IRX4204 / Io Therap - LARVOL DELTA

The RXR agonist IRX4204 promotes cytotoxicity of Her2+ breast cancer cells by Her2-targeted CAR-T cells (SABCS 2025) - "IRX4204 is far more RXR selective than bexarotene, being devoid of RAR, LXR, PPAR gamma nuclear receptor agonism. With our collaborators we have previously reported that: (1) IRX4204 has synergistic cytotoxic effects with Her2-targeted antibodies, Her2-tyrosine kinase inhibitors, and paclitaxel on Her2+ breast cancer cell lines; (2) IRX4204 promotes apoptosis of Her2+ breast cancer cells; (3) IRX4204 promotes in vivo CD8 T-cell infiltration into murine Brca1 mutant breast cancer tumors... Combination of the RXR agonist IRX4204 with Her2-targeted CAR-T cells showed a dose dependent increase in CAR-T infiltration and death of spheroids of Her2+ SKBR3 breast cancer cells in vitro. These promising results support further development of Her2-targeted CAR-T cells, and combination of such cells with the RXR agonist IRX4204 as a therapeutic option for patients with advanced Her2+ breast cancer."

CAR T-Cell Therapy • IO biomarker • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • BRCA1 • CD8 • HER-2 • ICAM1 • PPARG

RXR agonist IRX4204 induces ferroptosis in multiple myeloma via HMOX1/GPX4 axis and enhances lenalidomide efficacy (ASH 2025) - "To ultimately combine IRX4204 with lenalidomide for clinicalapplication, our current study investigated the effects and underlying mechanism of IRX4204 inenhancing lenalidomide anti-myeloma activity.Human MM cell lines (MM1.R and U266) were treated with IRX4204 (1µM), the ferroptosis inducer/GPX4inhibitor RSL3 (2 µM), lenalidomide, or combinations. IRX4204 promotes ferroptosis in MM cells by activating the PPARα/RXRα-HMOX1 axis and suppressingGPX4/SLC7A11-mediated antioxidant defense. This effect enhances the therapeutic efficacy oflenalidomide, both in vitro and in vivo. The correlation between high HMOX1 expression and improvedpatient survival suggests clinical relevance of this pathway."

Clinical • Hematological Malignancies • Multiple Myeloma • GPX4 • HMOX1 • PPARA • SLC7A11

RXR agonist IRX4204 enhances BCMA CAR-T-cell efficacy by suppressing ferroptosis via CHAC1 downregulation (ASH 2025) - "Ferroptosis involvement was further examined bychallenging CAR-T cells with RSL3 (Ferroptosis inducer) and Ferr-1 (Ferroptosis inhibitor) in the presenceor absence of IRX4204. The clinical correlation between high RXR expression and superior CAR-T outcomesunderscores the relevance of this pathway. Our findings lay the groundwork establishing RXR agonism asa promising strategy to improve CAR-T cell persistence and the durability of responses in MM. Thesepreclinical results provide a strong rationale for clinical translation, warranting exploration of thecombination strategy of IRX4204 plus CAR-T in future clinical trials."

CAR T-Cell Therapy • Clinical • IO biomarker • Hematological Malignancies • Multiple Myeloma • CD4 • CD69 • CHAC1 • GPX4 • PPARA • SLC7A11

Targeting the RXR Pathway for the Prevention of Triple Negative Breast Cancer. (PubMed, Cancer Prev Res (Phila)) - "In this study, we tested whether nuclear retinoid X receptor (RXR) ago-nists, IRX4204 and 9cUAB30, which have been evaluated in clinical trials, could prevent the de-velopment of ER-negative and triple-negative breast cancers (TNBCs). Biomarker analysis revealed that delayed tumors arising after IRX4204 treatment had decreased Ki-67 expression and increased infiltration of cytotoxic T-cells. Our pre-clinical study data support the further evaluation of use of RXR agonists for the prevention of TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • HER-2

Study of IRX4204 With Erlotinib in Previously Treated Advanced NSCLC (clinicaltrials.gov) - P1 | N=12 | Terminated | Sponsor: Io Therapeutics | No replacement manufactured. Sponsor did not want to continue study.

