Phase I Trial of BAY 1895344 ATR Inhibitor Combined With Stereotactic Body Radiation Therapy and Pembrolizumab for Recurrent Head and Neck Squamous Cell Carcinoma

This phase I trial evaluates the best dose, possible benefits and/or side effects of combination therapy with elimusertib (BAY 1895344), stereotactic body radiation, and pembrolizumab in treating patients with head and neck squamous cell cancer that has come back (recurrent) and cannot be removed by surgery (unresectable). BAY 1895344 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving BAY 1895344, stereotactic body radiation therapy in combination with pembrolizumab may shrink or stabilize head and neck squamous cell cancer for longer than treatment with radiation and immunotherapy without BAY 1895344.

开始日期2022-07-06

申办/合作机构

National Cancer Institute

NCT05010096 / Withdrawn临床1期IIT

Strategic Alliance: Phase 1b Trial of the Combination of the ATR Inhibitor BAY1895344 and PI3K Inhibitor Copanlisib in Molecularly Selected Patients With Advanced Solid Tumors (COPABAY)

This phase Ib trial finds out the best dose, possible benefits and/or side effects of BAY1895344 and copanlisib in treating molecularly selected patients with solid tumors that have spread to other places in the body (advanced). BAY1895344 and copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving BAY1895344 and copanlisib together may help control the progression of the disease in patients with advanced solid tumors.

开始日期2022-03-22

申办/合作机构

The University of Texas MD Anderson Cancer Center

NCT05071209 / Active, not recruiting临床1/2期IIT

A Phase 1/ 2 Study of BAY 1895344 (Elimusertib, NSC#810486) in Pediatric Patients With Relapsed or Refractory Solid Tumors

This phase I/II trial tests the safety, best dose, and whether elimusertib works in treating patients with solid tumors that have come back (relapsed) or does not respond to treatment (refractory). Elimusertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

开始日期2021-12-22

申办/合作机构

National Cancer Institute

100 项与 Elimusertib 相关的临床结果

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100 项与 Elimusertib 相关的转化医学

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100 项与 Elimusertib 相关的专利（医药）

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项与 Elimusertib 相关的文献（医药）

2024-12-01·BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

SLFN11 and ATR as targets for overcoming cisplatin resistance in ovarian cancer cells

Article

作者: König, Philipp ; Bendas, Gerd ; Eichhorn, Julia Maria ; Suparman, Eloy ; Cinatl, Jindrich ; Michaelis, Martin ; Bückreiß, Nico

The levels and activities of the DNA/RNA helicase schlafen11 (SLFN11) and the serine/threonine-protein kinase ataxia telangiectasia and Rad3-related protein (ATR) may determine cancer cell sensitivity to DNA damaging agents, including platinum drugs. Here, we studied the roles of SLFN11 and ATR in cisplatin resistance of ovarian cancer using cell lines displaying acquired or intrinsic cisplatin resistance. W1CR, the cisplatin-resistant subline of W1 ovarian cancer cells, displayed reduced SLFN11 levels. HDAC inhibition using entinostat returned an epigenetic downregulation of SLFN11 in W1CR cells, caused SLFN11 re-expression and re-sensitized these cells to cisplatin. Moreover, entinostat also sensitized intrinsically resistant EFO21 ovarian cancer cells to cisplatin by upregulating SLFN11. However, SLFN11 was not involved in cisplatin resistance in all other cell models. Thus, SLFN11 expression is not a general cisplatin resistance marker in ovarian cancer. In contrast, inhibition of the DNA damage repair master regulator ATR using sub-toxic concentrations of elimusertib sensitized parental cell lines as well as intrinsically resistant EFO21 cells to cisplatin, and fully reversed acquired cisplatin resistance in cisplatin-adapted sublines W1CR, A2780cis, and Kuramochi^rCDDP²⁰⁰⁰. Mechanisms underlying ATR-mediated cisplatin resistance differed between the cell lines and included CHK1/WEE1 signaling and induction of homologous recombination. In conclusion, SLFN11 and ATR are involved in ovarian cancer cisplatin resistance. Although our data identify ATR as key target for tackling cisplatin resistance in ovarian cancer, future studies are needed to identify biomarkers that indicate, which individual ovarian cancers benefit from SLFN11 re-activation and/or ATR inhibition.

