IRX-4204(IRX-4204) - 药物靶点：RXRs_在研适应症：非小细胞肺癌，HER2阳性乳腺癌，关节炎_专利_临床

概要

基本信息

药物类型

小分子化药

别名

+ [3]

靶点

RXRs

作用机制

RXRs激动剂(视黄醇类受体家族激动剂)

治疗领域

肿瘤呼吸系统疾病皮肤和肌肉骨骼疾病+ [3]

在研适应症

非小细胞肺癌HER2阳性乳腺癌关节炎+ [3]

非在研适应症

晚期非小细胞肺癌去势抵抗性前列腺癌帕金森病（青年型、早发型）

原研机构

Io Therapeutics, Inc.

在研机构

Io Therapeutics, Inc.

非在研机构-

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C24H32O2

InChIKeyBOOOLEGQBVUTKC-NVQSDHBMSA-N

CAS号220619-73-8

关联

5

项与 IRX-4204 相关的临床试验

NCT02991651 / Suspended临床1期

A Phase I Study of IRX4204 in Combination With Erlotinib in Patients With Previously Treated Advanced Non-Small Cell Lung Cancer

Patient selection: a) Pathological confirmation of non-small cell lung cancer without activating EGFR mutations; b) Advanced stage disease (IV or IIIB with malignant effusion) with at least two prior chemotherapy regimens; c) No available curative therapy; d) Pregnant women are excluded; e) Informed consent.
Pretreatment evaluation: a) Medical history and physical examination; b) Hepatic and renal function (bilirubin, aspartate aminotransaminase, creatinine); c) Preoperative staging evaluation including CT-chest or PET/CT scan;
Treatment plan: Three dose levels of IRX4204 and erlotinib will be studied using intra-patient dose escalation for dose levels 1 and 2. These study agents will be administered orally until progression of disease, unacceptable toxicities, activation of a phase II study of the combination, or exhaustion of the IRX4204 drug supply.
Evaluation on study: Adverse events will be graded on a scale of 0 to 5, using the Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0. Efficacy will be assessed using the RECIST v1.1 criteria based on CT-chest or PET/CT scan after 8 weeks of study treatment.

开始日期2016-05-01

申办/合作机构

Io Therapeutics, Inc.

[+1]

NCT02438215 / Completed临床1期

An Open-Label, Single Site Study Using [123I]β-CIT Single Photon Emission Tomography (SPECT) to Evaluate Dopamine Transporter Binding Following Treatment With IRX4204 in Early Parkinson's Disease Subjects

This is a single site, open-label study designed to examine dopamine transporter density using [123I]β-CIT SPECT imaging before and following treatment with IRX4204 for a 30-day period in early Parkinson's disease patients. In addition, clinical evaluations will be performed to evaluate the effect of IRX4204 treatment on the motor and cognitive symptoms of PD.

开始日期2014-08-01

申办/合作机构

Io Therapeutics, Inc.

NCT01540071 / Completed临床2期

A Phase II Trial of NRX 194204 in Castration- and Taxane-Resistant Prostate Cancer

This study is to evaluate the benefits of investigational drug, NRX 194204 in slowing down/stopping/reversing progression of the castration resistant and taxane resistant prostate cancer.

开始日期2011-08-01

申办/合作机构

Io Therapeutics, Inc.

100 项与 IRX-4204 相关的临床结果

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100 项与 IRX-4204 相关的转化医学

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100 项与 IRX-4204 相关的专利（医药）

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23

项与 IRX-4204 相关的文献（医药）

2024-06-03·Clinical Cancer Research

IRX4204 Induces Senescence and Cell Death in HER2-positive Breast Cancer and Synergizes with Anti-HER2 Therapy

Article

作者: Coleman, Darian ; Vuligonda, Vidyasagar ; Lanier, Amanda ; Hill, Jamal ; Mazumdar, Abhijit ; Brown, Powel H. ; Sanders, Martin E. ; Moyer, Cassandra L. ; Qian, Jing

AbstractPurpose:Rexinoids, agonists of nuclear retinoid X receptor (RXR), have been used for the treatment of cancers and are well tolerated in both animals and humans. However, the usefulness of rexinoids in treatment of breast cancer remains unknown. This study examines the efficacy of IRX4204, a highly specific rexinoid, in breast cancer cell lines and preclinical models to identify a biomarker for response and potential mechanism of action.Experimental Design:IRX4204 effects on breast cancer cell growth and viability were determined using cell lines, syngeneic mouse models, and primary patient-derived xenograft (PDX) tumors. In vitro assays of cell cycle, apoptosis, senescence, and lipid metabolism were used to uncover a potential mechanism of action. Standard anti-HER2 therapies were screened in combination with IRX4204 on a panel of breast cancer cell lines to determine drug synergy.Results:IRX4204 significantly inhibits the growth of HER2-positive breast cancer cell lines, including trastuzumab and lapatinib–resistant JIMT-1 and HCC1954. Treatment with IRX4204 reduced tumor growth rate in the MMTV-ErbB2 mouse and HER2-positive PDX model by 49% and 44%, respectively. Mechanistic studies revealed IRX4204 modulates lipid metabolism and induces senescence of HER2-positive cells. In addition, IRX4204 demonstrates additivity and synergy with HER2-targeted mAbs, tyrosine kinase inhibitors, and antibody–drug conjugates.Conclusions:These findings identify HER2 as a biomarker for IRX4204 treatment response and demonstrate a novel use of RXR agonists to synergize with current anti-HER2 therapies. Furthermore, our results suggest that RXR agonists can be useful for the treatment of anti-HER2 resistant and metastatic HER2-positive breast cancer.

