An Open Label, Randomized, Multicenter Study Comparing the Efficacy and Safety of the Combination of Lasofoxifene and Abemaciclib to the Combination of Fulvestrant and Abemaciclib for the Treatment of Pre- and Postmenopausal Women and Men With Locally Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation

The goal of this clinical trial is to assess the efficacy, safety and tolerability of the combination of lasofoxifene and abemaciclib compared to fulvestrant and abemaciclib for the treatment of pre- and postmenopausal women and men who have previously received ribociclib or palbociclib-based treatment and have locally advanced or metastatic estrogen receptor positive (ER+)/human epidermal growth factor 2 negative (HER2-) breast cancer with an estrogen receptor 1 (ESR1) mutation.
The main question the study aims to answer is:
• To compare the efficacy of the combination of lasofoxifene and abemaciclib with that of fulvestrant and abemaciclib Participants will receive either receive 5 mg/d of oral lasofoxifene plus oral abemaciclib 150 mg twice a day or the combination of fulvestrant 500 mg intramuscular (IM) on Days 1, 15, and 29 and then once monthly thereafter plus oral abemaciclib 150 mg twice a day.

开始日期2023-10-31

申办/合作机构

Sermonix Pharmaceuticals LLC初创企业

100 项与 Lasofoxifene Tartrate 相关的临床结果

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100 项与 Lasofoxifene Tartrate 相关的转化医学

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100 项与 Lasofoxifene Tartrate 相关的专利（医药）

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项与 Lasofoxifene Tartrate 相关的文献（医药）

2024-12-12·JOURNAL OF MEDICINAL CHEMISTRY

Discovery of Thiochroman Derivatives as Potent, Oral Selective Estrogen Receptor Degraders and Antagonists for the Treatment of Endocrine-Resistant Breast Cancer

Article

作者: Hu, Wenhao ; Yang, Yushe ; Zhang, Dan ; Meng, Xin ; Leng, Xin-Yu ; Lu, Zhengyu ; Lei, Xiang ; Sun, Lulu ; He, Yongqi ; Kong, Deyu

Selective estrogen receptor degraders (SERDs) deplete the ER signaling pathway via antagonism and degradation of ERα and represent a promising strategy to tackle endocrine resistance. Here, we report a new class of SERDs by pharmacological evolution of a selective estrogen receptor modulator, lasofoxifene. The structure-activity relationship study and efforts to circumvent the issue of human ether-a-go-go-related gene led to the identification of compounds 51. This bifunctional compound displayed broad activity across a vast array of cell backgrounds and was capable of effectively degrading and antagonizing wild-type ERα and clinically relevant ERα mutants. 51 exhibited favorable pharmacokinetic properties and good brain penetration, with a brain/plasma ratio of 3.05, and significantly suppressed the growth of tumor in a tamoxifen-resistant MCF-7 Tam1 xenograft model. Overall, the study demonstrates 51 as a highly potent, oral, and brain penetrant ER degrader and pure antagonist, showing a good potential in overcoming endocrine resistance.

2024-11-14·JOURNAL OF MEDICINAL CHEMISTRY

Discovery of ERD-1233 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader for the Treatment of ER+ Human Breast Cancer

Article

作者: Lu, Jianfeng ; Wu, Dimin ; Wen, Bo ; Rae, James M. ; Acharyya, Ranjan Kumar ; Wang, Yu ; Gersch, Christina L. ; Jiang, Wei ; Sarkari, Farzad ; Wu, WenXue ; Bai, Longchuan ; Sui, Zhihua ; McEachern, Donna ; Rej, Rohan Kalyan ; Wang, Shaomeng ; Hu, Biao ; Metwally, Hoda ; Tošović, Jelena ; Chen, Zhixiang ; Zhang, Weihong ; Sun, Duxin ; Priestley, E. Scott ; Xu, Guozhang

Despite the development of highly effective therapies for the treatment of estrogen receptor α (ERα)-positive human breast cancer, clinical resistance to current therapies requires the development of novel therapeutic strategies. Herein, we report the discovery of ERD-1233 as a potent and orally efficacious ERα degrader designed using the PROTAC technology. ERD-1233 was developed based on Lasofoxifene as the ER binding moiety and a novel cereblon ligand through extensive optimization of the linker. ERD-1233 potently and effectively reduces the ERα protein in vitro and achieves excellent oral bioavailability in mice and rats. Oral administration of ERD-1233 effectively reduces ER protein in ER+ tumors and achieves tumor regression in the ER wild-type MCF-7 xenograft tumor model and strong tumor growth inhibition in the ESR1^Y537S mutated model in mice. Our data demonstrate that ERD-1233 is a promising ER PROTAC degrader for extensive evaluation as a new therapy for the treatment of ER+ human breast cancer.

2024-06-01·Menopause (New York, N.Y.)

Oral lasofoxifene's effects on moderate to severe vaginal atrophy in postmenopausal women: two phase 3, randomized, controlled trials

Article

作者: Komm, Barry S. ; Simon, James A. ; Portman, David J. ; Jenkins, Simon N. ; Kagan, Risa ; Goldstein, Steven R.

Abstract:

Objective:

The aim of this study was to demonstrate whether lasofoxifene improves vaginal signs/symptoms of genitourinary syndrome of menopause.

Methods:

Two identical, phase 3 trials randomized postmenopausal women with moderate to severe vaginal symptoms to oral lasofoxifene 0.25 or 0.5 mg/d, or placebo, for 12 week. Changes from baseline to week 12 in most bothersome symptom, vaginal pH, and percentages of vaginal parabasal and superficial cells were evaluated. These coprimary endpoints were analyzed using analysis of covariance, except superficial cells, which were analyzed by the nonparametric, rank-based Kruskal-Wallis test.

