A phase III, randomized, open-label study evaluating efficacy and safety of Giredestrant compared with Fulvestrant, both combined with a CDK4/6 inhibitor, in patients with estrogen receptor-positive, HER2-negative advanced breast cancer with resistance to prior adjuvant endocrine therapy

开始日期2024-05-15

申办/合作机构

F. Hoffmann-La Roche Ltd.

[+1]

NCT05708235 / Recruiting临床2期

A Proof of Concept Study to Evaluate Treatments' Efficacy by Monitoring Minimal Residual Disease Using ctDNA in HR-positive/HER2-negative Early Breast Cancer Population

This trial is a multicenter, open-label, non-comparative, phase II, biomarker-driven adjuvant treatment study involving the periodic collection and analysis of blood samples from patients with HR-positive/HER2-negative early-stage BC at higher risk of relapse, who have undergone surgery within the previous five years, with no evidence of locoregional, contralateral, or distant disease.
The study design is composed by an initial pre-screening phase, a molecular follow-up phase (ctDNA surveillance phase), and an interventional therapeutic phase (treatment phase).
After informed consent is obtained, a total of1,260 eligible patients will enter a ctDNA surveillance in which primary tumor tissue and matched normal blood will be collected from each patient to obtain a patient-specific somatic mutations panel (tumor signature).
At the event of ctDNA positivity, patients will be screened to enter the treatment phase of the study. Upon confirmed eligibility, a total of 40 patients will be allocated in one of the following trial's arms adopting a sequential recruitment strategy:
Arm A: Control Arm (N=10) Arm B: Experimental Arm with giredestrant (N=10) Arm C: Experimental Arm with giredestrant + abemaciclib (N=10) Arm D: Experimental Arm with giredestrant + inavolisib (N=10)
If the strategy of ctDNA monitoring enables physicians to identify patients at high risk of relapse and assess whether treatment at molecular relapse can improve outcome, new cohorts may be added to the study.

开始日期2024-04-01

申办/合作机构

Medica Scientia Innovation Research SL

NCT06259929 / Not yet recruiting临床2期IIT

NEOadjuvant Abemaciclib and GIredestrant triaL in Patients With ER-positive, HER2-negative Early Breast Cancer

The objective of the study is to evaluate the efficacy and the safety of abemaciclib and giredestrant before surgery in participants with early stage, oestrogen receptor-positive (ER+), human epidermal receptor 2 negative (HER2-) breast cancer (BC).
Primary objective:
● To evaluate the efficacy of abemaciclib and giredestrant in complete cell cycle arrest (CCCA) rate at Week 2.
Secondary objectives:
To evaluate the efficacy of abemaciclib and giredestrant in reducing the relative Ki67 expression from baseline to Week 2
To evaluate the efficacy of abemaciclib and giredestrant in risk of recurrence (ROR) score reduction, clinical and radiological tumor response;
To evaluate the safety of abemaciclib and giredestrant.
Exploratory objectives:
To evaluate the mechanisms of response and resistance to therapy;
To evaluate the correlation between Ki-67% reduction and 18- Fluorothymidine (FLT) uptake reduction;
To evaluate the pathological complete response (pCR) rate (ypT0/is, ypN0) of giredestrant plus abemaciclib

开始日期2024-04-01

申办/合作机构-

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项与 Giredestrant 相关的文献（医药）

2024-02-16·Clinical cancer research : an official journal of the American Association for Cancer Research

Phase Ia/b Study of Giredestrant ± Palbociclib and ± Luteinizing Hormone-Releasing Hormone Agonists in Estrogen Receptor–Positive, HER2-Negative, Locally Advanced/Metastatic Breast Cancer

Article

作者: Sohn, Joohyuk ; Jhaveri, Komal L. ; Bond, John W. ; Moore, Heather M. ; Villanueva-Vázquez, Rafael ; Bellet, Meritxell ; Neilan, Tomas G. ; Gates, Mary R. ; Kabos, Peter ; Turner, Nicholas C. ; Lim, Elgene ; Eng-Wong, Jennifer ; Pérez-García, Jose M. ; García-Estévez, Laura ; Pérez-Fidalgo, J. Alejandro ; Chang, Ching-Wei ; Loi, Sherene ; Bardia, Aditya ; López-Miranda, Elena ; Fredrickson, Jill ; Boni, Valentina ; Yu, Jiajie

Abstract:

Purpose::

Giredestrant is an investigational next-generation, oral, selective estrogen receptor antagonist and degrader for the treatment of estrogen receptor–positive (ER+) breast cancer. We present the primary analysis results of the phase Ia/b GO39932 study (NCT03332797).

Patients and Methods::

Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy received single-agent giredestrant (10, 30, 90, or 250 mg), or giredestrant (100 mg) ± palbociclib 125 mg ± luteinizing hormone-releasing hormone (LHRH) agonist. Detailed cardiovascular assessment was conducted with giredestrant 100 mg. Endpoints included safety (primary), pharmacokinetics, pharmacodynamics, and efficacy.