Trial completion date • Trial primary completion date • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

IRX4204-Psoria: Evaluation of Safety and Efficacy of IRX4204 in Mild to Moderate Plaque Psoriasis (clinicaltrials.gov) - P2 | N=20 | Not yet recruiting | Sponsor: Io Therapeutics | Initiation date: Mar 2025 ➔ Jun 2025 | Trial primary completion date: Dec 2025 ➔ Mar 2026

Trial initiation date • Trial primary completion date • Dermatology • Immunology • Psoriasis

NOVEL OUTCOME MEASURES FOR PROOF -OF-CONCEPT CLINICAL TRIAL OF THE IMMUNOMODULATORY AND DOPAMINERGIC NEUROPROTECTANT RXR AGONIST IRX4204 IN PD (ADPD 2025) - "It is expected that the trial will provide placebo -controlled proof -of-concept evidence of safety and efficacy of IRX4204 for treatment of PD by utilizing multiple new types of assessments of biologic and clinical outcomes."

Clinical • Immunomodulating • Neuroprotectant • NR4A2

Selective retinoid X receptor agonism promotes functional recovery and myelin repair in experimental autoimmune encephalomyelitis. (PubMed, Acta Neuropathol Commun) - "Evidence that myelin repair is crucial for functional recovery in multiple sclerosis (MS) led to the identification of bexarotene (BXT). These results inform the discovery of restorative neural therapeutics for MS by demonstrating that selective RXR agonism is sufficient for effective myelin repair. Moreover, our findings support the therapeutic potential of IRX4204 to promote functional recovery in MS."

Journal • CNS Disorders • Dyslipidemia • Immunology • Inflammation • Multiple Sclerosis • Solid Tumor

IRX4204-Psoria: A Study Evaluating Safety and Efficacy of IRX4204 in Plaque Psoriasis (clinicaltrials.gov) - P2 | N=20 | Not yet recruiting | Sponsor: Io Therapeutics

New P2 trial • Dermatology • Immunology • Psoriasis

Io Therapeutics, Inc., presented data from studies of IRX4204, the company’s phase II clinical stage RXR agonist for treatment of normal aging-related neurodegeneration, at the FASEB Science Research Conference on Cellular and Molecular Mechanisms of Brain Aging (GlobeNewswire) - "The studies showed that IRX4204 inhibits brain inflammation by decreasing production of the pro-inflammatory cytokine IL-6 by microglial cells. It also promotes growth of immunosuppressive regulatory Treg cells and inhibits Th17 cells from producing the pro-inflammatory cytokine IL-17. Thereby IRX4204 has pharmacologic mechanisms of action addressing two types of neuroinflammation observed in normal aging-related neurodegeneration. IRX4204 also promotes development of myelin-producing cells, which protect and repair damaged myelinated nerve fibers. Further, IRX4204 has direct effects on survival of neurons, and neurorestorative effects on neurons, by increasing their growth of neurites...The company is planning a placebo-controlled double-blind phase II clinical trial of IRX4204 in Parkinson’s disease, to be initiated in Q1 of 2025."

Clinical • New P2 trial • CNS Disorders • Parkinson's Disease

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) (GlobeNewswire) - "Io Therapeutics, Inc., presented today results from studies of IRX4204...supporting its potential use for treatment of amyotrophic lateral sclerosis (ALS)...In support of the potential for IRX4204 as a new treatment for ALS, the company reported that IRX4204 promotes growth of human Treg cells and inhibits growth of human Th17 cells, restoring their balance while concomitantly inhibiting neurodegeneration. This effect has been demonstrated in multiple animal models of neuro-autoimmunity. IRX4204 is 100% effective in inhibiting transfer of neuro-autoimmunity in a model of transfer of autoimmune Th17 cells into non-diseased mice...IRX4204 is neuroprotective, myelin protective, and myelin reparative in mouse models of demyelination."

Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders

Io Therapeutics, Inc., presented data from studies of IRX4204, the company’s phase II clinical development stage, highly selective third generation RXR nuclear receptor agonist compound, supporting its potential use for prevention and treatment of normal aging-related neurodegeneration, Parkinson’s disease, and Alzheimer’s disease (GlobeNewswire) - "The presented studies showed that IRX4204 promotes differentiation and growth of immunosuppressive human Tregs, and inhibits differentiation of pro-inflammatory human Th17 cells, while reducing production of IL-17. IRX4204 also inhibits production by microglia of IL-6 and other pro-inflammatory factors. In addition, IRX4204 promotes differentiation and growth of myelin-producing oligodendrocytes in vitro and promotes myelinated nerve fiber protection and repair (remyelination) in mouse models of demyelination...The company is planning to initiate a placebo-controlled phase II clinical trial of IRX4204 in Parkinson’s disease patients in Q4 of 2024, to further demonstrate safety and efficacy in PD patients."