Results:

The two studies enrolled 444 and 445 women (mean age, ~60 y), respectively. Coprimary endpoints at week 12 improved with lasofoxifene 0.25 and 0.5 mg/d greater than with placebo (P < 0.0125 for all). Study 1: most bothersome symptom (least square mean difference from placebo: −0.4 and −0.5 for 0.25 and 0.5 mg/d, respectively), vaginal pH (−0.65, −0.58), and vaginal superficial (5.2%, 5.4%), and parabasal (−39.9%, −34.9%) cells; study 2: most bothersome symptom (−0.4, −0.5), vaginal pH (−0.57, −0.67), and vaginal superficial (3.5%, 2.2%) and parabasal (−34.1%, −33.5%) cells. Some improvements occurred as early as week 2. Most treatment-emergent adverse events were mild or moderate and hot flushes were most frequently reported (lasofoxifene vs placebo: 13%–23% vs 9%–11%). Serious adverse events were infrequent and no deaths occurred.

Conclusions:

In two phase 3 trials, oral lasofoxifene 0.25 and 0.5 mg/d provided significant and clinically meaningful improvements in vaginal signs/symptoms with a favorable safety profile, suggesting beneficial effects of lasofoxifene on genitourinary syndrome of menopause.

项与 Lasofoxifene Tartrate 相关的新闻（医药）

2024-12-24

·复宏汉霖

产品速递 | HLX78治疗ESR1突变ER+/HER2-乳腺癌的国际多中心III期临床研究完成中国首例患者给药

2024年12月24日，复宏汉霖（2696.HK）宣布，HLX78（lasofoxifene，拉索昔芬片）联合阿贝西利（CDK4/6 抑制剂）用于治疗既往接受过芳香化酶抑制剂（AI）治疗、雌激素受体α基因（ESR1）突变的雌激素受体阳性（ER+）、人表皮生长因子受体2阴性（HER2-）局部晚期或转移性乳腺癌患者的国际多中心III期临床研究（ELAINE-3研究，NCT05696626）完成中国首例患者给药。目前，该研究正同步于美国、加拿大、欧盟等国家和地区招募受试者。乳腺癌是全球发病率第二高的癌症，据GLOBOCAN数据显示，2022年全球乳腺癌新发病例约230万，中国乳腺癌新发病例逾35.7万[1]。雌激素受体（Estrogen receptor，ER）阳性乳腺癌占乳腺癌总数的60%-70%[2]。内分泌治疗是ER+乳腺癌的主要治疗手段，其中最常使用的芳香化酶抑制剂（aromatase inhibitor，AI）已被美国国立综合癌症网络（NCCN）和中国临床肿瘤学会（CSCO）等指南推荐成为ER+/HER2-乳腺癌患者的辅助及一线标准治疗方法[3,4]，然而几乎所有经AI治疗的患者会产生原发性或获得性耐药[5]，其中ESR1获得性突变最为常见，高达40%，被认为是内分泌治疗重要耐药机制[6]，目前针对ESR1突变的ER+/HER2-乳腺癌治疗方案有限，存在较大治疗需求。 HLX78是公司自Sermonix Pharmaceuticals, Inc. 许可引进的一款临床在研口服选择性雌激素受体调节剂 (selective estrogen receptor modulator，SERM) ，在ESR1突变的ER+/HER2-转移性乳腺癌的治疗中具有强大的靶向治疗作用。在已完成的两项II期临床研究（ELAINE-1和ELAINE-2研究）中，针对ESR1突变肿瘤，lasofoxifene作为单药或联合CDK4/6抑制剂使用均展现出抗肿瘤活性[7-8]。从lasofoxifene对雌激素受体突变的生物利用度和药物活性来看，该候选药物有望为内分泌治疗后产生获得性耐药ESR1突变的患者群体带来希望，并有望在晚期ER+乳腺癌的精准医学治疗中发挥关键作用。未来，公司也将继续以患者为中心，聚焦未满足的临床需求，垂直深耕乳腺癌领域领域，加快推进该项国际多中心临床试验进展，并以不断的创新与突破为更多病患带来更多质高价优的治疗方案。【参考文献】 [1] Bray F, Laversanne M, Sung H, et al. CA Cancer J Clin. 2024: 1-35. [2] Ignatiadis M, Sotiriou C. Luminal breast cancer: from biology to treatment[J]. Nat Rev Clin Oncol, 2013, 10(9): 494-506. doi: 10.1038/nrclinonc.2013.124. [3] Chinese Society of Clinical Oncology (CSCO) Breast Cancer guidelines 2023. [4] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.5.2023 [5] Rozeboom B, Dey N, De P. ER+ metastatic breast cancer: past, present, and a prescription for an apoptosis-targeted future. Am J Cancer Res. 2019;9(12):2821-2831. Published 2019 Dec 1. [6] Spoerke JM, Gendreau S, Walter K, et al. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nat Commun. 2016;7:11579. Published 2016 May 13. doi:10.1038/ncomms11579 [7] Goetz MP, Bagegni NA, Batist G, et al. Lasofoxifene versus fulvestrant for ER+/HER2- metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial. Ann Oncol. 2023;34(12):1141-1151. doi:10.1016/j.annonc.2023.09.3104 [8] S. Damodaran, C.C. O’Sullivan, A. Elkhanany, I.C. Anderson, M. Barve, S. Blau, M.A. Cherian, J.A. Peguero, M.P. Goetz, P.V. Plourde, D.J. Portman, H.C.F. Moore, Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2− breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2. Ann Oncol. 2023;34(12):1131-1140. doi:10.1016/j.annonc.2023.09.3103. 关于ELAINE-3研究本研究是一项开放标签、随机、对照、多中心的III期研究，旨在比较HLX78联合阿贝西利和氟维司群联合阿贝西利治疗ER+/HER2–的局部晚期或转移性乳腺癌的男性和绝经前/后女性患者的有效性、安全性和耐受性，患者在接受芳香化酶抑制剂联合哌柏西利或瑞波西利作为一线内分泌治疗转移性疾病后出现疾病进展且携带ESR1基因突变。符合条件的受试者将以1:1的比例随机分配，接受HLX78（每日5毫克，口服）联合阿贝西利或氟维司群联合阿贝西利。本研究的主要目标是评估各治疗组的无进展生存期（PFS），评估采用盲态独立中心评估（BICR）基于实体瘤评价标准（RECIST）1.1进行。次要目标为评估其他终点，包括客观缓解率、总生存期、临床获益率、缓解持续时间、至缓解时间、至细胞毒性化疗时间、生活质量和安全性。关于复宏汉霖复宏汉霖（2696.HK）是一家国际化的创新生物制药公司，致力于为全球患者提供可负担的高品质生物药，产品覆盖肿瘤、自身免疫疾病、眼科疾病等领域，已有6款产品在中国获批上市，3款产品在国际获批上市，25项适应症获批，4个上市申请分别获中国药监局、美国FDA和欧盟EMA受理。自2010年成立以来，复宏汉霖已建成一体化生物制药平台，高效及创新的自主核心能力贯穿研发、生产及商业运营全产业链。公司已建立完善高效的全球创新中心，按照国际药品生产质量管理规范（GMP）标准进行生产和质量管控，不断夯实一体化综合生产平台，其中，公司商业化生产基地已相继获得中国、欧盟和美国GMP认证。复宏汉霖前瞻性布局了一个多元化、高质量的产品管线，涵盖50多个分子，并全面推进基于自有抗PD-1单抗H药汉斯状®的肿瘤免疫联合疗法。截至目前，公司已获批上市产品包括国内首个生物类似药汉利康®（利妥昔单抗）、自主研发的中美欧三地获批单抗生物类似药汉曲优®（曲妥珠单抗，美国商品名：HERCESSI™，欧洲商品名：Zercepac®）、汉达远®（阿达木单抗）、汉贝泰®（贝伐珠单抗）以及汉奈佳®（奈拉替尼），此外，创新产品汉斯状®（斯鲁利单抗）已获批用于治疗微卫星高度不稳定（MSI-H）实体瘤、鳞状非小细胞肺癌、广泛期小细胞肺癌、食管鳞状细胞癌和非鳞状非小细胞肺癌，并成为全球首个获批一线治疗小细胞肺癌的抗PD-1单抗。公司亦同步就16个产品在全球范围内开展30多项临床试验，对外授权全面覆盖欧美主流生物药市场和众多新兴市场。 First Chinese Patient Dosed for Phase 3 MRCT on ER+/HER2- Breast Cancer of HLX78 Shanghai, China, December 24, 2024 - Shanghai Henlius Biotech, Inc. (2696.HK) announced that the first patient in China has been dosed in the international multi-centre Phase 3 clinical trial (ELAINE-3, NCT05696626) of HLX78 (oral lasofoxifene) in combination with abemaciclib (a CDK4/6 inhibitor) in patients with locally advanced or metastatic estrogen receptor-positive (ER+)/Human epidermal growth factor receptor 2-negative (HER2-) breast cancer who have disease progression on an aromatase inhibitor (AI) in combination with CDK4/6 inhibitor and have an estrogen receptor α gene (ESR1) mutation. ELAINE-3 is currently recruiting subjects in the United States, Canada, the European Union, in addition to other countries and regions. Breast cancer is the second most diagnosed cancer in the world, according to GLOBOCAN 2022. There were around 2.3 million new cases of breast cancer in 2022 globally, including more than 357,000 in China.