Results::

As of January 28, 2021, with 175 patients enrolled, no dose-limiting toxicity was observed, and the MTD was not reached. Adverse events (AE) related to giredestrant occurred in 64.9% and 59.4% of patients in the single-agent ± LHRH agonist and giredestrant + palbociclib ± LHRH agonist cohorts, respectively (giredestrant-only–related grade 3/4 AEs were reported in 4.5% of patients across the single-agent cohorts and 3.1% of those with giredestrant + palbociclib). Dose-dependent asymptomatic bradycardia was observed, but no clinically significant changes in cardiac-related outcomes: heart rate, blood pressure, or exercise duration. Clinical benefit was observed in all cohorts (48.6% of patients in the single-agent cohort and 81.3% in the giredestrant + palbociclib ± LHRH agonist cohort), with no clear dose relationship, including in patients with ESR1-mutated tumors.

Conclusions::

Giredestrant was well tolerated and clinically active in patients who progressed on prior endocrine therapy. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer.

Cancer chemotherapy and pharmacology

UGT1A4 Polymorphism is not Associated with a Clinically Relevant Change in Giredestrant Exposure

Article

作者: Chen, Ya-Chi ; Nowicka, Malgorzata ; Yu, Jiajie ; Waldvogel, Marie ; Malhi, Vikram ; Hafner, Marc ; Lien, Yi Ting Kayla ; Moore, Heather M ; Agarwal, Priya ; Perez-Moreno, Pablo

Abstract:

Purpose:

Giredestrant is a potent, orally bioavailable, small-molecule selective estrogen receptor antagonist and degrader (SERD) that is being developed for the treatment of patients with estrogen receptor (ER)-positive breast cancer. In vitro, giredestrant was primarily metabolized by UGT1A4. The goal of this study was to investigate if UGT1A4 polymorphism had a clinically relevant impact on giredestrant exposure.

Methods:

Genotyping and pharmacokinetic data were obtained from 118 and 61 patients in two clinical studies, GO39932 [NCT03332797] and acelERA Breast Cancer [NCT04576455], respectively.

Results:

The overall allelic frequencies of UGT1A4*2 and UGT1A4*3 were 3.3% and 11%, respectively. Giredestrant exposure was consistent between patients with wild-type UGT1A4 and UGT1A4*2 and *3 polymorphisms, with no clinically relevant difference observed. In addition, haplotype analysis indicated that no other UGT1A4 variants were significantly associated with giredestrant exposure.

Conclusion:

Therefore, this study indicates that UGT1A4 polymorphism status is unlikely a clinically relevant factor to impact giredestrant exposure and giredestrant can be administered at the same dose level regardless of patients’ UGT1A4 polymorphism status.

2023-12-15·Cancer research communications

Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer

Article

作者: Eng-Wong, Jennifer ; Wang, Jianshuang ; Yu, Jiajie ; Lam, Scott ; Malhi, Vikram ; Gates, Mary R ; Agarwal, Priya ; Perez-Moreno, Pablo ; Liu, Lichuan ; Chen, Ya-Chi ; De Bruyn, Tom

Abstract:

Purpose::

We describe the clinical pharmacology characterization of giredestrant in a first-in-human study.

Experimental Design::

This phase Ia/Ib dose-escalation/-expansion study (NCT03332797) evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of giredestrant in estrogen receptor–positive HER2-negative locally advanced/metastatic breast cancer. The single-agent dose-escalation stage evaluated giredestrant 10, 30, 90, or 250 mg once daily. The dose-expansion stage evaluated single-agent giredestrant at 30, 100, and 250 mg once daily. Dose-escalation and -expansion phases also evaluated giredestrant 100 mg combined with palbociclib 125 mg.

Results::

Following single-dose oral administration, giredestrant was rapidly absorbed and generally showed a dose-proportional increase in exposure at doses ranging from 10 to 250 mg. At the 30 mg clinical dose, maximum plasma concentration was 266 ng/mL (50.1%) and area under the concentration–time curve from 0 to 24 hours at steady state was 4,320 ng·hour/mL (59.4%). Minimal giredestrant concentrations were detected in urine, indicating that renal excretion is unlikely to be a major elimination route for giredestrant. Mean concentration of 4beta-hydroxycholesterol showed no apparent increase over time at both the clinical dose (30 mg) and a supratherapeutic dose (90 mg), suggesting that giredestrant may have low CYP3A induction potential in humans. No clinically relevant drug–drug interaction was observed between giredestrant and palbociclib. Giredestrant exposure was not affected by food and was generally consistent between White and Asian patients.

Conclusions::

This study illustrates how the integration of clinical pharmacology considerations into early-phase clinical trials can inform the design of pivotal studies and accelerate oncology drug development.

Significance::

This work illustrates how comprehensive clinical pharmacology characterization can be integrated into first-in-human studies in oncology. It also demonstrates the value of understanding clinical pharmacology attributes to inform eligibility, concomitant medications, and combination dosing and to directly influence late-stage trial design and accelerate development.