2023-08-03·Cells

RXR Agonists Enhance Lenalidomide Anti-Myeloma Activity and T Cell Functions while Retaining Glucose-Lowering Effect.

Article

作者: Mathews, Parker ; Wu, Jian ; Zhang, Min ; Wang, Xiaobei ; Kang, Yubin

Retinoid X receptor (RXR) heterodimerizes with the PPAR nuclear hormone receptor and regulates its downstream events. We investigated the effects of RXR agonists (LG100754, bexarotene, AGN194204, and LG101506) on lenalidomide's anti-myeloma activity, T cell functions, and the level of glucose and lipids in vivo. Genetic overexpression and CRISPR/Cas9 knockout experiments were conducted in multiple myeloma (MM) cell lines and Jurkat T cell lines to determine the roles of CRBN in RXR-agonist mediated effects. A xenograft mouse model of MM was established to determine the combination effect of LG100754 and lenalidomide. The combination of RXR agonists and lenalidomide demonstrated synergistic activity in increasing CRBN expression and killing myeloma cells. Mechanistically, the RXR agonists reduced the binding of PPARs to the CRBN promoter, thereby relieving the repressor effect of PPARs on CRBN transcription. RXR agonists downregulated the exhaustion markers and increased the activation markers of Jurkat T cells and primary human T cells. Co-administration of LG100754 and lenalidomide showed enhanced anti-tumor activity in vivo. LG100754 retained its glucose- and lipid-lowering effects. RXR agonists demonstrate potential utility in enhancing drug sensitivity and T-cell function in the treatment of myeloma.

2021-02-25·Blood1区 · 医学

Repurposing a novel anti-cancer RXR agonist to attenuate murine acute GVHD and maintain graft-versus-leukemia responses

1区 · 医学

Article

作者: Munn, David H. ; Blumberg, Bruce ; Murphy, William J. ; McDonald-Hyman, Cameron ; Wang, Chao ; MacDonald, Kelli P. ; Thangavelu, Govindarajan ; Osborn, Mark J. ; Furlan, Scott N. ; Aoyama, Kazutoshi ; Noelle, Randolph J. ; Hippen, Keli L. ; Brown, Chrysothemis ; Zeiser, Robert ; Saha, Asim ; Loschi, Michael ; Hill, Geoffrey R. ; Refaeli, Yosef ; Kuchroo, Vijay ; Janesick, Amanda S. ; Aguilar, Ethan G. ; Serody, Jonathan S. ; Chandraratna, Roshantha A. ; Panoskaltsis-Mortari, Angela ; Maillard, Ivan ; Kean, Leslie S. ; Blazar, Bruce R.

AbstractThe nuclear receptor (NR) subclass, retinoid X receptors (RXRs), exert immunomodulatory functions that control inflammation and metabolism via homodimers and heterodimers, with several other NRs, including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers, but not heterodimers. In this study, in vivo IRX4204 compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T-cell proliferation, reducing T-helper 1 differentiation, and promoting regulatory T-cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-γ and TNF-α serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating proinflammatory pathways. In vitro, inducible Treg differentiation from naive CD4+ T cells was enhanced by IRX4204. In vivo, IRX4204 increased the conversion of donor Foxp3− T cells into peripheral Foxp3+ Tregs in GVHD mice. Using Foxp3 lineage-tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked, we demonstrated that IRX4204 supports Treg stability. Despite favoring Tregs and reducing Th1 differentiation, IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably, IRX4204 reduced in vitro human T-cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively, these beneficial effects indicate that targeting RXRs with IRX4204 could be a novel approach to preventing acute GVHD in the clinic.