[1] ER+ breast cancer comprises 60-70% of all breast cancers.[2] Endocrine therapy remains the mainstay treatment for ER+ breast cancer and the most widely used class of aromatase inhibitor (AI) has been recommended by the National Comprehensive Cancer Network (NCCN) and Chinese Society of Clinical Oncology (CSCO) guidelines to be the adjuvant and first-line standard of care for patients with ER+/HER2- breast cancer.[3,4] However, almost all patients treated with AIs in the advanced setting develop resistance[5], with ESR1 mutations being one of the most prevalent alterations, present in up to 40% of patients and a significant mechanism of resistance to endocrine therapy[6]. Currently, there are limited treatment options for ER+/HER2- breast cancer with ESR1 mutations, and thus a large clinical need exists. HLX78 (lasofoxifene) is an oral selective estrogen receptor modulator (SERM) licensed by Henlius for Asia from Sermonix Pharmaceuticals, Inc. It has demonstrated robust target engagement in ER+/HER2- metastatic breast cancer, particularly in the presence of ESR1 mutations. In two completed Phase 2 clinal studies (ELAINE-1 and ELAINE-2), lasofoxifene has demonstrated anti-tumour activity against tumours with ESR1 mutations as monotherapy and in combination with a CDK4/6 inhibitor.[7,8] Lasofoxifene’s bioavailability and activity in mutations of the estrogen receptor could potentially hold promise for patients who have acquired endocrine resistance due to ESR1 mutations, and, if approved, play a critical role in the precision medicine treatment of advanced ER+ breast cancer. In the future, Henlius will continue to adopt a patient-centric approach, focusing on unmet clinical needs. The company will delve deeply into the breast cancer field and expedite the development of the international multi-center clinical trial ELAINE-3, aiming to bring more high-quality, affordable, and innovative treatments to patients worldwide. About ELAINE-3 This is a phase 3, open label, controlled, randomized, multicenter study comparing the efficacy, safety, and tolerability of the combination of lasofoxifene and abemaciclib with that of fulvestrant and abemaciclib for the treatment of men and pre- and postmenopausal women with locally advanced or metastatic ER+/HER2− breast cancer who have disease progression on an aromatase inhibitor in combination with either palbociclib or ribociclib as their first hormonal treatment for metastatic disease and who have an ESR1 mutation. Eligible participants will be randomized at 1:1 to receive lasofoxifene (5 mg/day, oral administration) combined with abemaciclib or fulvestrant combined with abemaciclib. The primary objective of this study is to evaluate the progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors 1.1 as determined by blinded independent central review of each treatment arm. The secondary objectives are to evaluate other endpoints, including objective response rate, overall survival, clinical benefit rate, duration of response, time to response, time to cytotoxic chemotherapy, quality of life, and safety. About Henlius Henlius (2696.HK) is a global biopharmaceutical company with the vision to offer high-quality, affordable and innovative biologic medicines for patients worldwide with a focus on oncology, autoimmune diseases and ophthalmic diseases. Up to date, 6 products have been launched in China, 3 have been approved for marketing in overseas markets, 25 indications are approved worldwide, and 4 marketing applications have been accepted for review in China, the U.S. and the EU, respectively. Since its inception in 2010, Henlius has built an integrated biopharmaceutical platform with core capabilities of high-efficiency and innovation embedded throughout the whole product life cycle including R&D, manufacturing and commercialization. It has established global innovation centre and Shanghai-based commercial manufacturing facilities certificated by China, the EU and U.S. GMP. Henlius has pro-actively built a diversified and high-quality product pipeline covering over 50 molecules and has continued to explore immuno-oncology combination therapies with proprietary HANSIZHUANG (anti-PD-1 mAb) as the backbone. Apart from the launched products HANLIKANG (rituximab), the first China-developed biosimilar, HANQUYOU (trastuzumab, trade name: HERCESSI™ in the U.S., Zercepac® in Europe), a China-developed mAb biosimilar approved in China, Europe and U.S., HANDAYUAN (adalimumab) and HANBEITAI (bevacizumab), the innovative product HANSIZHUANG has been approved by the NMPA for the treatment of MSI-H solid tumors, squamous non-small cell lung cancer (sqNSCLC), extensive-stage small cell lung cancer (ES-SCLC), esophageal squamous cell carcinoma (ESCC) and non-small cell lung cancer (nsNSCLC), making it the world’s first anti-PD-1 mAb for the first-line treatment of SCLC. What’s more, Henlius has conducted over 30 clinical studies for 16 products, expanding its presence in major markets as well as emerging markets. 联系方式媒体：PR@Henlius.com 投资者：IR@Henlius.com 喜欢本文内容点击下方按钮·分享 ·收藏 ·点赞 ·在看