项与 Giredestrant 相关的新闻（医药）

2024-02-21

·药智网

全球药物净现值TOP100

毫无疑问，默沙东的Keytruda已经坐上了2023年药王宝座，而Keytruda的更大优势，体现在它的净现值（Net Present Value,NPV）上。净现值（NPV）是一种用于评估投资项目的财务指标，它将未来现金流量折现到当前时间（因为人们更迫切的想知道，2030年1000亿美元的收入，对于当下来说是个什么概念）。近期，Evaluate分析了100款主要药物净现值，包括Keytruda、Tirzepatide、CagriSema等重磅药物，给出了医药领域关键药物和药物候选物的净现值，每个点对应一款药物，其颜色代表该药物的上市年份区间。图1 Evaluate分析的100款主要药物净现值图片来源：In Vivo01Keytruda净现值排名榜遥遥领先Keytruda刚刚坐上2023年药王宝座，但从NPV指标来看，它是全球所有药物中当之无愧的净现值之王。虽然Keytruda很快就要面对专利悬崖，但keytruda仍然是当今行业中最有价值的药物。其净现值高达惊人的1200亿美元，这个数字甚至大于其主要竞争对手的全部市值。值得注意的是，Keytruda仍在不断发挥自身潜力，其目前的处方信息文件已经厚达144页，而且随着新的组合疗法和辅助试验结果的发布，这个数字仍在不断增长。从销售额的角度来看，Keytruda在2028年的销售额可能上涨到310亿美元，它在2023年的最新销售额为250亿美元。Keytruda超强的生命周期管理策略，如皮下注射和与其他药物的联合疗法开发，将进一步维持其药王的地位。02GLP-1集团军优势，未来可期作为一个整体，GLP-1受体激动剂药物的NPV保持在一个较高水准的级别，显示出开发此类药物有可能的高回报。紧随Keytruda排在NPV榜单上的第二名就是GLP-1药物——礼来的tirzepatide，其NPV也超过了1000亿美元，但这来自于Mounjaro和Zepbound的捆绑数据。诺和诺德的Ozempic的NPV为790亿美元，其孪生兄弟Wegovy的NPV为570亿美元。如果将这两款药物也捆绑统计的话，它们甚至还要超过Keytruda。这与2024年药王预测类似，如果将Semaglutide一起统计的话，Keytruda可能将不再是2024年的药王。在NPV榜单前100名中的其他GLP-1成员，包括诺和诺德的semaglutide口服2型糖尿病药物Rybelsus，礼来的2型糖尿病注射剂Trulicity（dulaglutide），以及诺和诺德的管线资产CagriSema（胰淀素类似物cagrilintide和semaglutide的联合疗法）。相对于Keytruda，semaglutide和tirzepatide的NPV略逊一筹的主要原因在于礼来和诺和诺德还需要大量的追加投资进行这些药物的长期研究，况且它们的生产制造产能的提高还需要很多的投入。但如果它们能在心血管疾病和非酒精性脂肪性肝炎（代谢功能障碍相关脂肪性肝炎）上取得监管审批的话，它们的净现值可能超越Keytruda。03NPV谨慎评估管线资产对于那些尚未获得监管审批的管线资产和2023年刚获批的新药，Evaluate Pharma只选择了8款药物进行NPV评估。它们代表了当前行业管线和新上市药物中最具有吸引力的资产。除了数量较少外，这些研发阶段的药物的NPV评估还略显保守，没有一款产品超过200亿美元。这种NPV评估的保守性，说明临床阶段产生的关键数据和获批上市只能支持一定市场潜力，并不能作为未来获得大量现金流入的全部凭据。即使对于针对阿尔茨海默病的β-淀粉样蛋白的礼来单抗资产Donanemab和葛兰素史克推出的市场首款呼吸道合胞病毒疫苗Arexvy这样的临床突破，更广泛的市场占有也将取决于更有说服力的长期数据和临床结果。生命周期管理是市场成功的关键组成部分，既能提高商业上限，又能保护收入免受潜在竞争对手的侵害。值得注意的是，根据净现值排名，前四位管线或新上市药物中，有三种药物本身就是生命周期管理策略的一部分：CagriSema、Eylea HD、Vyvgart Hytrulo，它们预测和估值，受到了它们的“先药”过去成功的极大背书。无独有偶，Statista也专门针对研发管线资产的NPV进行了排名（图2）。图2 Statista管线资产NPV评估图图片来源：Statista与Evaluate Pharma的榜单类似，Statista的管线资产中NPV最高的项目同样是诺和诺德的CagriSema，但比Evaluate的估值更高，为302亿美元。排在第二的也是一款GLP-1受体激动剂，来自于礼来的小分子口服减肥药Orforglipron，NPV为130亿美元。接下来分别是Vertex的囊性纤维资产Vanzacaftor（107亿美元）、罗氏的肿瘤药物Tiragolumab（52亿美元）、Cytokinetics的梗阻性肥厚性心肌病药物Aficamten（46亿美元）、阿斯利康的乳腺癌药物Camizestrant（45亿美元）和罗氏的肿瘤药物Giredestrant（38亿）美元。04结语净现值（NPV）能够帮助投资者决定是否应该进行某项投资，因为它考虑了投资的时间价值和风险。对于专家来说，净现值是促进投资决策的重要工具。根据净现值给出的信息，他们需要做出是否将药物推进到下一阶段开发的决策。Ref.1.Dunleavy,K.Who's No.1?With$25B in sales,Merck's Keytruda looks to be the top-selling drug of 2023.FiercePharma.01.02.2024.2.2024 Preview.Evaluate.Retrieved on 03.01.2024.3.Chancellor,D.The Next Mega-Blockbusters Are Already Approved.In Vivo.07.02.2024.4.Selected top pharmaceutical R&D projects based on net present value(NPV)as of December 2023.Statista.Retrieved on 09.02.2024.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 | 中华转载开白 | 马老师 18996384680（同微信）商务合作 | 王存星 19922864877（同微信）阅读原文，是昨天最受欢迎的文章哦

