Lasofoxifene Tartrate

1. 研究背景 雌激素受体 α（ERα，由 ESR1 基因编码）作为一种经典的核转录因子，在约 70% 的乳腺癌发生发展中发挥着关键的转录驱动作用，长期以来一直是内分泌治疗的核心靶点。尽管选择性雌激素受体调节剂（如他莫昔芬）和芳香化酶抑制剂（如来曲唑）等阻断雌激素信号通路的药物已成为 ER+ 乳腺癌的一线临床标准疗法，但原发性和获得性耐药仍是难以攻克的主要临床挑战。其中，ESR1 基因配体结合域发生的获得性激活突变（特别是 Y537S、Y537N 和 D538G）会使受体呈现出非配体依赖性的持续构象激活状态，从而显著降低肿瘤对传统内分泌治疗的敏感性。为克服耐药性，既能拮抗受体活性又能诱导受体蛋白降解的选择性雌激素受体降解剂（SERD）应运而生。高亲和力竞争性拮抗剂氟维司群作为首个批准的 SERD 药物，长期以来占据临床主导地位，但其极差的药代动力学特性导致必须通过肌肉注射给药，极大地限制了患者依从性与给药剂量上限。尽管随后开发了多种口服 SERD 候选药物（如 Elacestrant、Imlunestrant、Amcenestrant、Giredestrant 和 Camizestrant 等），但绝大部分分子在 III 期临床试验中因疗效未达预设终点或安全性问题而相继宣告失败。为了解决这一问题，通讯作者团队在《Drug Discov. Today》发表了题为《The PROTAC milestone: FDA approval of vepdegestrant (ARV-471) for ESR1-mutated breast cancer》的研究成果。 2. 研究目的 本研究旨在深刻阐明靶向蛋白降解（TPD）技术从传统占用驱动型抑制剂向事件驱动型催化降解剂跨越的机制优势，并全面系统地剖析首个获得美国 FDA 批准上市的 PROTAC 分子 Vepdegestrant (ARV-471) 的分子设计逻辑、理化性质突破、临床药理学表现以及监管决策依据。研究深入探讨了传统基于占用率的 SERD 药物在面对 ESR1 突变体时降解深度不足的内在原因，揭示了异双功能分子通过募集 E3 泛素连接酶 CRBN 诱导 ERα 泛素化及蛋白酶体降解的催化作用机制。此外，本研究梳理了超越传统 Lipinski 类药五原则（beyond-Rule-of-5）的口服 PROTAC 药物化学设计规律（如控制溶剂暴露氢键供体数 eHBD ≤ 2、刚性接头设计及构象变色龙效应），总结了基于 Guardant360 CDx 伴随诊断的精准医疗策略，并展望了诱导近接药理学在拓展不可药化靶点和多元化 E3 连接酶招募工具箱方面的未来发展前景。 3. 研究结果 3.1 口服 SERD 类药物的分子结构演进与临床转化挑战 研究团队详细梳理了已进入临床评估的口服选择性雌激素受体降解剂（SERD）的化学结构及其临床研发进展，揭示了不同化学骨架对受体降解机制和临床成药性的深远影响 (Figure 1)。分析表明，含有丙烯酸侧链的 SERD 分子主要通过 UBR5 途径介导 ERα 降解，而含有碱性氨基侧链的分子（例如 Elacestrant、Giredestrant、Imlunestrant 和 Camizestrant）则通过诱导 Helix 12 发生显著构象位移并招募 RNF111 泛素连接酶触发蛋白酶体降解。然而，大多数口服 SERD 候选分子的临床转化之路充满坎坷，包括 Amcenestrant 在 Phase III AMEERA-5 试验中未达到无进展生存期（PFS）主要终点，AZD9496、LSZ102 和 GDC-0927 等因药代动力学缺陷或商业策略终止开发，这充分凸显了仅依赖配体占有型机制调控 ERα 转录和降解的药效局限性。 Figure 1：已进入临床试验的口服选择性雌激素受体降解剂（SERD）的化学结构及最高临床与监管状态标注，展示了氟维司群及多种口服候选药物的分子差异与研发状态。 3.2 靶向 ERα 信号通路的四大药理学作用机制对比 研究团队从分子机制层面对比了四种不同类型的 ERα 信号通路阻断策略，阐明了 PROTAC 技术相对于传统小分子抑制剂的独特催化优势 (Figure 2)。芳香化酶抑制剂通过抑制芳香化酶以阻断外源性雌激素的合成，从而间接抑制 ERα 的配体结合与活性；选择性雌激素受体调节剂（SERM）通过竞争性结合 ERα 并诱导 Helix 12 构象重排，进而阻断辅激活因子的招募以转录抑制下游基因表达；传统 SERD 分子结合 ERα 后置换 Helix 12，导致受体热稳定性降低并触发被动降解，其药效高度依赖于药物对靶蛋白的持续占有率；而作为异双功能分子的 PROTAC（如 Vepdegestrant）能够同时高亲和力结合 ERα 和 CRBN E3 泛素连接酶，诱导形成高效的三元复合物，通过事件驱动的亚化学计量催化机制引发 ERα 的多泛素化和蛋白酶体高深度降解。 Figure 2：乳腺癌中靶向 ERα 信号通路的四大区别性药理学作用机制对比示意图，详细对比了从芳香化酶抑制剂到 PROTAC 的催化降解差异。 3.3 PROTAC 研发历程与 Vepdegestrant 的分子设计逻辑 研究总结了自 2001 年 PROTAC 概念提出以来至 2026 年首款药物获批的历史里程碑，并重点解析了 Vepdegestrant (ARV-471) 的构效关系优化与理化参数突破 (Figure 3a, Figure 3b)。Vepdegestrant 由三部分合理拼接而成：衍生自 Lasofoxifene 的高亲和力 ERα 配体、刚性含氮杂环接头以及选择性结合 CRBN 的沙利度胺衍生物配体。刚性接头极大地降低了构象熵损失，显著增强了三元复合物形成的协同性、代谢稳定性及口服生物利用度。虽然 Vepdegestrant 计算分子量约为 800 Da 且 cLogP = 6.8，严重违背经典 Lipinski 规则，但其实测 Lipophilicity（pH 7.4 下 logD = 4.6）显著低于预测值，其实测 PSA 与氢键供体数完全符合口服 PROTAC 的设计准则。体外实验显示，该分子在 MCF-7 细胞中对 ERα 展现出极强的降解活性（DC50 = 0.94 nM），并在多个临床模型中表现出优异的疗效，于 2026 年 5 月 1 日获得 FDA 批准上市。 Figure 3：PROTAC 靶向降解技术发展里程碑及 Vepdegestrant 的结构优化策略与理化参数表征，涵盖了从早期概念到获批上市的关键节点与分子设计演进。 3.4 全球临床阶段 PROTAC 降解剂的结构与管线布局 研究团队汇总分析了全球已进入临床试验阶段且化学结构已公开的 23 个异双功能 PROTAC 分子的结构特征，揭示了该领域的药物化学分子设计范式 (Figure 4)。结构分析表明，绝大多数口服 PROTAC 均招募 CRBN E3 连接酶，这得益于其优异的物化性质；相比之下，基于 VHL 连接酶的降解剂通常采用静脉注射方式给药。值得注意的是，RNK05047 作为首个招募 HSP90 的 BRD4 降解剂，代表了除传统连接酶之外扩展降解效应子工具箱的重要突破。同时，全球 PROTAC 候选管线不仅覆盖实体瘤与血液瘤，更拓展至自身免疫性疾病及中枢神经系统疾病（如 ARV-102），充分证实了异双功能蛋白降解平台广泛的临床转化潜力。 Figure 4：全球已公开化学结构的临床阶段异双功能 PROTAC 降解剂分子全景图，详细展示了靶蛋白结合 moiety、接头与不同 E3 连接酶的匹配关系。 4. 结论与展望 Vepdegestrant (ARV-471) 获得 FDA 官方批准上市，标志着异双功能蛋白降解靶向嵌合体（PROTAC）技术完成了从学术概念验证到临床成药的历史性跨越。这一里程碑不仅为克服 ESR1 突变内分泌耐药的 ER+/HER2- 晚期乳腺癌患者提供了全新的口服精准治疗方案，更彻底打破了传统 Lipinski 类药五原则对大分子量超规则药物研发的思想禁锢，确立了以低溶剂暴露氢键供体数、刚性低熵接头和构象变色龙效应为核心的口服 PROTAC 药物化学设计新准则。展望未来，为进一步拓展 PROTAC 的临床应用空间，研究界亟需加快拓展全新的 E3 泛素连接酶招募配体，以克服对 CRBN/VHL 的过度依赖并打破组织选择性瓶颈；同时，通过联合用药克服耐药机制，并积极推动 RIPTACs、LYTACs 等新模态的发展，全面开启近接药理学引领的新药研发新时代。 5. 原文出处 https://doi.org/10.1016/j.drudis.2026.104772628