2024-09-16·JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS

Factors influencing the Central Nervous System (CNS) distribution of the ATR inhibitor elimusertib (BAY1895344): Implications for the treatment of CNS tumors.

Article

作者: Sarkaria, Jann N ; Oh, Ju-Hee ; He, Lihong ; Rathi, Sneha ; Hu, Zeng ; Carlson, Brett L ; Zhang, Wenqiu ; Elmquist, William F ; Mladek, Ann C ; Zhang, Wenjuan ; Dragojevic, Sonja ; Bakken, Katrina K ; Burgenske, Danielle M ; Talele, Surabhi ; Connors, Margaret A

Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact BBB. GBM has a poor prognosis despite aggressive treatment, in part due to lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemo-sensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent, temozolomide, however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro - in vivo disconnect was explored to understand factors influencing CNS distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-gp efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for inter-species differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited. Significance Statement This study examined the disconnect between the in vitro synergy and in vivo efficacy of elimusertib/temozolomide combination therapy by exploring systemic and CNS distributional pharmacokinetics. Results indicate that the lack of improvement in in vivo efficacy in GBM PDX models could be attributed to inadequate exposure of pharmacologically active drug concentrations in the CNS. These observations can guide further exploration of elimusertib for the treatment of GBM, or other CNS tumors.

2024-05-03·International journal of radiation biology

The ATR inhibition by Elimusertib enhances the radiosensitivity of MDA-MB-231 triple negative breast cancer in vitro

Article

作者: Haciefendi, Ayten ; Guney Eskiler, Gamze ; Halis, Hatice ; Hamarat, Kaan Furkan ; Derlioglu, Rabia Rana ; Ugurlu, Berat Tugrul

PURPOSE:

DNA damage response (DDR) is the principal mechanism regulating genomic stability and cell cycle checkpoint activation by coordinating DNA repair and apoptotic pathways. Ataxia telangiectasia and Rad3-related protein (ATR) play a significant role in the DDR due to its capability to detect a wide spectrum of DNA damage. Therefore, targeting DDR, specifically ATR, is a promising therapeutic strategy in cancer treatment. Furthermore, the inhibition of ATR sensitizes cancer cells to radiotherapy (RT). Herein, we, for the first time, investigated the synergistic effects of Elimusertib (BAY-1895344) as a highly potent selective ATR inhibitor with RT combination in triple-negative breast cancer (TNBC), in vitro.

METHODS:

MDA-MB-231 TNBC cells were firstly treated with different concentrations of Elimusertib for 24 h and then exposed to 4 and 8 Gy of X-ray irradiation. After post-irradiation for 72 h, WST-1, Annexin V, cell cycle, acridine orange/propidium iodide, mitochondria staining and western blot analysis were conducted.

RESULTS:

Our findings showed that 4 Gy irradiation and lower doses (especially 2 and 4 nM) of Elimusertib combination exerted a considerable anticancer activity at 72 h post-irradiation through apoptotic cell death, marked nuclear and mitochondrial damages and the suppression of ATR-Chk1 based DDR mechanism.

CONCLUSION:

ATR inhibition by Elimusertib in combination with RT may be a promising new treatment strategy in the treatment of TNBC. However, further experiments should be performed to elucidate the underlying molecular mechanisms of the therapeutic efficacy of this combination treatment and its association with DNS repair mechanisms in TNBC, in vitro and in vivo.

项与 Elimusertib 相关的新闻（医药）

2024-04-10

·PRNewswire

Blacksmith Medicines To Highlight Preclinical Oncology Data Demonstrating a Potent and Selective FEN1 Inhibitor Has Synergy with Multiple DDR Drug Classes at AACR Annual Meeting 2024