CSCO会议临床3期临床1期临床2期

2024-11-08

·精准药物

【JMC】王少萌等报道一种口服有效的雌激素受体降解剂ERD-1233

近日，来自美国密歇根大学研的王少萌教授在Journal of Medicinal Chemistry上发表了一篇题为《Discovery of ERD-1233 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader for the Treatment of ER+ Human Breast Cancer》的文章。他们研究揭示了一种新型的雌激素受体α（ERα）降解剂ERD-1233的设计、合成和活性评估。ERD-1233基于PROTAC技术，利用Lasofoxifene作为ER结合基团和新型CRBN配体，通过多样的链接子优化开发而成。该化合物在体外实验中显示出强大的ERα蛋白降解能力，并在小鼠和大鼠中实现了卓越的口服生物利用度。此外，ERD-1233在ER+肿瘤模型中有效降低了ER蛋白表达，并在ER野生型MCF-7异种移植瘤模型中实现了肿瘤消退，同时对ESR1Y537S突变模型也显示出强大的肿瘤生长抑制效果。这些数据表明，ERD-1233作为一种有前景的ER PROTAC降解剂，值得进一步评估，以作为ER+人类乳腺癌治疗的新疗法。 ERα是大多数人类乳腺癌中过表达的主要治疗靶点，目前的治疗包括芳香酶抑制剂（AIs）、选择性雌激素受体调节剂（SERMs）和选择性雌激素受体降解剂（SERDs）。然而，这些疗法存在局限性，如SERMs的临床抗性、SERDs的给药途径限制（如需要肌肉注射）以及口服SERD分子的内在和获得性抗性问题。图1 高亲和力 CRBN 配体的设计研究人员聚焦于设计新型的Cereblon(CRBN)配体，这些配体具有高亲和力并且具有良好的药物样性质。研究人员以已知的CRBN配体Thalidomide及其衍生物Lenalidomide和Pomalidomide为起点，通过化学修饰来提高其与CRBN的结合亲和力。研究人员首先测试了Thalidomide与CRBN的结合活性，发现其IC50值为3.2 μM。通过结构优化，Pomalidomide和4-羟基Thalidomide显示出比Thalidomide更高的结合亲和力。进一步的改造，如去除一个羰基团，生成了Lenalidomide和4-羟基Lenalidomide，它们的CRBN结合IC50值分别为1.7和0.7 μM。基于4-羟基Lenalidomide，研究人员设计了新的配体8和9，通过在苯环的C-5位置引入哌嗪并使羟基与哌嗪环发生环化。配体8（RR-11055）显示出0.38 μM的IC50值，比配体9（RR-11163）的1.42 μM IC50值更优，比Lenalidomide和Thalidomide分别提高了3.7倍和8.6倍。此外，RR-11055在人、小鼠和大鼠的血浆和微粒体中显示出优异的稳定性。基于这些结果，研究人员选择了RR-11055（8）作为设计新型ER PROTAC降解剂的Cereblon配体。图2 设计 ER PROTAC 降解剂基于前期工作积累，其中使用了不同的ER配体来设计口服有效的ER PROTAC降解剂。他们发现，使用Lasofoxifene作为ER配体和TX-16作为CRBN配体的ERD-2217具有优秀的药代动力学特性，尽管其诱导ER降解的效力不如ARV-471。由于RR-11055（8）显示出比TX-16更高的CRBN结合亲和力，研究人员推测使用这个新的CRBN配体可能会发现更有效和口服可用的ER降解剂。在设计过程中，研究人员发现在链接子中引入酰胺基团可以提高ER降解效力。因此，他们合成了一系列具有柔性链接子和酰胺基团的降解剂，发现这些化合物的DC50值在0.1-0.3 nM之间，而Dmax值从56%提高到89%。接下来，他们设计并合成了一系列使用刚性链接子的降解剂，这些降解剂在诱导ER降解方面表现出更高的效力和效率。最终，研究人员发现ERD-1233（33）作为候选分子。图3 药代动力学性质研究人员对ERD-1233在小鼠和大鼠中的药代动力学特性进行了全面评估。结果显示，ERD-1233在小鼠体内表现出缓慢的清除率和适度的分布容积，并且在静脉给药后，通过口服给药在小鼠中实现了优秀的口服暴露，Cmax达到926 ng/mL，AUC0-24h为7901 h·ng/mL，整体口服生物利用度为50%。在大鼠中，ERD-1233也显示出缓慢的清除率和适度的分布容积，并且口服给药后达到了优秀的口服暴露，Cmax为1283 ng/mL，AUC0-24h为12747 h·ng/mL，整体口服生物利用度为37%。此外，与ARV-471相比，ERD-1233在小鼠和大鼠中分别实现了11.5倍和52倍更高的口服血浆暴露量。图4 稳定性和安全性评价研究人员对ERD-1233的血浆和代谢稳定性、对hERG的抑制作用以及对细胞色素P450（CYP）酶系的抑制作用进行了评估。结果显示，ERD-1233在血浆和微粒体中表现出优异的稳定性，其半衰期（T1/2）在人、狗、猴、大鼠和小鼠中均超过240分钟。此外，ERD-1233对hERG通道没有显著抑制作用，IC50值大于30 μM，表明其心脏安全性可能较高。在CYP酶系方面，ERD-1233对所有测试的CYP同工酶（包括1A2、2C8、2C9、2C19、2D6和3A4）均无显著抑制作用，最高测试浓度为10 μM。这些数据表明ERD-1233具有良好的药代动力学特性和较低的心脏及肝脏毒性风险，为其作为潜在的临床候选药物提供了有力支持。图5 体外降解活性验证 Western blot分析了ERD-1233在ER阳性的MCF-7和T47D乳腺癌细胞系中对雌激素受体α（ERα）蛋白水平的影响。结果显示，ERD-1233能够在剂量依赖性的方式中有效降低这两种细胞系中的ERα蛋白水平。具体来说，ERD-1233在3-10 nM的浓度下实现了约1 nM的DC50值（即减少ERα蛋白50%所需的浓度）和约75%的最大降解效率（Dmax）。这些数据证实了ERD-1233作为一种有效的ERα降解剂，在体外实验中具有显著的生物学活性。图6 体内活性评价。研究人员评估了ERD-1233在ER野生型MCF-7和ESR1Y537S突变型MCF-7乳腺癌异种移植小鼠模型中的抗肿瘤效果。研究发现，ERD-1233在ER野生型MCF-7肿瘤模型中以10 mg/kg和20 mg/kg的剂量通过口服给药，能够实现34%和68%的肿瘤回归，显示出比ARV-471（30 mg/kg剂量下实现32%肿瘤回归）更强的疗效。在ESR1Y537S突变型MCF-7模型中，ERD-1233以10 mg/kg的剂量能够有效抑制肿瘤生长，并且在提高剂量至30 mg/kg后能够实现肿瘤回归。综上所述，这篇文献报道了一种新的雌激素受体α（ERα）降解剂ERD-1233的研究。ERD-1233的设计基于Lasofoxifene作为ER结合基团和新设计的Cereblon配体RR-11055（8），通过优化链接子来提高其降解活性。研究发现，ERD-1233在体外实验中能有效降低ERα蛋白水平，并且在小鼠和大鼠中显示出良好的口服生物利用度。此外，ERD-1233在ER野生型和ESR1Y537S突变型MCF-7乳腺癌异种移植瘤模型中均显示出显著的抗肿瘤效果。作者：LGC 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

