulatory approvals of our product candidates, (5) risks related to doing business in China, and (6) other factors identified in our most recent annual and quarterly reports and in other reports we have filed with the U.S. Securities and Exchange Commission. We anticipate that subsequent events and developments will cause our expectations and assumptions to change, and we undertake no obligation to update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise, except as may be required by law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release. Our SEC filings can be found on our website at www.zailaboratory.com and the SEC’s website at www.sec.gov. Notes: 1 Bingfeng Han et al., "Cancer incidence and mortality in China, 2022" Journal of the National Cancer Center, 2024. DOI: 10.1016/j.jncc.2024.01.006. 2 The threshold for statistical significance is 0.0226 (2-sided). View source version on businesswire.com: https://www.businesswire.com/news/home/20250115437262/en/ Investor Relations: Christine Chiou / Lina Zhang +1 (917) 886-6929 / +86 136 8257 6943 christine.chiou1@zailaboratory.com / lina.zhang@zailaboratory.com Media: Shaun Maccoun / Xiaoyu Chen +1 (857) 270-8854 / +86 185 0015 5011 shaun.maccoun@zailaboratory.com / xiaoyu.chen@zailaboratory.com Source: Zai Lab Limited

01   引言 组合药物疗法因其多靶点协同作用的特性，正在癌症、传染病等复杂疾病的治疗中发挥越来越重要的作用。然而，如何从成千上万种潜在的药物组合中筛选出安全有效的方案，成为科学家和药物开发者面临的巨大挑战。现有的高通量筛选方法受限于固定的实验设计和高昂的资源需求，难以全面挖掘组合药物的潜力。基于此，《A Bayesian active learning platform for scalable combination drug screens》提出了一种全新的解决方案：BATCHIE（Bayesian Active Treatment Combination Hunting via Iterative Experimentation）。该框架采用贝叶斯主动学习，通过动态调整实验设计，突破了组合药物筛选的瓶颈。 本文将围绕BATCHIE的核心技术、研究成果及其潜在应用展开分析，探索其如何助力药物开发从“高耗时、高成本”向“高效、智能”转变。 图1: 自适应实验设计的好处  02   研究背景2.1 组合药物筛选的困境 药物组合的筛选复杂性主要体现在实验空间的指数增长。例如，对于一组包含100种药物的单药筛选，实验数目为药物数量和剂量条件的乘积（如5000次）；而在二元组合筛选中，实验数目迅速膨胀至数百万次，三元组合更是高达数十亿次。如此庞大的实验需求令研究者望而却步，即便是最先进的实验室也难以全面完成。传统的固定实验设计方法和机器学习模型难以应对这些规模化问题，造成药物组合研究的滞后。2.2 现有方法的局限性 目前常用的筛选策略包括： 固定实验设计：对一部分药物组合进行随机抽样或系统性实验，随后利用机器学习模型预测未测试的组合效果。然而，这种方法依赖于预设的实验设计，容易忽略潜在的高效组合。 全覆盖筛选：理论上可以解决上述问题，但实验成本和时间消耗过高，在现实中并不可行。 启发式优化：如RECOVER算法，虽然能够动态调整实验方向，但缺乏理论上的最优性保证，且难以扩展到大规模实验空间。 