SHANGHAI, Aug. 21, 2026 /PRNewswire/ -- On August 21, Henlius (2696.HK) announced its interim results for the 2026 fiscal year. During the reporting period, the company showcased strong organic growth momentum and sustainable earnings generation, with revenue reaching RMB 3.5882 billion, a 27.3% increase YoY, and net profit amounting to RMB 430.4 million, up 10.3% YoY. In the first half of 2026, Henlius reported non-IFRS profit of RMB 572.3 million, a 46.7% YoY increase, and adjusted EBITDA (a non-IFRS measure) of RMB 904.1 million, rising 35.2% YoY. Key financial and operational metrics maintained a steady upward trajectory. Driven by sustained global growth of its core products and end-to-end lean operations across the entire value chain, the company continues to strengthen both revenue scale and earnings quality. Dr. Jason Zhu, Executive Director and Chief Executive Officer of Henlius, stated: "2026 marks a pivotal year of acceleration in Henlius' journey toward becoming a C-MNC. In the first half of the year, our core products continued to generate tangible value through global commercialization, while multiple differentiated pipeline assets entered critical stages of value validation. The benefits of this dual-engine growth model are increasingly taking shape. Looking ahead, we will remain anchored in addressing unmet patient needs, build on the virtuous cycle of 'global commercialization fueling innovation and differentiated innovation driving global expansion', further deepen our Globalization 2.0 strategy, and advance steadily toward high-quality, sustainable growth." Global Commercialization Advances Across Multiple Fronts, Core Portfolio Reinforces the Foundation for Growth As of the reporting period, Henlius has 10 products approved in over 60 countries and regions across Asia, Europe, Latin America, North America, and Oceania, and has benefited over 1.1 million patients worldwide. In the first half of 2026, the company maintained its strategic focus on key therapeutic areas, including breast cancer, lung cancer, and gastrointestinal cancers. Global product sales revenue amounted to RMB 2.9386 billion, up 14.9% YoY. Notably, sales revenue from ex-China markets increased significantly by 159.4% year on year to RMB 105.3 million, while product profit from ex-China markets reached RMB 59.5 million, more than four times that of the same period last year, further strengthening the company's ability to generate value from global commercialization. In the breast cancer therapeutic area, the company continued to advance its "Full-Course, All-Domain, Global" breast cancer treatment landscape, with global sales revenue from its breast cancer product portfolio reaching RMB 1.6983 billion during the reporting period. The four marketed products collectively delivered strong volume growth, with HANQUYOU (trastuzumab, HERCESSI™ in the U.S. and Zercepac® in Europe), HANBEIYOU (pertuzumab, POHERDY® in the U.S. and Europe), HANNAIJIA (neratinib), and fovinaciclib generating sales revenues of RMB 1.4844 billion, RMB 7.7 million, RMB 195.5 million, and RMB 10.7 million, respectively. In the first half of 2026, HANBEIYOU received sequential marketing authorizations from the European Commission and China's NMPA, marking it as the first and only** Chinese-developed pertuzumab biosimilar approved across all three major markets—China, the U.S., and the EU. In combination with HANQUYOU, it establishes the first Chinese-developed dual HER2-targeted