临床研究

2024-02-14

·BioSpace

Carrick Therapeutics Announces First Patient Dosed in Phase 1b/2 Clinical Trial of Samuraciclib in Combination with Vepdegestrant in Patients with Advanced Breast Cancer

BOSTON, Feb. 14, 2024 (GLOBE NEWSWIRE) -- Carrick Therapeutics, Ltd., an oncology-focused biopharmaceutical company discovering and developing highly differentiated therapies, today announced that the first patient has been dosed in its Phase 1b/2 clinical trial evaluating the combination of samuraciclib (CT7001), an investigational oral and first-in-class inhibitor of CDK7, and vepdegestrant (ARV-471), an investigational oral PROTAC® (PROteolysis TArgeting Chimera) estrogen receptor (ER) degrader, being jointly developed by Arvinas (Nasdaq: ARVN) and Pfizer (NYSE: PFE) in women with ER+, HER2- metastatic breast cancer who have previously received a CDK4/6 inhibitor. “We’re excited to expand clinical development of samuraciclib with our Phase 1b/2 clinical trial evaluating the combination of samuraciclib and vepdegestrant, another step forward in addressing an important need for patients with advanced breast cancer,” said Tim Pearson, Chief Executive Officer of Carrick Therapeutics. “We believe there is great potential for this combination treatment, based on the encouraging initial clinical trial data for vepdegestrant and Pfizer’s deep expertise in developing treatments for breast cancer.” The Phase 1b/2 clinical trial has two parts. In Phase 1b, escalating doses of samuraciclib and vepdegestrant will be tested to determine appropriate doses of each therapy to be used in combination. In Phase 2, additional patients will be enrolled to further explore the safety and efficacy of the selected doses. This clinical trial evaluating the novel combination of samuraciclib and vepdegestrant is being conducted as part of the TACTIVE-U study in collaboration with Arvinas and Pfizer under a clinical trial collaboration and supply agreement. Clinical trial details can also be found on under study ID: NCT06125522. For additional information on the clinical trial, please contact hello@carricktherapeutics.com. About Vepdegestrant (ARV-471) Vepdegestrant is an investigational, orally bioavailable PROTAC protein degrader designed to specifically target and degrade the estrogen receptor (ER) for the treatment of patients with ER positive (ER+)/human epidermal growth factor receptor 2 (HER2) negative (ER+/HER2-) breast cancer. In preclinical studies, vepdegestrant demonstrated up to 97% ER degradation in tumor cells, induced robust tumor shrinkage when dosed as a single agent in multiple ER-driven xenograft models, and showed increased anti-tumor activity when compared to a standard of care agent, fulvestrant, both as a single agent and in combination with a CDK4/6 inhibitor. In July 2021, Arvinas announced a global collaboration with Pfizer for the co-development and co-commercialization of vepdegestrant; Arvinas and Pfizer will equally share worldwide development costs, commercialization expenses, and profits. Ongoing and planned clinical trials will continue to monitor and evaluate the safety and anti-tumor activity of vepdegestrant. About Samuraciclib (CT7001) Samuraciclib is the most advanced CDK7 inhibitor in clinical development. Inhibiting CDK7 is a promising therapeutic strategy in cancer as CDK7 regulates the transcription of cancer-causing genes, promotes uncontrolled cell cycle progression and promotes resistance to anti-hormone therapy. Samuraciclib has demonstrated a favorable safety pro encouraging efficacy in early clinical studies. In addition to the above studies, samuraciclib has further potential in prostate, pancreatic, ovarian and colorectal cancers. Samuraciclib has been granted Fast Track designation from the U.S. Food and Drug Administration (FDA) for use in combination with fulvestrant for the treatment of CDK4/6i resistant HR+, HER2- advanced breast cancer. Carrick is collaborating with Roche, Menarini Group and Arvinas/Pfizer to evaluate novel combinations of samuraciclib with Roche’s oral SERD giredestrant, Menarini Group’s oral SERD elacestrant, and Arvinas/Pfizer’s proteolysis targeting chimera (PROTAC) Estrogen Receptor degrader vepdegestrant (ARV-471) in late-stage CDK4/6i resistant HR+, HER2- metastatic breast cancer. About Carrick Therapeutics Carrick Therapeutics is an oncology-focused biopharmaceutical company developing highly differentiated novel therapies that address significant unmet needs. The Company’s lead program, samuraciclib, is a novel CDK7 inhibitor currently in Phase 2 clinical trials for HR+ breast cancer. Additionally, Carrick is developing CT7439, a novel CDK12/13 inhibitor / Cyclin-K glue-degrader, which is expected to enter a Phase 1 clinical trial in mid-2024. For more information about Carrick Therapeutics, please visit Carrick Contacts Carrick Therapeutics Jenny Horsfield, Chief Business Officer jenny.horsfield@carricktherapeutics.com Investors and Media Luke Heagle, Real Chemistry lheagle@realchemistry.com