SAN DIEGO, April 10, 2024 /PRNewswire/ -- Blacksmith Medicines, Inc. (Blacksmith), a leading biopharma dedicated to discovering and developing medicines targeting metalloenzymes, today announced preclinical data on its oncology program targeting flap endonuclease 1 (FEN1), a structure-specific metallonuclease that cleaves 5' DNA flaps during replication and repair, at the American Association for Cancer Research (AACR) Annual Meeting 2024, taking place April 5-10 at the San Diego Convention Center, San Diego CA. "FEN1 has been identified as an important therapeutic metalloenzyme involved in DNA replication and repair but previous drug discovery efforts have been hampered by chemistry limitations resulting in inhibitors lacking potency and selectivity," said Zachary Zimmerman, Ph.D. CEO of Blacksmith. "Using our metalloenzyme fragment-based drug discovery approach, we have identified a highly potent and selective inhibitor of FEN1 having synergies with multiple DDR drug classes that include inhibitors of PARP, PARG, USP1, and ATR." The Blacksmith fragment-based drug discovery platform identified a novel metal-binding pharmacophore that binds to the two magnesium ions in the FEN1 active site. Further elaboration using fragment growth strategies resulted in highly potent and selective inhibitors. The current lead (BSM-1516) is ~65-fold more potent against FEN1 than its related enzyme Exonuclease 1 (Exo1) in biochemical assays (IC50 of 7 nM and 460 nM, respectively), an improvement of more than an order of magnitude in selectivity compared to earlier efforts. FEN1 target engagement in live cells was validated by cellular thermal shift assay (CETSA EC50 of 24 nM). Inhibition of FEN1 led to its increased association with chromatin in S-phase cells and recruitment of PARP1 enzyme. In clonogenic assay, BRCA2-deficient DLD1 cells were ~15-fold more sensitive to FEN1 inhibition than their isogenic BRCA2-wild-type counterparts (EC50 of 350 nM and 5 µM, respectively), confirming the increased susceptibility of HR deficient cancer cells to FEN1 inhibition. Treatment of BRCA2-deficient but not wild-type DLD1 cells with BSM-1516 resulted in cell cycle arrest accompanied by DNA damage signaling and accumulation of chromatin-bound RPA32, a marker of ssDNA. In FEN1-inhibitor-anchored CRISPR screen, it was observed that perturbations in EXO1, USP1, PARP1 and HR pathway genes sensitized cells to FEN1 inhibition. Synergistic relationships of BSM-1516 and its combination potential were further explored in viability studies with a panel of DDR inhibitors (n=25) in BRCA2-proficient and deficient cell lines. Strong synergy was identified with multiple drug classes that included inhibitors of USP1 (KSQ-4279), PARP (Olaparib, Niraparib, Talazoparib, AZD5305), PARG (PDD 00017273) and ATR (AZD6738, VE-822, Elimusertib). In vitro ADME assays and in vivo PK studies showed that BSM-1516 has properties suitable for in vivo testing, either as a single agent or in combination with synergistic DDR inhibitors, an investigation that is currently underway. Poster presentation details Abstract Number: 7148 Title: "Small molecule inhibitor of FEN1 nuclease utilizing a novel metal binding pharmacophore synergizes with inhibitors of USP1, PARP, PARG and ATR" Session Category: Experimental and Molecular Therapeutics Session Title: Novel Antitumor Agents 6 Session Date and Time: Wednesday April 10, 2024 9:00 AM - 12:30 PM Location: Poster Section 23 Poster Board Number: 10 About FEN1 Flap endonuclease 1 (FEN1) is a structure-specific di-magnesium metallonuclease that cleaves 5' DNA flaps during replication and repair. FEN1 is an attractive target for development of anticancer therapeutics because it is overexpressed in many tumor types and has a large number of synthetic lethality partners including genes in Homologous Recombination (HR) pathway. About metalloenzymes and the Blacksmith platform Metalloenzymes utilize a metal ion cofactor in the enzyme active site to perform essential biological functions. This diverse class of targets has historically been difficult to drug due to small molecule chemistry limitations that have plagued the industry. The Blacksmith metalloenzyme platform has solved this problem by leveraging the following: A large proprietary fragment library of metal-binding pharmacophores (MBPs); A comprehensive database containing a full characterization of the metalloenzyme genome including functions, metal cofactors, and associations to disease; A first-of-its-kind metallo-CRISPR library of custom single guide RNAs; An industry-leading metalloenzyme computational toolkit for docking, modeling and structure-based drug design; and A robust and blocking intellectual property estate covering bioinorganic, medicinal, and computational chemistry approaches for metalloenzyme-targeted medicines. About Blacksmith Medicines At Blacksmith Medicines, we are developing medicines targeting metal-dependent enzymes. Over 30% of known enzymes are metalloenzymes, covering all major enzyme classes: oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. Metal ions, including magnesium, zinc, iron, manganese and copper, are the essential ingredient in these metalloenzymes. We recognized a large unmet need for new chemical matter and innovative approaches to drug this important class of enzymes. Our purpose-built platform for metalloenzyme-targeted medicines combines, for the first time in industry, a focused library of metal-binding pharmacophores with proprietary computational modeling approaches to rapidly and rationally design small molecule inhibitors that interact with key metal ions in the enzyme's active site. Our comprehensive knowledge of the metal environment and key active site interactions enables Blacksmith to rapidly build potent and selective inhibitors in a stepwise and predictable manner. Blacksmith has executed strategic drug discovery collaborations with Basilea Pharmaceutica International Ltd., Cyteir Therapeutics Inc., Eli Lilly and Company (Lilly), Hoffmann-La Roche Ltd., and Zoetis LLC., and has been awarded non-dilutive Federal funding agreements with CARB-X and NIH/NIAID. Blacksmith investors include Lilly, Evotec A.G., MP Healthcare Partners, MagnaSci Ventures, and Alexandria Venture Investments. For further information, please visit the company's website and LinkedIn Media Contact: Amy Conrad Juniper Point [email protected] 858-366-3243 SOURCE Blacksmith Medicines