临床结果蛋白降解靶向嵌合体

2024-10-14

·复星医药

复宏汉霖亮相CPHI Worldwide 2024，拓展国际合作新机遇

10月8-10日，2024年世界制药原料展（CPHI Worldwide）在意大利米兰国际展览中心（Fiera Milano, Italy）举行。复宏汉霖以“The partner of choice”为主题，展示了公司6款已上市产品，丰富的在研生物药产品管线以及国际化的研产销一体化生物制药平台。展会期间，复宏汉霖吸引了大量专业观众驻足和交流，并参与了250多场会面。作为全球最大的制药行业专业展览会，CPHI Worldwide迄今已经成功举办35届。本次展会期间，在“The Partner of Choice”为主题的生物药国际化经验交流会上，复宏汉霖药政事务部副总经理严皓珩从药政监管角度就中国生物类似药加速国际化进程的实践经验发表主题演讲。随后，公司总裁黄玮、高级副总裁兼首席商务发展官曹平、高级副总裁兼首席技术官许胜昌、严皓珩等嘉宾共同参与了以“Innovation Spirit and Partnership Philosophy at Henlius”为主题的专题讨论，现场反应热烈，多位合作伙伴到场交流互动。滑动查看图片复宏汉霖高级副总裁、首席商务发展官曹平女士： CPHI Worldwide汇集了全球制药行业的领先企业和专业人士。在这里，我们不仅能够深入探讨行业最前沿的技术动态，还能够与行业专家与同业广泛交流，分享彼此的成功经验与实践成果。更重要的是，这为复宏汉霖提供了拓展全球合作网络的绝佳机会，帮助我们发现更多潜在的合作伙伴。通过深化国际合作，我们有信心继续推进公司在生物制药领域的创新举措，努力为全球患者提供高质量且可负担的创新药物。本次展会期间，复宏汉霖于14A20展台展示了丰富的产品管线，包括中国首个生物类似药汉利康®（利妥昔单抗）、中美欧三地获批的单抗生物类似药汉曲优®（曲妥珠单抗，美国商品名：HERCESSI™，欧洲商品名Zercepac®）和全球首个获批一线治疗小细胞肺癌的抗PD-1单抗汉斯状®（斯鲁利单抗）等。其中，汉曲优®作为中国单抗生物类似药的“出海先驱”，已在全球49个国家和地区获批，为获批上市国家和地区最多的国产单抗生物类似药，累计惠及超过21万名患者。创新产品汉斯状®（斯鲁利单抗）已获批用于治疗微卫星高度不稳定（MSI-H）实体瘤、鳞状非小细胞肺癌、广泛期小细胞肺癌和食管鳞状细胞癌，并于印尼、泰国、柬埔寨等东南亚国家获批，累计惠及逾8万名患者，近期亦获得欧盟委员会积极意见，有望进一步推动全球更多患者获益。滑动查看图片依托商业合作伙伴丰富的商业化经验，复宏汉霖不断加快产品在全球主流生物药市场和新兴国家市场的布局。2024年，公司与Sermonix达成亚洲区域合作，共同推进乳腺癌新型内分泌疗法HLX78（拉索昔芬）的临床阶段研发；此外，公司还与甫康药业合作，推动汉奈佳®（奈拉替尼）的商业化进程。近日，汉奈佳®的首批处方已在全国落地，标志着该药物进入临床应用并加速其商业化步伐。公司亦携手Accord、Eurofarma、KGbio、Organon等国际合作伙伴加速推进更多产品在全球的上市注册进程，共同助力中国生物医药创新与全球化发展。展望未来，复宏汉霖将继续以临床需求为导向，深耕肿瘤、自身免疫性疾病等领域，深化产品创新、市场拓展和国际合作，夯实国际化的“研产销一体”能力，进一步推动中国生物医药行业的创新成果走向国际化，为全球更多患者带来福音。关于复宏汉霖复宏汉霖（2696.HK）是一家国际化的创新生物制药公司，致力于为全球患者提供可负担的高品质生物药，产品覆盖肿瘤、自身免疫疾病、眼科疾病等领域，已有6款产品在中国获批上市，3款产品在国际获批上市，24项适应症获批，3个上市申请分别获中国药监局和欧盟EMA受理。自2010年成立以来，复宏汉霖已建成一体化生物制药平台，高效及创新的自主核心能力贯穿研发、生产及商业运营全产业链。公司已建立完善高效的全球创新中心，按照国际药品生产质量管理规范（GMP）标准进行生产和质量管控，不断夯实一体化综合生产平台，其中，公司商业化生产基地已相继获得中国、欧盟和美国GMP认证。复宏汉霖前瞻性布局了一个多元化、高质量的产品管线，涵盖50多个分子，并全面推进基于自有抗PD-1单抗H药汉斯状®的肿瘤免疫联合疗法。截至目前，公司已获批上市产品包括国内首个生物类似药汉利康®（利妥昔单抗）、自主研发的中美欧三地获批单抗生物类似药汉曲优®（曲妥珠单抗，美国商品名：HERCESSI™，欧洲商品名：Zercepac®）、汉达远®（阿达木单抗）、汉贝泰®（贝伐珠单抗）以及汉奈佳®（奈拉替尼），此外，创新产品汉斯状®（斯鲁利单抗）已获批用于治疗微卫星高度不稳定（MSI-H）实体瘤、鳞状非小细胞肺癌、广泛期小细胞肺癌和食管鳞状细胞癌，并成为全球首个获批一线治疗小细胞肺癌的抗PD-1单抗。公司亦同步就16个产品在全球范围内开展30多项临床试验，对外授权全面覆盖欧美主流生物药市场和众多新兴市场。 Henlius Shines at CPHI Worldwide 2024, Expanding New Opportunities for International Collaboration From October 8 to 10, the CPHI Worldwide 2024 was held at Fiera Milano in Italy. With the theme of "The Partner of Choice", Henlius showcased 6 launched products, its robust biologic pipeline and integrated global biopharmaceutical platform. Henlius drew a large crowd at the booth, and concluded the conference with over 250 meetings. As the largest professional exhibition in the global pharmaceutical industry, CPHI Worldwide has successfully held 35 editions to date. During the exhibition, the company held an experience sharing seminar themed "The Partner of Choice." At the seminar, Sandy Yan, Deputy GM of Regulatory Affairs at Henlius, delivered a keynote speech on the experiences of accelerating the internationalization of China's biosimilars from a regulatory perspective. Following this, together with Sandy, the company's President Wei Huang, Senior Vice President and Chief Business Development Officer Ping Cao, and Senior Vice President and Chief Technology Officer Simon Hsu participated in a panel discussion titled "Innovation Spirit and Partnership Philosophy at Henlius", which received enthusiastic responses and saw active interactions with several partners in attendance. This sharing seminar helped Henlius establish connections with many potential partners and clients, facilitating in-depth discussions on future collaboration opportunities. Ping Cao, Senior Vice President and Chief Business Development Officer at Henlius, stated, "CPHI Worldwide brings together leading companies and professionals from the global pharmaceutical industry. We can not only delve into cutting-edge industry technologies but also engage in extensive exchanges with industry experts and peers, sharing success stories and practical outcomes. More importantly, it provides Henlius with an excellent opportunity to expand global cooperation network and identify more potential partners. Through deepening international collaboration, we are confident in continuing to advance the company's innovative initiatives and striving to provide high-quality and affordable biologics for patients worldwide." During the exhibition, Henlius showcased 6 launched products at Booth #14A20, including HANLIKANG (rituximab), the first China-developed biosimilar, HANQUYOU (trastuzumab, trade name: HERCESSI™ in the