临床2期快速通道临床1期

2024-02-12

·药事纵横

2024年生物制药最具价值研发项目TOP10

声明：因水平有限，错误不可避免，或有些信息非最及时，欢迎留言指出。本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及）;本文不构成任何投资建议。近日，行业媒体Evaluate Pharma针对2024年生物医药产业趋势发布了一项分析报告，其中对生物制药最有价值的研发项目TOP10进行了预测。本表列出该报告盘点出的价值最高的研究项目TOP10并按净现值进行排序。一、公司名：Novo Nordisk 项目：Cagrisema 净现值：302亿美元诺和诺德正在投入巨额资金，以确保其保持市场领先地位。诺和诺德的Cagrisema是包含长效胰淀素类似物卡格列肽（Cagrilintide）和GLP-1药物司美格鲁肽（Semaglutide）两种成分的复方制剂，提供了一种影响肠脑轴的新机制。第二阶段研究结果表明，每周一次皮下注射CagriSema可使长期血糖水平降低2.2个百分点，在减轻体重方面的效果优于其单个成分，因此决定进入第三阶段研发。CagriSema目前安全且耐受性良好，此前已于2022年开始在肥胖症领域进行大规模3期试验，反映出其在多个治疗领域的广泛潜力。2024年1月26日，CDE官网显示CagriSema注射液获批临床，拟用于血糖控制不佳的成人2型糖尿病患者。2023年11月14日，诺和诺德在Clinicaltrials.gov网站上注册了CagriSema与替尔泊肽头对头对照用于减肥的三期临床试验。该三期临床计划入组800例肥胖或超重患者，预计2025年8月完成。患者将接受2.4mg Cagrilintide+2.4mg司美格鲁肽或替尔泊肽高剂量15mg治疗。据诺和诺德2023年财报显示，CagriSema已进入2型糖尿病和肥胖症的3期临床开发阶段，以及代谢功能障碍相关性脂肪性肝炎的2期临床开发阶段。二、公司名：Eli Lilly 项目：Orforglipron 净现值：130亿美元Orforglipron（LY3502970）是中外制药开发的一款可口服的非肽类胰高血糖素样肽-1 受体（GLP-1R）激动剂。2018 年，礼来与中外制药达成合作，以5000万美元首付款获得处于临床前阶段的该药的全球开发和商业化权益。2024年1月11日，药物临床试验登记与信息公示平台显示礼来Orforglipron在国内启动新一项III期临床ACHIEVE-5研究（登记号：CTR20240093），旨在使用甘精胰岛素单用或联合二甲双胍和/或SGLT-2抑制剂后血糖控制不佳的2型糖尿病成人受试者中评价每日一次口服orforglipron与安慰剂相比的有效性和安全性。2023年12月29日，药物临床试验登记与信息公示平台显示，礼来启动了orforglipron的一项III期ACHIEVE-2研究（CTR20244303），旨在二甲双胍治疗后血糖控制不佳的2型糖尿病成人受试者中评估每日一次口服orforglipron与达格列净相比的有效性和安全性。2023年9月21日，礼来在Clinicaltrials.gov网站上注册了Orforglipron用于2型糖尿病的三期临床试验ACHIEVE-3。该三期临床计划入组1576例二型糖尿病患者，预计2025年7月完成。除在糖尿病领域，肥胖领域也是礼来Orforglipron的开发重点方向。ATTAIN-1研究旨在肥胖或超重伴体重相关合并症的成人受试者中评价orforglipron对比安慰剂的有效性和安全性；ATTAIN-2研究旨在合并肥胖或超重的2型糖尿病成人受试者中评价Orforglipron对比安慰剂的有效性和安全性。三、公司名：Vertex Pharmaceuticals 项目：Vanzacaftor 净现值：107亿美元Vanzacaftor是一种囊性纤维化跨膜电导调节体(CFTR)的调节剂，用于治疗囊性纤维化。根据Vervex 2月5日发布的2023年财报，vanzacaftor/tezacaftor/deutivacaftor（简称vanza三联疗法）在三项3期临床试验中获得积极结果。基于此结果，2024 年Vanzacaftor有望于年中在美国、欧洲和加拿大提交监管申请。在名为SKYLINE 102和SKYLINE 103的3期临床试验中，在随机分组前，患者接受了4周的Trikafta初始治疗以建立基线值，然后患者随机接受Trikafta或vanza三联疗法的治疗。试验结果显示，接受治疗24周后，基于ppFEV1数值的评估，vanza三联疗法的疗效与Trikafta相当，达到试验的主要终点。