AACR会议

2023-04-10

·Bayer

Bayer to present latest research across its advancing oncology portfolio at AACR 2023 Annual Meeting

Abstracts: ND04, 5047, CT276, 2116, 4035, 433, CT126, 1964, 925, CT228, 311, 5043, CT082 Berlin, April 11, 2023 – Bayer will present latest research across its oncology portfolio at the American Association for Cancer Research (AACR) 2023 Annual Meeting , taking place from April 14-19 in Orlando (FL), USA. Bayer is advancing its oncology R&D efforts in three scientific areas that have the potential to address unmet needs in cancer patients: next-generation Immuno-Oncology, Targeted Radionuclide Therapies and Precision Molecular Oncology. Data from all three areas of scientific focus will be showcased during this year’s meeting. Bayer is progressing novel research around its prostate cancer treatment darolutamide. The presentation highlights the synergistic anti-cancer effects of a PSMA (prostate-specific membrane antigen)-actinium-225 conjugate in combination with darolutamide in preclinical prostate cancer models. Darolutamide, which is jointly developed by Bayer and Orion Corporation, is an oral androgen receptor inhibitor indicated for the treatment of men with non-metastatic castration-resistant prostate cancer (nmCRPC), who are at high risk of developing metastatic disease and for the treatment of men with metastatic hormone-sensitive prostate cancer (mHSPC). Bayer will present the first clinical Phase 1 results on aryl hydrocarbon receptor (AhR) inhibitor BAY 2416964, the company’s most advanced Immuno-Oncology program. A focus of the presentation will be on the target engagement results and pharmacokinetics from its ongoing monotherapy dose-escalation study to explore a potential optimal dose and schedule to effectively inhibit AhR. These results, along with a mathematical model-informed approach have supported the currently ongoing dose expansion for BAY 2416964. In the New Drugs on the Horizon session at AACR, Bayer will present preclinical data on its novel selective diacylglycerol kinase (DGK) zeta inhibitor BAY 2965501, which is under Phase 1 clinical evaluation. The enzyme DGKzeta is a lipid kinase that can down-modulate T-cell activation by catalyzing the conversion of diacylglycerol to phosphatidic acid, thus acting as a ligand-independent, intracellular immune checkpoint. An inhibition of DGKzeta has been demonstrated to enhance T-cell priming against suboptimal tumor antigens and has the potential to overcome multiple immune-suppressive mechanisms in the tumor microenvironment. Based on these data, a first-in-human trial with BAY 2965501 in patients with advanced solid tumors was initiated and is currently enrolling patients. Both small molecule inhibitors in Immuno-Oncology are being jointly developed in a strategic research alliance with the German Cancer Research Center (DKFZ) in Heidelberg, Germany. From its focus area Precision Molecular Oncology, Bayer will show new preclinical data on its mutEGFR/HER2 inhibitor, which was developed in collaboration with the Broad Institute of MIT and Harvard in Cambridge (MA), USA. BAY 2927088 is a reversible small molecule inhibitor that is currently being evaluated in a first-in-human, Phase 1 clinical trial in non-small cell lung cancer (NSCLC) patients with mutations in epidermal growth factor receptors (EGFR & HER2) including exon20 insertions and point mutations. For the first time, Bayer will present the design of the clinical trial and the preclinical activity profile of the inhibitor in human epidermal growth factor receptor 2 ( HER2) mutant NSCLC. Bayer will also report new data looking at larotrectinib, a highly selective and central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor, approved for the treatment of patients with TRK fusion solid tumors, exploring the concordance between tissue and circulating tumor DNA (ctDNA) testing for neurotrophic tyrosine receptor kinase (NTRK) gene fusions from samples in larotrectinib clinical trials. Additional research to be presented from Bayer’s Targeted Alpha Therapy program evaluates the antitumor efficacy and potential benefit of the combination of radium-223 with 177Lu-PSMA-617 in a preclinical model of bone metastatic prostate cancer. The combination of radium-223 and 177Lu PSMA imaging and therapy (I&T) is currently being investigated in patients with metastatic castration-resistant prostate cancer (mCRPC) in a phase 1/2 trial (AlphaBet, NCT05383079). Key presentations on Bayer research to be presented at AACR 2023 are listed below: Oral presentation: BAY 2965501: A highly selective DGKzeta inhibitor for cancer immuno-therapy with first-in-class potential Abstract ND04, Session DDT001 – New Drugs on the Horizon: Part 1 Sunday, April 16, 2:05 PM – 2:20 PM (EDT), Tangerine Ballroom 2 (WF2) - Convention Center Poster presentations: PSMA-targeted actinium-225 conjugate (225Ac-pelgifatamab) potentiates the antitumor efficacy of darolutamide in hormone-dependent and -independent prostate cancer models Abstract #5047 / 14, Session PO.ET08.02 - Theranostics and Radionuclides/Pharmacologic Approaches Tuesday, April 18, 1:30 PM - 5:00 PM (EDT), Section 19, Convention Center Preliminary analysis