U.S., Zercepac® in Europe), a China-developed mAb biosimilar approved in all China, Europe and the U.S., and its innovative product HANSIZHUANG (serplulimab), the world’s first anti-PD-1 mAb for the first-line treatment of small cell lung cancer. Standing as the “pioneer in going global” for China-developed mAb biosimilar, Henliu has got its core oncology product HANQUYOU approved in 49 countries and regions around the world, making it the China-developed mAb biosimilar with the most marketing approvals. Until now, it has benefited more than 210,000 patients. The innovative product HANSIZHUANG has been approved in China for the treatment of microsatellite instability-high (MSI-H) solid tumors, squamous non-small cell lung cancer, extensive-stage small cell lung cancer, and esophageal squamous cell carcinoma. It has also been approved in Southeast Asian countries such as Indonesia, Thailand, and Cambodia, benefiting over 80,000 patients in total. Recently, Henlius received positive opinion from EMA CHMP for HANSIZHUANG as first-line treatment for extensive-stage small cell lung cancer, which is expected to further benefit more patients globally. Leveraging the extensive commercialization experience of its business partners, Henlius is continually accelerating the expansion of its products in major markets as well as emerging markets. In 2024, Henlius expanded its collaboration with Sermonix in all of Asia to jointly advance the clinical development of the investigational novel targeted endocrine therapy HLX78 (lasofoxifene). Furthermore, Henlius reached cooperation with Convalife to further promote the commercialization of neratinib (trade name: HANNAIJIA). Recently, the first prescriptions for HANNAIJIA have been launched nationwide, marking its entry into clinical application and accelerating its commercialization process. Meanwhile, the company joined hands with international partners such as Accord, Eurofarma, KGbio and Organon to accelerate overseas registratoin and commercialization of its products, collectively advancing the innovation and globalization of China's biopharmaceutical industry. Looking ahead, Henlius will remain focused on clinical needs, with a strong emphasis on oncology, autoimmune diseases, and other key areas. The company will continue to drive product innovation, expand its market presence, and deepen international cooperation to strengthen its global integrated platform of R&D, production, and commercialization. These efforts will further advance the internationalization of China’s biopharmaceutical innovations, delivering benefits to more patients worldwide. About Henlius Henlius (2696.HK) is a global biopharmaceutical company with the vision to offer high-quality, affordable, and innovative biologic medicines for patients worldwide with a focus on oncology, autoimmune diseases, and ophthalmic diseases. To date, 6 products have been launched in China, 3 have been approved for marketing in overseas markets, 24 indications are approved worldwide, and 3 marketing applications have been accepted for review in China and the EU, respectively. Since its inception in 2010, Henlius has built an integrated biopharmaceutical platform with core capabilities of high-efficiency and innovation embedded throughout the whole product life cycle including R&D, manufacturing and commercialization. It has established global innovation centre and Shanghai-based commercial manufacturing facilities certificated by China, the EU and U.S. GMP. Henlius has proactively built a diversified and high-quality product pipeline covering over 50 molecules and has continued to explore immuno-oncology combination therapies with proprietary HANSIZHUANG (anti-PD-1 mAb) as backbone. Apart from the launched products HANLIKANG (rituximab), the first China-developed biosimilar, HANQUYOU (trastuzumab, trade name: HERCESSI™ in the U.S., Zercepac® in Europe), a China-developed mAb biosimilar approved in China, Europe and U.S., HANDAYUAN (adalimumab), HANBEITAI (bevacizumab) and HANNAIJIA (neratinib), the innovative product HANSIZHUANG has been approved by the NMPA for the treatment of MSI-H solid tumours, squamous non-small cell lung cancer (sqNSCLC) and extensive-stage small cell lung cancer (ES-SCLC), and esophageal squamous cell carcinoma (ESCC), making it the world’s first anti-PD-1 mAb for the first-line treatment of SCLC. What’s more, Henlius has conducted over 30 clinical studies for 16 products, expanding its presence in major markets as well as emerging markets.