在三个关键次要终点第24周与基线相比的汗液氯化物（SwCl）绝对变化，第24周SwCl低于60 mmol/L的患者比例以及SwCl低于30 mmol/L的患者比例中，vanza三联疗法均优于Trikafta。在RIDGELINE 105研究中，主要终点为安全性和耐受性。6-11岁儿童遵循了相同的方案，先接受至少4周的Trikafta治疗以建立基线值，然后再接受vanza三联疗法治疗。在所有三项研究中，vanza三联疗法耐受性良好，与Trikafta治疗组的安全性特征相似。此外，vanza三联疗法在6至11岁的儿童中的安全性与12岁及以上人群中的安全性类似。四、公司名：Roche 项目：Tiragolumab 净现值：52亿美元Tiragolumab是一种抗体，可识别人类细胞上的TIGIT蛋白。通过阻断TIGIT蛋白，Tiragolumab可增强免疫系统并阻止或逆转肿瘤的生长。ASCO GI上，罗氏宣布TIGIT 抗体tiragolumab 在去年连续两次晚期失败后，联合阿替利珠单抗和化疗在针对食管鳞癌的III期 SKYSCRAPER-08 研究中获得了胜利，数据显示tiragolumab与Tecentriq和化疗联合使用，达到了无进展生存期和总生存期的两个主要终点，但由于试验没有和最新的标准疗法对照而受到质疑。根据Roche 2023年财报中披露，Tiragolumab联合Tecentriq 治疗1L PD-L1+NSCLC的III期SKYSCRAPER-01研究最终OS结果预计将于2024年下半年公布。Tight抑制剂曾一度被认为是下一个免疫肿瘤学靶点，但其潜力仍是一个未解之谜。其他几家开发商也在为该机制投入大量资金，因此其结果将产生广泛影响。药物临床试验登记与信息公示平台显示，在国内Tiragolumab有12项临床试验正在进行中，应用于非小细胞肺癌、肝癌、胃癌、直肠癌、食管鳞癌等疾病。五、公司名：Cytokinetics 项目：Aficamten 净现值：46亿美元aficamten是新一代心肌肌球蛋白抑制剂，通过减少每个心动周期中活性肌球蛋白产力横桥的数量，抑制与肥厚型心肌病相关的心肌过度收缩。在临床前模型中，aficamten通过在一个独特的选择性异位结合位点直接与心肌肌球蛋白结合，从而阻止肌球蛋白进入产力状态，从而降低心肌收缩力。FDA 和国家药品监督管理局已经分别授予 aficamten 用于治疗症状性梗阻性肥厚型心肌病的突破性治疗药物认定。2023年12月27日，Cytokinetics宣布了SEQUOIA-HCM的积极顶线结果，这是aficamten在有症状的梗阻性肥厚型心肌病（HCM）患者中进行的关键3期临床试验。结果显示，与安慰剂相比，Aficamten治疗显著改善了运动能力。受此消息影响和Dealreporter报道称Cytokinetics正在接受诺华制药(NVS.US)和阿斯利康(AZN.US)的收购兴趣后，Cytokinetics的股价目前大涨82%，该公司目前市值75.44亿美元。六、公司名：AstraZeneca 项目：Camizestrant 净现值：45亿美元Camizestrant是一种口服生物可利用的、高效的新一代SERD，在一系列临床前模型中表现出抗肿瘤特性，包括那些具有ER激活突变的模型。一项I期研究（SERENA-1）已证明，该药具有良好的耐受性，并且在单独给药或与 CDK4/6 抑制剂palbociclib联合给药时具有良好的抗肿瘤特性。II期 SERENA-2研究（NCT04214288）是在晚期ER+/HER2-乳腺癌患者中评估不同剂量水平Camizestrant（75mg、150mg）相比氟维司群的疗效和安全性。结果显示，与fulvestrant（氟维司群）相比，Camizestrant每日一次75mg和150mg剂量在治疗ER阳性HER2阴性转移性乳腺癌女性患者中均显示在无进展生存期（PFS）上具有统计学显著性和临床意义的优势。目前Camizestrant在乳腺癌领域有9条管线布局，四项研究处于III期临床，二项研究处于II期临床，三项研究处于I期临床。七、公司名：Roche 项目：Giredestrant 净现值：38亿美元Giredestrant是罗氏开发的潜在“best-in-class”选择性雌激素受体降解剂（SERD），通过与ER强效结合，导致ER无法激活靶向基因的转录，并促使ER蛋白降解，从而更彻底地阻断ER信号传导，抑制肿瘤细胞增殖。2022年4月，罗氏宣布SERD抑制剂giredestrant治疗乳腺癌的II期研究（Acelera）没有达到PFS的主要终点，惨遭失败。目前Giredestrant治疗乳腺癌的多项单药和联合疗法的III期临床试验正在进行中，预计于2025年公布III期数据。