1

项与 IRX-4204 相关的新闻（医药）

2024-07-18

·药明康德

穿越血脑屏障小分子展现渐冻症治疗潜力！2期临床试验即将开展

Io Therapeutics今天公布其在研RXR核受体激动剂IRX4204的研究结果。分析显示，IRX4204能够恢复细胞抗自身免疫作用，促进髓鞘保护和修复，具穿越血脑屏障的能力，以及在人类中良好的安全性结果，支持其用于治疗肌萎缩侧索硬化症（ALS）的潜力。目前Io Therapeutics正在计划开展该药物用于ALS的相关2期试验。 ALS是一种逐渐衰弱并最终致命的神经退行性疾病，其病因和发病机制尚不完全清楚。过去研究发现，中枢神经系统（CNS）自身免疫失衡是是造成ALS患者的病理表征的原因之一，ALS患者体内的免疫抑制性Treg细胞过少，而促自身免疫性Th17细胞过多。此外，在部分ALS患者体内也观察到小胶质细胞介导的神经炎症和脱髓鞘（包围神经元的髓鞘丧失）现象。 Io Therapeutics所进行的临床前研究结果显示，在多种神经自身免疫动物模型中，IRX4204可促进人类Treg细胞生长并抑制人类Th17细胞生长，恢复其平衡，同时抑制神经退化，具有用于治疗ALS的潜力。在将自身免疫性Th17细胞转移至未患病小鼠的模型中，IRX4204在抑制神经自身免疫转移方面表现出100%的效果。在该模型中，受体小鼠的自身免疫神经炎症完全依赖于转移的自身免疫性Th17细胞的致病作用。实验结果显示，IRX4204抑制Th17细胞产生促炎细胞因子IL-17，并抑制CNS小胶质细胞产生的另一个重要促炎细胞因子IL-6。IRX4204还可促进少突胶质前体细胞成熟，并促进其生长为产生髓鞘的少突胶质细胞，从而修复受损的髓鞘。IRX4204在脱髓鞘小鼠模型中具有神经与髓鞘保护和髓鞘修复的作用。功能和组织病理学分析显示，IRX4204在多发性硬化症、帕金森病（PD）和阿尔茨海默病的动物模型中对多巴胺能和皮质神经元具有保护作用。目前IRX4204已经在1期和2期临床试验中对85名各种癌症患者和15名PD患者进行了长达20个月的持续治疗，并显示出口服给药的安全性和耐受性。在PD患者中，IRX4204显示能够穿越血脑屏障，并在开放标签评估中改善了患者的运动功能。基于IRX4204在Treg和Th17细胞上的平衡恢复抗自身免疫作用，促进少突胶质细胞成熟、髓鞘保护和修复作用，以及在人类中良好的安全性结果，Io Therapeutics决定开展IRX4204在ALS患者中的2期临床试验。参考资料： [1] Io Therapeutics, Inc., presented today results from studies of IRX4204, the company’s phase II clinical development stage, highly selective RXR nuclear receptor agonist compound, supporting its potential use for treatment of amyotrophic lateral sclerosis (ALS). Retrieved July 16, 2024 from https://www.globenewswire.com/news-release/2024/07/16/2913870/0/en/Io-Therapeutics-Inc-presented-today-results-from-studies-of-IRX4204-the-company-s-phase-II-clinical-development-stage-highly-selective-RXR-nuclear-receptor-agonist-compound-support.html 内容来源于网络，如有侵权，请联系删除。

临床2期临床结果

100 项与 IRX-4204 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11806

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
非小细胞肺癌	临床2期	美国	Io Therapeutics, Inc.	-
晚期非小细胞肺癌	临床1期	美国	Io Therapeutics, Inc.	2016-05-01
HER2阳性乳腺癌	临床1期	美国	Io Therapeutics, Inc.	-
关节炎	临床前	美国	Io Therapeutics, Inc.	2023-08-15
神经变性	临床前	美国	Io Therapeutics, Inc.	2023-08-15
银屑病	临床前	美国	Io Therapeutics, Inc.	2023-08-15
阿尔茨海默症	临床前	美国	Io Therapeutics, Inc.	-
帕金森病（青年型、早发型）	药物发现	美国	Io Therapeutics, Inc.	2014-08-01
去势抵抗性前列腺癌	药物发现	美国	Io Therapeutics, Inc.	2011-08-01

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临床结果

适应症

分期

评价

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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


SABCS2021	N/A	BRCA突变阳性乳腺癌 BRCA1 mutations	-	Sesame oil control	(鏇膚鹽齋鹽鑰選鹽壓廠) = 鑰壓窪鬱糧襯衊淵廠醖範襯獵鏇觸積鏇遞選糧 (壓築醖顧網願遞蓋顧廠 )	积极	2021-10-15
SABCS2021	N/A	BRCA突变阳性乳腺癌 BRCA1 mutations	-	IRX-4204 10mg/kg	(鏇膚鹽齋鹽鑰選鹽壓廠) = 夢鹹獵獵簾網蓋鬱膚網範襯獵鏇觸積鏇遞選糧 (壓築醖顧網願遞蓋顧廠 )	积极	2021-10-15
NCT01540071 (CTgov)	临床2期	去势抵抗性前列腺癌	38	NRX 194204	廠鏇選窪鹹壓襯築醖選(鑰獵蓋網簾獵膚廠廠範) = 蓋顧膚鬱壓鹽範築鏇廠鹹襯廠積壓艱艱顧艱廠 (襯鬱願願構繭構鑰夢夢, 憲積範繭遞簾積遞壓蓋 ~ 遞鹽構顧積糧範蓋遞願) 更多	-	2021-05-14
NCT01540071 (ASCO2014)	临床2期	转移性去势抵抗性前列腺癌	23	IRX4204 (20 mg/orally daily)	(糧廠餘範蓋襯築鹹網鬱) = 憲廠醖壓繭齋遞艱願繭壓淵壓艱壓遞選繭鏇願 (積遞糧獵衊鑰鏇鹹襯醖 )	积极	2014-05-20