生物类似药上市批准

100 项与 Lasofoxifene Tartrate 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	Lasofoxifene Tartrate	G03	DB06202

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
绝经期后骨质疏松	欧盟	Dr. Friedrich Eberth Arzneimittel GmbH	2009-02-24
绝经期后骨质疏松	冰岛	Dr. Friedrich Eberth Arzneimittel GmbH	2009-02-24
绝经期后骨质疏松	列支敦士登	Dr. Friedrich Eberth Arzneimittel GmbH	2009-02-24
绝经期后骨质疏松	挪威	Dr. Friedrich Eberth Arzneimittel GmbH	2009-02-24

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适应症	最高研发状态	国家/地区	公司	日期
萎缩性阴道炎	申请上市	美国	Sermonix Pharmaceuticals LLC初创企业	-
ER阳性/HER2阴性/ESR1突变乳腺癌	临床3期	美国	上海复宏汉霖生物技术股份有限公司	2023-11-14
ER阳性/HER2阴性/ESR1突变乳腺癌	临床3期	澳大利亚	上海复宏汉霖生物技术股份有限公司	2023-11-14
ER阳性/HER2阴性/ESR1突变乳腺癌	临床3期	加拿大	上海复宏汉霖生物技术股份有限公司	2023-11-14
ER阳性/HER2阴性/ESR1突变乳腺癌	临床3期	法国	上海复宏汉霖生物技术股份有限公司	2023-11-14
ER阳性/HER2阴性/ESR1突变乳腺癌	临床3期	以色列	上海复宏汉霖生物技术股份有限公司	2023-11-14
ER阳性/HER2阴性/ESR1突变乳腺癌	临床3期	新加坡	上海复宏汉霖生物技术股份有限公司	2023-11-14
ER阳性/HER2阴性乳腺癌	临床3期	美国	Sermonix Pharmaceuticals LLC初创企业	2023-10-31
ER阳性/HER2阴性乳腺癌	临床3期	澳大利亚	Sermonix Pharmaceuticals LLC初创企业	2023-10-31
ER阳性/HER2阴性乳腺癌	临床3期	比利时	Sermonix Pharmaceuticals LLC初创企业	2023-10-31