八、公司名：Merck KGaA 项目：Evobrutinib 净现值：36亿美元evobrutinib是一种口服、高选择性、中枢神经系统（CNS）渗透性免疫调节剂，通过抑制B细胞和小胶质细胞中的布鲁顿酪氨酸激酶（BTK）信号，解决炎症的外周和中枢驱动因素，有潜力成为一种安全高效的RMS治疗选择。2023年12月5日，德国默克宣布研究性BTK抑制剂evobrutinib在复发性多发性硬化症 (RMS)的III期evolutionRMS 1和evolutionRMS 2试验中未达到降低年复发率的主要终点。在evolutionRMS 1中，接受evobrutinib治疗的患者的年复发率（ARR）为0.11，与接受赛诺菲的Aubagio（特利氟胺片）治疗的患者相似。在evolutionRMS 2 中，接受 evobrutinib 治疗后的年复发率为 0.15，而接受赛诺菲 Aubagio 治疗的患者的年复发率为 0.14。该项目中的患者每天两次服用45毫克的evobrutinib，而Aubagio每天一次服用14毫克。治疗至少持续24周，最长可达156周。两种治疗效果均未达到统计学意义。九、公司名：Johnson&Johnson 项目：Nipocalimab 净现值：36亿美元nipocalimab是一款在研的具有高亲和力、全人源、糖基化、无效应的单克隆抗体，旨在选择性地阻断FcRn以降低循环中免疫球蛋白 G (IgG) 抗体的水平，包括导致多种疾病的自身抗体和异体抗体。2024年2月5日，强生宣布FcRn单抗nipocalimab治疗全身型重症肌无力 (gMG) 的关键性III期VIVACITY研究以及治疗干燥综合征（Sjögren syndrome）的II期DAHLIAS研究获得积极结果。在针对gMG的3期VIVACITY研究中nipocalimab达到了主要终点，与安慰剂 (PBO) 相比，第22至24周的MG-ADLa 评分与基线相比有统计学意义的显著降低。下一步，强生计划与全球监管机构合作，将nipocalimab用于gMG患者。在针对SjD的2期DAHLIAS研究中也达到了主要终点，与安慰剂（PBO）相比，第24周时clinESSDAIb评分较基线有了统计学意义上的显著降低。这些数据代表了抗FcRn治疗这种慢性、使人衰弱的自身抗体疾病的研究首次取得积极成果，而这种疾病目前还没有获得批准的先进疗法。DAHLIAS 2 期研究的结果支持了尼泊卡单抗在 SjD 领域的进一步临床开发。强生公司的nipocalimab数据将有助于确定Argenyx公司在价值很高的FcRn领域是否面临竞争。十、公司名：Vertex Pharmaceuticals 项目：VX-548 净现值：34亿美元VX-548是一款由Vertex开发的口服选择性NaV1.8抑制剂，相对于其他NaV通道，VX-548对NaV1.8具有高度选择性。Vertex的策略是通过选择性地抑制NaV1.8，开发一种新的药物类型，有可能有效缓解疼痛，而不受阿片类药物的限制，包括其成瘾性。VX-548已经获得了美国FDA的快速通道资格和突破性疗法认可，适用于治疗中度到重度的急性疼痛。2024年1月30日，Vertex宣布VX-548治疗中度至重度急性疼痛的3期临床试验达到主要终点。该3期研究包括两项随机、双盲、安慰剂对照的关键试验（一项是腹部整形手术后的试验，另一项是拇趾外翻切除手术后的试验），以及一项单臂安全性和有效性研究，该研究招募了多种手术和非手术疼痛患者。与安慰剂相比，腹部整形术或拇趾外翻切除术后使用VX-548治疗在主要终点0至48小时疼痛强度差异的时间加权总和（SPID48）上取得了统计学意义上的显著改善。对于第一个关键次要终点疗效优于阿片类镇痛药物氢可酮/对乙酰氨基酚（HB/APAP），两项试验均为达到；第二个关键次要终点疼痛明显缓解的时间与安慰剂相比，NPRS从基线下降≥2分，两项试验中VX-548都比安慰剂更快开始有意义的疼痛缓解。Vertex计划在2024年中期之前向 FDA 提交新药申请。总结进入临床研究阶段的新药品，其治疗效果可以得到初步的评价，该阶段的新药品具有一定的使用价值和潜在经济价值。但是一旦新药品在临床研究阶段疗效不足，未达研究终点或出现严重不良反应，其使用价值和潜在经济价值也不复存在。因此即便是现在最具有价值的研发项目也仍面临“危机”，能否一直保持其价值仍需拭目以待。参考资料：[1]www.evaluate.com[2]各公司官网-END-药事纵横投稿须知：稿费已上调，欢迎投稿各位朋友好，觉得本文对您有帮助，请随手点一下下方的在看，以便让你的朋友也能看到哦。

