Delving into the Latest Updates on IRX-4204 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [3]

Target

RXRs

Mechanism

RXRs agonists(Retinoid X receptor agonists)

Therapeutic Areas

NeoplasmsRespiratory DiseasesSkin and Musculoskeletal Diseases+ [3]

Active Indication

Non-Small Cell Lung CancerHER2 Positive Breast CancerArthritis+ [3]

Inactive Indication

Advanced Lung Non-Small Cell CarcinomaCastration-Resistant Prostatic CancerYoung onset Parkinson disease

Originator Organization

Io Therapeutics, Inc.

Active Organization

Io Therapeutics, Inc.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC24H32O2

InChIKeyBOOOLEGQBVUTKC-NVQSDHBMSA-N

CAS Registry220619-73-8

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.

Start Date01 May 2016

Sponsor / Collaborator

Io Therapeutics, Inc.

[+1]

NCT02438215 / CompletedPhase 1

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.

Start Date01 Aug 2014

Sponsor / Collaborator

Io Therapeutics, Inc.

NCT01540071 / CompletedPhase 2

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.

Start Date01 Aug 2011

Sponsor / Collaborator

Io Therapeutics, Inc.

100 Clinical Results associated with IRX-4204

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100 Translational Medicine associated with IRX-4204

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100 Patents (Medical) associated with IRX-4204

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23

Literatures (Medical) associated with IRX-4204

03 Jun 2024·Clinical Cancer Research

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

Article

Author: 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.

03 Aug 2023·Cells

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

Article

Author: Wu, Jian ; Mathews, Parker ; 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.

25 Feb 2021·BloodQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Munn, David H. ; Blumberg, Bruce ; McDonald-Hyman, Cameron ; Murphy, William J. ; Wang, Chao ; MacDonald, Kelli P. ; Thangavelu, Govindarajan ; Osborn, Mark J. ; Furlan, Scott N. ; Aoyama, Kazutoshi ; Noelle, Randolph J. ; Hippen, Keli L. ; Zeiser, Robert ; Loschi, Michael ; Saha, Asim ; Brown, Chrysothemis ; 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.

100 Deals associated with IRX-4204

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11806

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Young onset Parkinson disease	Phase 2	US	Io Therapeutics, Inc.	01 Aug 2014
Castration-Resistant Prostatic Cancer	Phase 2	US	Io Therapeutics, Inc.	01 Aug 2011
Non-Small Cell Lung Cancer	Phase 2	US	Io Therapeutics, Inc.	-
Advanced Lung Non-Small Cell Carcinoma	Phase 1	US	Io Therapeutics, Inc.	01 May 2016
HER2 Positive Breast Cancer	Phase 1	US	Io Therapeutics, Inc.	-
Arthritis	Preclinical	US	Io Therapeutics, Inc.	15 Aug 2023
Nerve Degeneration	Preclinical	US	Io Therapeutics, Inc.	15 Aug 2023
Psoriasis	Preclinical	US	Io Therapeutics, Inc.	15 Aug 2023
Alzheimer Disease	Preclinical	US	Io Therapeutics, Inc.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01540071 (CTgov)	Phase 2	Castration-Resistant Prostatic Cancer	38	NRX 194204	bayilrvjte(djtsnvjaoq) = hdzvukycee slclzsvksb (lhklboowpa, qhtoxqhwle - ibvxrcfyzm) View more	-	14 May 2021
NCT01540071 (ASCO2014)	Phase 2	Metastatic castration-resistant prostate cancer	23	IRX4204 (20 mg/orally daily)	(lbfnjtdppc) = vmgwkuylrd dujnmomhgi (mcshayxqxt )	Positive	20 May 2014
WPC	Not Applicable	Parkinson Disease	-	IRX4204	mrhszdutwl(gvobkposzq) = significant attenuation of PD-type motor impairments jtdusfpabz (zggyoubnkj ) View more	-	01 Oct 2013
WPC	Not Applicable	Parkinson Disease	-	Placebo		-	01 Oct 2013