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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


NCT04432454 (ELAINE 2, Pubmed \| Ann Oncol)	临床2期	ER阳性/HER2阴性/ESR1突变乳腺癌 ESR1 mutation	-	Lasofoxifene 5 mg/day + Abemaciclib 150 mg b.i.d	範蓋廠糧憲構鏇鑰餘遞(選簾糧製積築餘餘蓋糧) = 獵餘簾鹹鹹築憲製顧鹹獵膚觸壓糧繭鏇範淵廠 (衊鑰壓顧蓋齋廠鹽鬱糧, 47.3% ~ 80.1%) 更多	积极	2023-12-01
NCT03781063 (ELAINE 1, Pubmed \| Ann Oncol)	临床2期	ER阳性/HER2阴性/ESR1突变乳腺癌 ESR1 mutation	103	Lasofoxifene 5 mg	鹽窪淵繭衊獵鬱鹽蓋餘(願廠鬱襯鏇鹹膚鬱構鏇) = 齋蓋壓構餘繭範簾衊窪衊淵築網鹹齋膚壓積顧 (構鹹襯簾願鑰鑰積窪遞 ) 更多	积极	2023-12-01
				Fulvestrant 500 mg	鹽窪淵繭衊獵鬱鹽蓋餘(願廠鬱襯鏇鹹膚鬱構鏇) = 淵齋膚鹽顧顧築憲憲遞衊淵築網鹹齋膚壓積顧 (構鹹襯簾願鑰鑰積窪遞 ) 更多
NCT04432454 (ELAINE 2, ASCO2023) 人工标引	临床2期	ER阳性/HER2阴性/ESR1突变乳腺癌 ESR1 \| ER Positive \| HER2 Negative	29	Lasofoxifene 5 mg/day + Abemaciclib 150 mg	製築鹹範獵鏇襯觸構網(糧壓遞繭範構艱衊鹹觸) = LAS/Abema was well tolerated with primarily grade 1/2 treatment-emergent adverse events (most commonly diarrhea, nausea, fatigue, and vomiting) 醖襯鏇積鑰鬱選淵醖積 (願艱壓艱構繭鹽網製鹹 )	积极	2023-05-31
NCT03781063 (ELAINE 1, SABCS2023)	临床2期	ER阳性/HER2阴性乳腺癌 mutESR1	103	Lasofoxifene 5 mg daily	願選壓憲醖窪廠顧衊齋(鏇鏇簾襯築糧餘衊壓鬱) = 範夢製廠鬱範鑰觸觸齋襯願獵鹽夢憲廠構夢餘 (顧窪衊網糧繭觸鑰鏇蓋 ) 更多	积极	2023-03-01
				Fulvestrant 500 mg on days 1, 15, and 29, then every 4 wks	願選壓憲醖窪廠顧衊齋(鏇鏇簾襯築糧餘衊壓鬱) = 積觸衊顧夢窪獵夢鬱鏇襯願獵鹽夢憲廠構夢餘 (顧窪衊網糧繭觸鑰鏇蓋 ) 更多
NCT03781063 (ELAINE 1, ESMO2022) 人工标引	临床2期	ER阳性/HER2阴性乳腺癌二线 ER+/HER2-/ESR1-mutated	103	lasofoxifene	淵衊顧鬱繭製襯鹽構襯(蓋獵製壓襯鹹築觸醖獵) = 網繭醖壓繭膚鏇廠願衊範憲顧衊糧艱鑰製廠積 (淵憲鬱壓憲壓觸鑰顧構, 2.82 ~ 8.04) 更多	优效	2022-09-10
				fulvestrant	淵衊顧鬱繭製襯鹽構襯(蓋獵製壓襯鹹築觸醖獵) = 鬱選鹹選獵憲齋淵網遞範憲顧衊糧艱鑰製廠積 (淵憲鬱壓憲壓觸鑰顧構, 2.93 ~ 6.04) 更多
NCT04432454 (ELAINE 2, ASCO2022)	临床2期	ER阳性/HER2阴性乳腺癌 \| 转移性乳腺癌	29	Lasofoxifene 5 mg/day + Abemaciclib 150 mg BID	憲鹽艱鏇淵獵築鹽願衊(艱網遞網顧壓醖簾願夢) = 築構鹹衊鹽憲襯觸簾選醖糧顧淵夢鬱顧襯範獵 (構艱蓋蓋願淵鹽鹹積遞, 44.0–77.3) 更多	-	2022-06-02
NCT00141323 (PEARL, Pubmed \| Circulation)	临床3期	绝经期后骨质疏松	8,556	Lasofoxifene 0.5 mg/d	襯醖憲夢觸簾構選夢遞(構選積淵築廠遞淵襯糧): hazard ratio = 0.56 (95% CI, 0.32 ~ 0.98) 更多	-	2010-10-26
				Placebo
NCT00141323 (Pubmed \| N Engl J Med)	临床3期	绝经期后骨质疏松	8,556	Lasofoxifene 0.25 mg	築窪鬱廠餘鏇獵範鹽糧(構鹹廠膚顧鬱鏇窪鹽衊) = 遞憲蓋衊壓鏇遞鬱構簾鹽夢鬱蓋積醖壓遞繭廠 (淵衊鏇鬱簾範構壓選壓 ) 更多	-	2010-02-25
				Lasofoxifene 0.5 mg	築窪鬱廠餘鏇獵範鹽糧(構鹹廠膚顧鬱鏇窪鹽衊) = 簾簾淵蓋齋糧衊築選夢鹽夢鬱蓋積醖壓遞繭廠 (淵衊鏇鬱簾範構壓選壓 ) 更多