面对这些挑战，BATCHIE通过引入动态实验设计和贝叶斯概率建模，为组合药物筛选提供了高效的解决方案。 图2: BATCHIE示意图  03   BATCHIE的技术原理3.1 贝叶斯主动学习的核心 BATCHIE的核心是主动学习（active learning），通过对实验结果的动态反馈调整后续实验设计，以最大化信息增益。其基本流程包括以下步骤： 初始实验设计：对药物组合进行种子实验，覆盖药物和细胞系空间中的基本条件。 模型更新：利用实验结果训练贝叶斯预测模型，估算每种组合的响应分布。 不确定性评估：通过模型的不确定性（如后验分布的广度）确定信息量最大的实验。 动态实验设计：设计新一批实验，重点关注预测最不确定的区域，逐步提高模型准确性。3.2 PDBAL准则 BATCHIE采用了“概率直径主动学习”（PDBAL）准则，该算法通过选择能够最大限度减少后验分布中样本之间距离的实验，确保每轮实验都具有理论上的最优性。与传统的固定设计不同，PDBAL在模型训练和实验设计之间形成了闭环，显著提升了实验效率。3.3 技术实现的模块化 BATCHIE的设计具有高度模块化，能够与多种贝叶斯模型兼容。例如，可以针对不同实验目标（如药物协同作用或毒性评估）调整模型结构。这种灵活性为不同领域的应用奠定了基础。 图3: 回顾性研究设计和结果 图4:  前瞻性研究设计和随机验证结果  04  研究成果与关键发现4.1 回顾性实验验证 研究团队在多个大规模数据集上验证了BATCHIE的性能，包括： ALMANAC：包含60种癌症细胞系和104种药物。 GDSC2：涵盖126种细胞系和66种药物。 MERCK：涉及39种细胞系和38种药物。 在这些数据集中，BATCHIE仅使用15轮实验即可达到与全数据集相近的预测准确性。同时，与随机设计相比，BATCHIE减少了超过10万次实验，尤其在实验空间较大的情况下，效率优势更加显著。4.2 前瞻性研究成果 研究团队应用BATCHIE对206种药物在16种癌症细胞系上的组合效果进行了筛选，成功预测并验证了Talazoparib与Topotecan的组合疗效。这一组合不仅在体外实验中表现出高治疗指数（TI），还在患者来源的细胞模型中进一步验证了其潜力，显示了强大的临床转化价值。4.3 扩展性与灵活性 除了预测药物组合疗效，BATCHIE还适用于协同作用和拮抗作用的筛选任务。通过灵活调整目标函数，BATCHIE可以快速适应不同的实验需求。  05   应用与前景5.1 在肿瘤药物开发中的应用 BATCHIE在Ewing肉瘤中的成功应用展示了其在肿瘤药物筛选中的广阔前景。未来，它有望帮助研究者快速筛选出具有临床转化潜力的药物组合，为个性化治疗提供更多选择。5.2 在高维度实验中的优势 随着3D类器官模型和多路CRISPR技术的兴起，实验成本和复杂性日益增加。BATCHIE能够通过优化实验设计，显著减少资源消耗，推动这些新技术的广泛应用。5.3 助力高阶组合疗法 药物组合不仅限于二元组合，三元及以上组合可能更具协同作用。然而，高阶组合的实验复杂性更高，传统方法难以胜任。BATCHIE的动态设计能力使其成为高阶组合疗法开发的重要工具。5.4 潜在跨领域应用 BATCHIE的技术原理不仅限于药物筛选，还可扩展至材料科学、农业研究等领域。例如，优化化合物混合物的性能或筛选高效抗病基因组合。  06   总结与展望 BATCHIE通过创新的动态实验设计方法，为组合药物筛选提供了突破性的解决方案。其在提高实验效率、准确性和灵活性方面的表现，为药物开发领域带来了重要启示。未来，随着技术的进一步完善和扩展，BATCHIE有望在癌症治疗、抗耐药药物开发等领域发挥更大作用。同时，随着3D生物模型和高维实验技术的推广，BATCHIE将成为研究者探索复杂生物系统的强大助手。 通过BATCHIE，我们看到了智能化技术在生命科学领域的无限潜力。从庞大的实验数据中提取高价值信息，BATCHIE为我们展示了一种高效、精准且可扩展的科学研究新范式。Reference： Tosh, C., Tec, M., White, J. B., Quinn, J. F., Ibanez Sanchez, G., Calder, P., Kung, A. L., Dela Cruz, F. S., & Tansey, W. (2025). A Bayesian active learning platform for scalable combination drug screens. Nature Communications, 16(156). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41467-024-55287-7 版权信息 本文系AIDD Pro接受的外部投稿，文中所述观点仅代表作者本人观点，不代表AIDD Pro平台，如您发现发布内容有任何版权侵扰或者其他信息错误解读，请及时联系AIDD Pro (请添加微信号sixiali_fox59)进行删改处理。 本文为原创内容，未经授权禁止转载，授权后转载亦需注明出处。有问题可发邮件至sixiali@stonewise.cn 关注我，更多资讯早知道↓↓↓