of pharmacokinetic (PK) and target engagement biomarkers from a first-in-human Phase I study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 Abstract #CT276 / 16, Session PO.CT01.04 - Phase I Clinical Trials 2 Tuesday, April 18, 1:30 PM - 5:00 PM (EDT), Section 47, Convention Center Phosphorylated extracellular signal-regulated kinase (pERK) activation in T effector cells as a target engagement biomarker for the DGKζ inhibitor BAY 2965501 in clinical trials Abstract #2116 / 19, Session PO.CL01.11 - Biomarkers for Elucidation of Tumor Biology and Metastasis Monday, April 17, 9:00 AM – 12:30 PM (EDT), Section 38, Convention Center Preclinical activity of BAY 2927088 in HER2 mutant non-small cell lung cancer Abstract #4035 / 9, Session PO.ET09.08 - Tyrosine Kinase and Phosphatase Inhibitors 2 Tuesday, April 18, 9:00 AM - 12:30 PM (EDT), Section 21, Convention Center Mechanisms of resistance to BAY 2927088, the first reversible inhibitor targeting EGFR exon 20 insertion mutations in non-small cell lung cancer Abstract #433 / 28, Session PO.ET03.02 - Drug Resistance in Molecular Targeted Therapies 2 Sunday, April 16, 1:30 PM - 5:00 PM (EDT), Section 15, Convention Center An open-label, first-in-human study of BAY2927088 in patients with advanced non-small cell lung cancer (NSCLC) harboring an EGFR and/or HER2 mutation Abstract #CT126 / 14, Session PO.CTP01.02 - Phase I Clinical Trials in Progress Monday, April 17, 1:30 PM - 5:00 PM (EDT), Section 46, Convention Center Racial and ethnic trends in next-generation sequencing (NGS) utilization among adult patients with selected advanced tumor types: a large commercial database analysis Abstract #1964 / 5, Session PO.PR01.02 - Cancer Disparities Research Monday, April 17, 9:00 AM - 12:30 PM (EDT), Section 28, Convention Center NTRK gene fusion in adults and pediatrics with solid tumors: a record linkage study of expression frequency and patient characteristics using the Auria Biobank in Finland Abstract #925 / 8, Session PO.CL11.01 - Analyses Using Clinical and Genomic Databases Sunday, April 16, 1:30 PM – 5:00 PM (EDT), Section 38, Convention Center Concordance between tissue and circulating tumor DNA (ctDNA) testing for neurotrophic tyrosine receptor kinase (NTRK) gene fusions in larotrectinib (laro) clinical trials Abstract #CT228 / 18, Session PO.CT02.02 - Phase II Clinical Trials 2 Tuesday, April 18, 9:00 AM - 12:30 PM (EDT), Section 47, Convention Center Optimization of treatment schedule for the combination therapy of ATR inhibitor elimusertib and PARP inhibitor niraparib in preclinical tumor models Abstract #311 / 13, Session: Targeting Replication Stress and the Immune Microenvironment Sunday, April 16, 1:30 PM - 5:00 PM (EDT), Section 11, Convention Center Radium-223 demonstrates increased antitumor activity in combination with 177Lu-PSMA-617 in the intratibial LNCaP xenograft model of bone metastatic prostate cancer Abstract #5043 / 10, Session PO.ET08.02 - Theranostics and Radionuclides/Pharmacologic Approaches Tuesday, April 18, 1:30 PM - 5:00 PM (EDT), Section 19, Convention Center Next-generation sequencing (NGS) and cytokine assessment from a Phase III study of copanlisib in combination with rituximab in patients with indolent non-Hodgkin lymphoma (iNHL) – associations with survival endpoints Abstract #CT082 / 10, Session PO.CT03.01 - Phase III and Pediatric Clinical Trials Monday, April 17, 9:00 AM - 12:30 PM (EDT), Section 47, Convention Center About Oncology at Bayer Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The company has the passion and determination to develop innovative medicines that help improve and extend the lives of people living with cancer. The oncology franchise at Bayer includes six marketed products across various indications and several compounds in different stages of clinical development. Bayer focuses its research activities on first-in-class innovations across the following scientific platforms: Precision Molecular Oncology, Targeted Alpha Therapies, and Immuno-Oncology. Across the areas of focus, we have several prostate cancer treatments on the market or in development, with the goal of extending survival while limiting side effects of treatment throughout the different stages of the disease. Another key focus at Bayer is on innovative precision oncology treatments, with an approved TRK inhibitor exclusively designed to treat tumors that have an NTRK gene fusion, the oncogenic driver of tumor growth and spread. The company’s approach to research prioritizes targets and pathways with the potential to impact the way that cancer is treated. About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. Its products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2022, the Group employed around 101,000 people and had sales of 50.7 billion euros. R&D expenses before special items amounted to 6.2 billion euros. For more information, go to www.bayer.com . Find more information at https://pharma.bayer.com Follow us on Facebook: http://www.facebook.com/bayer Follow us on Twitter: @BayerPharma Forward-Looking Statements This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com . The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