regimen combining trastuzumab and pertuzumab approved in China, the U.S., and the EU, spanning the treatment continuum from neoadjuvant setting to first-line treatment of advanced disease. Furthermore, the company is accelerating the development of a diversified breast cancer pipeline including lasofoxifene (HLX78), a novel endocrine therapy; dulpatatug* (HLX22), a novel-epitope monoclonal antibody (mAb) targeting HER2; HLX87, a HER2-targeted ADC; HLX97, an oral KAT6A/B inhibitor; HLX49, a HER2 biparatopic ADC; and HLX319, the first Chinese-developed fixed-dose subcutaneous co-formulation of pertuzumab and trastuzumab—all aimed at establishing a comprehensive, multidimensional breast cancer treatment portfolio across the disease continuum. In solid tumor indications, including lung cancer and gastrointestinal malignancies, a multi-product synergistic strategy is cultivating new growth momentum. Serplulimab (Hetronifly® in Europe) recorded global sales revenue of RMB 0.5975 billion in the first half of 2026. In June, the product received approval in China for the perioperative treatment of gastric cancer through a priority review pathway, becoming the first and only*** anti-PD-1 mAb globally to be approved for this indication and thereby addressing a significant unmet need in this treatment setting. In terms of international expansion, serplulimab has secured marketing approvals in over 50 countries and regions. During the reporting period, it has obtained approvals for three additional first-line indications—non-squamous non-small cell lung cancer (nsqNSCLC), esophageal squamous cell carcinoma (ESCC), and squamous non-small cell lung cancer (sqNSCLC) in the EU—and has been incorporated into the national healthcare or public reimbursement systems of 12 European countries, including the United Kingdom (UK), Germany, Italy, Spain, and Sweden. HANBEITAI (bevacizumab), another key oncology product in the company's portfolio, generated sales revenue of RMB 0.2182 billion in the first half of the year, up 87.6% YoY, with a decision on its Biologics License Application expected in the second half of 2026. Furthermore, HLX903, a third-generation oral EGFR-TKI introduced via a licensing-in arrangement, is expected to receive marketing approval in the first half of 2027 and address targeted treatment needs among patients with EGFR-mutant NSCLC upon approval. In parallel, mature products including HANLIKANG (rituximab) and HANDAYUAN (adalimumab) continued to deliver stable cash flow contributions in the hematology and autoimmune disease therapeutic areas, generating RMB 335.7 million and RMB 30.4 million in sales revenue and licensing income, respectively, in accordance with the relevant collaboration agreements. HLX14 (denosumab), available in two dosage strengths as BILDYOS® (60mg/mL) and BILPREVDA® (120mg/1.7mL), secured regulatory approvals in the U.S. and European Union, and UK during the second half of 2025, and contributed sales revenue and licensing income of RMB 73.1 million in the reporting period. In the first half of 2026, with China as its global headquarters, the company moved swiftly to build out its international proprietary commercialization organization, establishing five core functional pillars—commercial alliance, affiliate commercial, market access and pricing, commercial strategy and operations, and medical affairs—thereby creating a dual-engine model combining in-house commercialization with strategic partnerships. Since the start of 2026, the company has announced three major international strategic collaborations