临床3期财报引进/卖出临床2期临床1期

100 项与 Giredestrant 相关的药物交易

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外链

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
ER阳性乳腺癌	临床3期	美国	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	日本	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	阿根廷	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	德国	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	希腊	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	意大利	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	新加坡	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	南非	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	韩国	Genentech, Inc.	2022-08-03
ER阳性乳腺癌	临床3期	西班牙	Genentech, Inc.	2022-08-03

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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


NCT04802759 (MORPHEUS Breast Cancer, ASCO2024)	临床1/2期	ER阳性/HER2阴性乳腺癌 Akt pathway mutation	15	Giredestrant (G) + Everolimus (EVERO)	範窪蓋餘鹽窪衊鏇壓獵(鬱鹽鬱簾壓鏇願獵夢窪) = 鹹願製醖夢積衊糧鑰鹹醖淵鹽膚艱遞夢遞齋範 (鑰蓋膚襯憲鹽遞遞範觸 )	积极	2024-05-24
NCT04576455 (acelERA BC study, Pubmed)	临床2期	ER阳性/HER2阴性乳腺癌	303	Giredestrant	網築範淵齋網鹹鏇繭鑰(壓簾窪廠鏇積遞窪襯夢): HR = 0.81 (95% CI, 0.6 ~ 1.1)	积极	2024-03-27
				Physician's choice of endocrine monotherapy
NCT03332797 (GO39932, Pubmed)	临床1期	ER阳性/HER2阴性乳腺癌 ER+ \| HER2-negative \| ESR1-mutated tumors	175	Giredestrant 10 mg	憲膚衊範糧憲遞齋艱鹹(鑰鏇廠鑰網繭願襯襯顧) = 範鹽衊網鑰範衊膚齋淵餘選構蓋積積獵製顧積 (顧壓衊襯齋遞衊簾鬱鹽 )	积极	2024-01-23
				Giredestrant 30 mg	憲膚衊範糧憲遞齋艱鹹(鑰鏇廠鑰網繭願襯襯顧) = 鹽壓齋壓製壓網艱鬱艱餘選構蓋積積獵製顧積 (顧壓衊襯齋遞衊簾鬱鹽 )
NCT03332797 (phase Ia/Ib dose-escalation/-expansion study, Pubmed)	临床1期	晚期乳腺癌	-	Giredestrant 10 mg	製醖網鹽夢遞選襯襯夢(膚鏇鏇鹹選網鏇顧顧獵) = 膚願膚範壓糧夢鬱構遞觸製獵夢壓鑰築鹽襯鹹 (鑰蓋衊獵願憲壓憲簾鑰 )	积极	2023-12-15
				Giredestrant 30 mg	製醖網鹽夢遞選襯襯夢(膚鏇鏇鹹選網鏇顧顧獵) = 鑰廠餘夢繭選窪鹽繭簾觸製獵夢壓鑰築鹽襯鹹 (鑰蓋衊獵願憲壓憲簾鑰 )
Phase Ia/b study (SABCS2023)	临床1期	HER2 阴性乳腺癌 \| ER阳性乳腺癌 ESR1 mutations \| ER pathway activity	-	Giredestrant	襯網獵壓憲鹽膚簾鏇繭(繭夢構鬱積壓淵觸蓋膚) = 糧網憲淵醖鹽鏇鹹膚蓋網襯簾淵繭顧壓築蓋淵 (積艱構選觸網鬱齋鬱簾 )	积极	2023-12-05
NCT03332797 (GO39932, SABCS2023)	临床1期	HER2 阴性乳腺癌 \| ER阳性乳腺癌 ESR1 mutation	111	Giredestrant	憲願膚築獵範鹹憲蓋鑰(襯選鑰製範鬱鏇選衊鏇) = 齋範鏇膚夢獵糧襯夢鑰選構範糧衊襯夢遞衊鹹 (觸製網餘糧繭願選構顧 ) 更多	-	2023-12-05
NCT04436744 (coopERA BC, ASCO2023) 人工标引	临床2期	ER阳性/HER2阴性乳腺癌新辅助 ER Positive \| HER2 Negative	-	Palbociclib+Giredestrant	獵範鹽窪糧夢構顧鑰壓(鏇鬱蓋齋夢餘築觸餘餘) = 憲簾鹽築憲襯觸夢齋餘艱願觸築蓋醖願廠積製 (觸網選鹽鬱獵衊窪簾艱 ) 更多	积极	2023-05-26
				Palbociclib+anastrozole	獵範鹽窪糧夢構顧鑰壓(鏇鬱蓋齋夢餘築觸餘餘) = 蓋憲壓鏇餘顧糧齋觸襯艱願觸築蓋醖願廠積製 (觸網選鹽鬱獵衊窪簾艱 ) 更多
NCT04802759 (MORPHEUS BC, ASCO2023) 人工标引	临床1/2期	ER阳性/HER2阴性乳腺癌 ER Positive \| HER2 Negative	40	Abemaciclib+Giredestrant	膚鏇網襯繭範鹽淵範選(製鏇衊築鑰齋獵鏇繭鹹) = 糧艱憲襯壓願獵餘艱廠範構顧糧憲選簾網廠襯 (繭積獵淵選範選範鏇醖 ) 更多	积极	2023-05-26
				ribociclib +Giredestrant	膚鏇網襯繭範鹽淵範選(製鏇衊築鑰齋獵鏇繭鹹) = 夢觸簾餘齋蓋選繭遞醖範構顧糧憲選簾網廠襯 (繭積獵淵選範選範鏇醖 ) 更多
NCT04802759 (MORPHEUS Breast Cancer, SABCS2023)	临床1/2期	ER阳性/HER2阴性乳腺癌 PIK3CAmut \| ESR1mut	-	Giredestrant + Inavolisib	網壓願製選遞憲糧遞簾(醖齋範蓋蓋廠願齋衊鏇) = 襯襯淵範簾觸簾艱衊鬱繭構夢窪範選觸壓餘鹽 (醖壓鑰餘鬱壓鹽製築壓 ) 更多	积极	2023-04-18
NCT03916744 (CTgov)	临床1期	ER阳性乳腺癌	75	Surgery+Giredestrant (Giredestrant 10 mg)	選築衊網憲築積廠襯蓋(窪襯鏇網鑰廠醖築膚齋) = 選獵積網製夢淵鹽觸鏇襯襯餘網鹽艱夢襯鹽簾 (膚鏇鹽簾襯網壓構鹹衊, 憲鹽選觸齋遞衊範獵窪 ~ 夢糧餘壓蓋蓋憲製構願) 更多	-	2023-03-10
				Surgery+Giredestrant (Giredestrant 30 mg)	選築衊網憲築積廠襯蓋(窪襯鏇網鑰廠醖築膚齋) = 廠糧膚窪艱獵鬱憲遞願襯襯餘網鹽艱夢襯鹽簾 (膚鏇鹽簾襯網壓構鹹衊, 鑰鑰餘鬱鹹糧夢鹽壓壓 ~ 積選遞範構襯餘遞選壓) 更多