临床1期临床3期临床2期免疫疗法

2023-01-16

·CPHI制药在线

新药 | ATR抑制剂：或合成致死新星，泰德制药TCC1727申报临床，罗氏超13亿美元引进

关注并星标CPHI制药在线1月11日，北京泰德制药股份有限公司1类新药「TCC1727片」的临床试验申请获CDE受理。据公开资料，TCC1727是选择性ATR激酶抑制剂，靶向作用于DNA损伤修复（DDR）通路重要激酶ATR 。 TCC1727作用机理为合成致死，通过抑制ATR功能，干扰DNA损伤修复，使癌细胞DNA损伤后得不到修复而死亡，同时ATR还参与调节肿瘤微环境，现有数据显示其对多个瘤种具有显著的抗肿瘤活性。 TCC1727 拟开发用于治疗非小细胞肺癌、小细胞肺癌、卵巢癌、三阴乳腺癌等多个癌种，重点针对 PD-(L)1 疗法、铂类化疗及 PARP 抑制剂治疗进展或耐药的癌症患者群体。 ATR，即共济失调毛细血管扩张和 Rad-3-相关蛋白，是一类蛋白丝氨酸/苏氨酸家族激酶，是DNA损伤修复通路的核心成员。而且，ATR 激酶是临床多种抗肿瘤疗法耐药的关键因子，包括铂类、吉西他滨及 PARP 抑制剂等重磅品种。合成致死是抗肿瘤药物开发热门领域，PARP是目前研发最快，且最成功的合成致死靶点。ATR被业界认为是继PARP后最有希望的合成致死靶点之一。 ATR和ATM是DNA损伤反应信号网络中的两种重要蛋白，被DNA损伤激活。ATR抑制剂通过阻断ATR介导的信号通路，可以扰乱DNA损伤修复。研究显示，在ATM缺失的肿瘤细胞中，ATR抑制剂可以产生合成致死效应，在导致ATM缺失肿瘤细胞死亡的同时，并不影响正常细胞。目前，全球已出现多款在研ATR抑制剂（详见下表），这些药物被开发作为单药疗法或联合其他药物用于治疗多种肿瘤，其中已有多款取得积极结果。值得一提的是，我国药企如英派药业、智康弘义也积极布局ATR抑制剂市场。 ♦ Camonsertib是一种选择性ATR口服小分子抑制剂，用于治疗具有特定合成致死基因组改变的肿瘤，包括 ATM（共济失调-毛细血管扩张突变）基因。2022 AACR大会上公布的1/2期临床试验结果显示：Camonsertib在晚期卵巢癌（n=20）队列中表现出可喜的活性。这些患者中90%曾经接受过PARP抑制剂治疗后出现耐药性，85%对含铂化疗耐药。Camonsertib在这一患者群体中的总缓解率达到25%，包括1名完全缓解和3名部分缓解。中位无进展生存期为35周。 ♦ Berzosertib是一种首创、强效、选择性ATR抑制剂，原名为VX-970，2017年默克从Vertex制药公司获得许可。由美国国家癌症研究所(NCI)开展并发表于国际医学期刊《癌症细胞》(Cancer Cell)的一项2期概念验证研究(NCT02487095)的结果证实：berzosertib联合化疗拓扑替康(TOP1抑制剂)治疗复发性小细胞肺癌(SCLC)患者疗效显著，客观缓解率(ORR)达36%(n=9/25)，达到了主要疗效终点。特别是，在病情缓解的铂耐药患者中，大部分患者表现出持久缓解。 ♦ M1774 是德国默克子公司EMDSerono 研究所研发的一种ATR激酶抑制剂，目前正处于单药或联合PARP抑制剂尼拉帕立治疗转移性或局部晚期不可切除实体瘤正的1期临床试验中。 ♦ Ceralasertib是阿斯利康开发的一款ATR抑制剂。2021 ASCO大会上公布的2期临床研究结果显示：ceralasertib联合度伐利尤单抗表现出有前景的抗肿瘤活性，尤其是在标准治疗（包括抗PD-1单抗治疗）失败的黑色素瘤患者中。不过，2022 ESMO乳腺癌大会上公布的奥拉帕利联合ceralasertib或WEE1抑制剂adavosertib二/三线治疗转移性三阴性乳腺癌（mTNBC）中的2期临床研究（VIOLETTE）结果显示：无论是否存在同源重组修复(HRR)基因突变和BRCA突变，与奥拉帕利单药治疗相比，奥拉帕利+ceralasertib未能改善mTNBC患者的无进展生存期（PFS）。 ♦ ART-0380 是由Artios Pharma 公司从美国MD Anderson 癌症中心和中国Shang PharmaInnovation获得许可开发的一种新的口服ATR抑制剂，2021年1月在美国启动单药或联合吉西他滨治疗晚期或转移性实体瘤的1/2a期临床研究。 ♦ elimusertib是拜耳开发的一款高度选择性强力ATR抑制剂。AACR大会上公布的1b期扩展临床研究显示：在143名携带不同DDR缺陷的晚期实体瘤患者中，elimusertib让约35%的患者疾病得到控制至少16周。在卵巢癌患者中，27.8%的患者临床获益时间超过6个月，其中包括对含铂化疗耐药并且接受过PARP抑制剂治疗的患者。在ATM表达缺失的患者中，部分缓解率为8.9%，55.9%的患者疾病稳定。 ♦ IMP9064是英派药业自主研发的一款ATR抑制剂。临床前数据显示，IMP9064对ATR具有高抑制活性，相比于其他激酶也展示了高选择性。同时，IMP9064在ATM缺陷型细胞系和移植瘤模型中都显示了良好的抗肿瘤活性和体内活性，具有获得更宽的治疗窗口、以及单药长期用药和联合用药的潜力。 ♦ SC0245是国内首个获批临床的ATR抑制剂，目前正在开展一项开放、单臂的1a/1b期研究。据悉，SC0245在临床前研究中展现出良好的安全性，在体内体外药效均优于同靶点产品AZD6738。 ♦ ATG-018是一款由德琪医药研发团队自主开发的作用于ATR激酶的口服、强效、选择性小分子抑制剂。2022 AACR大会上公布的临床前研究结果显示：ATG-018在多个具有同源重组缺乏的实体瘤/血液肿瘤的体内模型和体外试验中显示了单药疗效。而且，研究还发现了多个与ATG-018敏感性相关的基因表达变化，这些差异基因具有成为预测性生物标志物的潜力。整体来看，ATR抑制剂的研发还处于早期阶段，但其市场潜力已被越来越多的企业看重。值得一提的是，去年6月，罗氏与Repare Therapeutics就Camonsertib达成全球许可和合作协议，交易金额超13亿美元。期待未来ATR抑制剂可以早日问世，造福广大肿瘤患者。扫描下方二维码，发送“新年快乐”，领取新年好礼来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