in succession, reinforcing its Globalization 2.0 strategy across multiple fronts: in high-value mature markets, the company entered into an agreement with Eisai Co., Ltd., granting Eisai exclusive commercialization rights for serplulimab in Japan; to accelerate its presence in emerging markets, the company formed a strategic collaboration with Abbott to expand serplulimab's commercial footprint across Asia-Pacific, Africa, Central Asia, and Eastern Europe; and to maximize the global potential of its biosimilar portfolio, the company established a broad-based strategic partnership with Sandoz, covering up to ten biosimilar products, thereby substantially broadening the commercial reach of its pipeline assets across key global markets. Innovation Pipeline Accelerates, Global Biosimilar Expansion Drives Further Value Creation Meanwhile, the company continues to ramp up its innovation efforts, with R&D expenditure reaching RMB 1.4507 billion during the reporting period, representing a 45.7% YoY increase. The company's differentiated innovation pipeline continues to expand, and it has now established multiple technology platforms—next-generation IO, Hanjugator ADC, multi-specific T-cell engager (TCE), and AI—with more than 50 early-stage pipeline molecules in reserve, covering therapeutic areas including oncology, immunology and inflammation, neuroscience, and metabolism diseases. As a potential best-in-class (BIC) broad-spectrum anti-tumor PD-L1 ADC, HLX43 has demonstrated encouraging preliminary efficacy and a favorable safety profile across multiple solid tumors, including NSCLC. Its phase 2 and phase 2/3 international multi-center studies in NSCLC are advancing across regions including China, Europe, the United States, Japan, and Australia. Specifically, the phase 2/3 study in advanced sqNSCLC has received implied approval from Japan's PMDA and has dosed its first patient in China. In addition, the phase 1b/2 study of HLX43 in combination with serplulimab or pimurutamab (HLX07) for the treatment of advanced/metastatic colorectal cancer (mCRC) has also completed first-patient-in dosing in China. To date, the company has initiated more than ten clinical studies of HLX43 as monotherapy or in combination regimens, with over 1,500 patients enrolled globally, continuing to evaluate its broad therapeutic potential across multiple solid tumors. Other key pipeline assets are also advancing efficiently. Among them, dulpatatug* is making steady progress in an international multi-center phase 3 clinical study that features a head-to-head comparison against the current first-line standard of care for HER2-positive gastric cancer. First patient enrollment has been completed across a broad geographic footprint, including China, the U.S., Europe, Japan, Australia, South Korea, and Latin America. Concurrently, a phase 2 study of dulpatatug* for HER2-low breast cancer and a phase 2/3 study of dulpatatug* in combination with the HER2-directed ADC HLX87 for first-line treatment of HER2-positive breast cancer are also advancing steadily. The phase 2/3 clinical trial of pimurutamab in combination with serplulimab and chemotherapy for first-line treatment of advanced sqNSCLC has completed clinical trial notification with Australia's Therapeutic Goods Administration (TGA) and has reached first patient dosing in China. Meanwhile, next-generation innovative molecules with BIC/FIC potential, including HLX3901 (DLL3 x DLL3 x CD3 x CD28 tetra-specific TCE), HLX3902 (STEAP1 x CD3 x CD28 tri-specific TCE), HLX48( c-MET x EGFR bispecific ADC) , HLX97 (small-molecule KAT6A/B inhibitor) and HLX316 (B7-H3 sialidase fusion protein), are advancing efficiently in parallel with high efficiency, continuously strengthening the company's long-term growth pipeline. Furthermore, the Company will accelerate the development of early-stage assets, including HLX105 (PD-1×IL-2v fusion protein), HLX109 (IL-1R3 mAb), HLX49 (HER2 biparatopic ADC), and HLX403 (CDH17 ADC), with plans to submit Investigational New Drug (IND) applications for these candidates in the second half of 2026. By leveraging its robust CMC capabilities, the company is further increasing the probability of success in developing complex molecules, thereby enhancing overall drug developability. In addition, the company is proactively applying AI-powered approaches to the R&D of innovative molecules such as HLX203, with the goal of continuously improving the efficiency of drug discovery and development. In line with its Globalization 2.0 strategy, the company remains committed to unlocking the global potential of its biosimilar portfolio through a parallel China-U.S. development and registration pathway. HLX05-N (proposed cetuximab biosimilar) and HLX18 (proposed nivolumab biosimilar) have each received clinical trial authorizations from regulators in both China and the U.S., and dosed their first patient. In addition, HLX13 (proposed ipilimumab biosimilar), HLX15 (proposed daratumumab biosimilar), and HLX17 (proposed pembrolizumab biosimilar) have all achieved first subject dosing in both China and the U.S. The company is continuously accumulating global clinical data for these assets, laying the foundation for subsequent regulatory development and commercialization. Globalization 2.0 in Place, Integrated End-to-End Capabilities Reinforce the C-MNC Ambition Henlius has established a comprehensive and systematic capability for global expansion spanning R&D, clinical development, regulatory affairs, manufacturing, and commercialization, steadily advancing its Globalization 2.0 strategy and marking the initial formation of its "C-MNC" model—a China-headquartered multinational biopharmaceutical company. On clinical development and regulatory affairs, the company has established dedicated in-house teams in Europe, the U.S., Japan, and Australia, with clinical trials concurrently ongoing in nearly 30 countries and regions, in partnership with over 1,000 clinical research centers. During the reporting period, the company received 32 new clinical trial approvals and 25 marketing authorizations worldwide, covering nearly 50 countries and regions. On manufacturing and supply, its delivery capabilities continued to strengthen. To date, the company has completed more than 1,400 GMP commercial production batches and successfully passed over 100 on-site inspections and audits conducted by regulatory authorities worldwide and international collaborators, with a 100% pass rate. During the period, it also completed 9 first commercial shipments and 18 batch shipments to ex-China markets. In the first half of 2026, the clinical value of Henlius' core innovative pipeline continued to emerge, while international regulatory and commercialization milestones were achieved in succession. Synergies across global R&D, manufacturing, and commercialization were further strengthened, collectively demonstrating that the company's Globalization 2.0 strategy has entered a critical phase of accelerated validation. Looking toward 2030, Henlius will continue to pursue innovation-driven and global growth, accelerating its journey toward becoming a C-MNC. The company aims to bring 10 new products to markets worldwide, with over 5 expected to reach European and U.S. markets, and to grow into a globally influential innovative biopharmaceutical company. * Status: pINN ** Received U.S. FDA approval in November 2025, EC approval in April 2026, and NMPA approval in May 2026. As of August 2026, it remains the only one. *** In June 2026, serplulimab received NMPA approval as the world's first anti-PD-1 mAb for perioperative gastric cancer treatment. As of August 2026, it remains the only one. About Henlius Shanghai Henlius Biotech, Inc. (2696.HK) is a global, innovation-driven biopharmaceutical company committed to delivering high-quality, affordable biologic therapies to patients worldwide. The Company focuses on major disease areas including oncology, autoimmune diseases, and ophthalmic diseases. Founded in 2010, Henlius has established an integrated, end-to-end biopharmaceutical platform encompassing global R&D, clinical operations, regulatory affairs, manufacturing, and commercialisation. The Company employs nearly 4,000 people globally and operates across multiple regions, including China, the United States, and Japan. Leveraging the stable cash flow generated from its biosimilar portfolio to support innovation, Henlius is steadily advancing into its "Globalisation 2.0" phase, building a scalable and sustainable global growth model. Up to date, Henlius has achieved regulatory approvals for 10 products across over 60 countries and regions worldwide, including eight approvals in China. The Company has also reached multiple milestones in major biopharmaceutical markets, with four products approved by the U.S. Food and Drug Administration (FDA) and five products approved by the European Commission (EC), reflecting its globally aligned R&D capabilities, quality systems, and manufacturing standards. Driven by innovation, Henlius has built a diversified, platform-based technology ecosystem through coordinated R&D efforts across Shanghai, the United States, and other regions. Its innovation platforms span immune checkpoint inhibitors, immune cell engager technologies (including multispecific T cell engagers), antibody-drug conjugates (ADCs), and AI-enabled early discovery platforms. The Company currently has more than 50 early-stage innovative assets, approximately 70% of which are expected to be best-in-class, with over 30 clinical trials ongoing globally. Henlius' core product, serplulimab (trade name: Hetronifly® in Europe), is the world's first anti–PD-1 mAb approved for first-line treatment of small cell lung cancer and for perioperative gastric cancer. Up to date, it has been approved in 50 markets worldwide with an accelerated globalisation process. In parallel, multiple high-potential innovative assets—including the PD-L1 ADC HLX43 and the novel epitope anti-HER2 mAb dulpatatug (HLX22) — are advancing through global pivotal clinical development. Supported by a biologics manufacturing network with a total capacity of 84,000L and GMP certifications from regulatory authorities in China, Europe, and the United States, Henlius has established a stable global supply system serving six continents. Guided by a patient-centred mission, Henlius remains focused on addressing unmet medical needs and translating scientific innovation into meaningful clinical value and patient access, contributing sustainably to the global biopharmaceutical ecosystem. To learn more about Henlius, visit and connect with us on LinkedIn at . SOURCE Henlius 21% more press release views with Request a Demo