AACR会议临床结果临床2期临床申请

100 项与 Elimusertib 相关的药物交易

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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
小泡型横纹肌肉瘤	临床2期	美国	National Cancer Institute	2021-12-22
小泡型横纹肌肉瘤	临床2期	加拿大	National Cancer Institute	2021-12-22
复发性尤文肉瘤	临床2期	美国	National Cancer Institute	2021-12-22
复发性尤文肉瘤	临床2期	加拿大	National Cancer Institute	2021-12-22
复发性淋巴瘤	临床2期	美国	National Cancer Institute	2021-12-22
复发性淋巴瘤	临床2期	加拿大	National Cancer Institute	2021-12-22
难治性尤文肉瘤	临床2期	美国	National Cancer Institute	2021-12-22
难治性尤文肉瘤	临床2期	加拿大	National Cancer Institute	2021-12-22
难治性淋巴瘤	临床2期	美国	National Cancer Institute	2021-12-22
难治性淋巴瘤	临床2期	加拿大	National Cancer Institute	2021-12-22

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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


NCT04514497 (ETCTN 10402, ASCO2024) 人工标引	临床1期	晚期恶性实体瘤	21	Irinotecan 150 mg/m2 IV D1 + Elimusertib 10 mg BID PO D1,D2 (biweekly)	鬱獵構網襯範網製窪鏇(艱築鬱遞鹹壓簾齋觸蓋) = For the Biweekly cohort: 3/3 patients enrolled at dose level (DL) 1 experienced hematologic dose-limiting toxicity (DLT); 6 patients received DL-1 without any DLTs. The weekly regimen escalation comprised of 12 patients: 6 enrolled in DL1 with 2/6 having hematologic DLT and 5/6 unable to complete ≥75% of cycle 1 dosing; 6 enrolled in DL-1 with no DLTs observed. 廠襯獵鏇廠衊繭醖簾獵 (衊簾齋選齋鹽鏇範繭蓋 )	积极	2024-05-24
NCT04514497 (ETCTN 10402, ASCO2024) 人工标引	临床1期	晚期恶性实体瘤	21	Irinotecan 25 mg/m2 IV on D1 + Elimusertib 20 mg PO daily on D2,D3 (weekly)		积极	2024-05-24
NCT04514497 (ETCTN 10402, ASCO2024)	临床1期	不可切除的恶性实体瘤 \| 转移性肺癌 \| 转移性胰腺腺癌 ... Top1 inhibitor 更多	8	Topotecan 1 mg/m2IV	獵簾繭襯壓網艱廠願夢(齋積廠衊壓夢鹹襯憲夢) = one of patient experiencing respiratory failure and cardiac arrest in setting of pancytopenia related to study drug 獵觸鏇構襯夢憲淵網範 (範窪構廠夢簾廠夢築構 ) 更多	不佳	2024-05-24
NCT05071209 (ASCO2023) 人工标引	临床1期	实体瘤	8	Elimusertib	壓窪鹹築築獵遞觸顧構(願遞鑰鏇憲構製夢網淵) = At 24 mg/m2/dose, no DLTs were observed. 製鏇簾壓醖鏇顧遞簾觸 (壓築淵蓋築願範齋選築 ) 更多	积极	2023-05-26
NCT03188965 (EP294/#883, IGCS2022)	临床1期	女性生殖器官肿瘤 \| DNA损伤 BRCA1 \| BRCA2 \| ATM mutations	45	Elimusertib 40 mg	憲鬱齋齋鏇獵積鑰鹹選(觸艱構鑰淵衊膚網觸襯) = observed in 69%/20% of patients 膚夢膚襯網繭壓鹹膚顧 (鬱簾艱壓鹽築獵製範製 ) 更多	积极	2022-12-04