New P2 trial • Preclinical • CNS Disorders • Parkinson's Disease

The retinoid X receptor (RXR) agonist IRX4204 potentiates the efficacy of trabectedin and pioglitazone in myxoid liposarcoma preclinical models (AACR 2024) - "The combination of IRX4204 and PIO, even without ET, could be a clinically effective option, especially for patients not suitable to receive ET or as maintenance therapy. Further studies are ongoing to better define the mechanism of action of these combinations through in vivo histological and molecular analysis."

Preclinical • Liposarcoma • Oncology • Sarcoma • Solid Tumor • ADIPOQ • FABP4 • FUS

IRX4204 Induces Senescence and Cell Death in HER2-positive Breast Cancer and Synergizes with Anti-HER2 Therapy. (PubMed, Clin Cancer Res) - "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."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor

Study of IRX4204 With Erlotinib in Previously Treated Advanced NSCLC (clinicaltrials.gov) - P1 | N=12 | Suspended | Sponsor: Io Therapeutics | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Jul 2023 ➔ Dec 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

The RXR agonist, IRX4204, delays the formation of Brca1 mutant mammary tumors via modulation of the anti-tumor immune response (SABCS 2023) - "These data demonstrate a novel use of the RXR agonist, IRX4204, to delay the formation of Brca1-deficient mammary tumors. We have found that IRX4204 treatment modulates the tumor immune response through increased infiltration of cytotoxic CD8-positive T-cells in Brca1-deficient mammary tumors in vivo. We have also determined that IRX4204 modulates lipid metabolism in breast cancer cell lines in vitro."

Breast Cancer • Oncology • Solid Tumor • BRCA1 • CASP3 • CD8

RXR Agonists Enhance Lenalidomide Anti-Myeloma Activity and T Cell Functions while Retaining Glucose-Lowering Effect. (PubMed, Cells) - "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. 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."

Journal • Diabetes • Dyslipidemia • Hematological Malignancies • Metabolic Disorders • Multiple Myeloma • Oncology • CRBN

The combination of the PPARγ agonist pioglitazone and the RXR agonist IRX4204 induces adipocytic differentiation in myxoid liposarcoma (EACR 2023) - "Interestingly, despite both pioglitazone and IRX4204 were inactive alone, their combination caused a significant inhibition of tumor growth and complete responses in ML017 wt, even without trabectedin. Also in the ML006 model, the addition of IRX4204 improved tumor growth inhibition during and after treatments.ConclusionIRX4204 combination with trabectedin and pioglitazone is able to improve their antitumor activity enhancing their differentiating capabilities, causing more rapid and long-lasting tumor responses, potentially allowing the application of this combination even in case of rapid tumor progression."

Liposarcoma • Oncology • Sarcoma • Solid Tumor • ADIPOQ • FABP4 • FUS

IRX4204 in combination with erlotinib to target distinct pathways in lung cancer cells. (ASCO 2017) - P1; "Our prior work with the less specific rexinoid bexarotene and erlotinib showed clinical activity in patients with lung cancer cases that harbored KRAS mutations. Taken together, these data highlight specific mechanisms and candidate pharmacodynamic biomarkers of response to the combination of this rexinoid and EGFR-TKI in lung cancer. Based on these findings, a clinical trial (NCT02991651) with IRX4204 in combination with erlotinib is underway to treat patients with chemotherapy-refractory non-small cell lung cancer."

Combination therapy • Biosimilar • Non Small Cell Lung Cancer • Ophthalmology

Study of IRX4204 With Erlotinib in Previously Treated Advanced NSCLC (clinicaltrials.gov) - P1 | N=12 | Suspended | Sponsor: Io Therapeutics | Trial completion date: Dec 2021 ➔ Dec 2023 | Recruiting ➔ Suspended | Trial primary completion date: Jul 2021 ➔ Jul 2023

Combination therapy • Trial completion date • Trial primary completion date • Trial suspension • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Targeting the Retinoid X Receptor Pathway Prevents and Ameliorates Murine Chronic Graft-Versus-Host Disease. (PubMed, Front Immunol) - "In a minor histocompatibility antigen disparate sclerodermatous model, IRX4204 treatment significantly prevented and ameliorated skin cGVHD by reducing Th1 and Th17 differentiation due to anti-inflammatory properties. Together, these results indicate that IRX4204 is a promising therapeutic option to treat cGVHD with bronchiolitis obliterans or sclerodermatous manifestations."

Journal • Preclinical • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Fibrosis • Graft versus Host Disease • Immunology • Oncology • Pulmonary Disease • Respiratory Diseases • Scleroderma • Systemic Sclerosis • Transplantation

The RXR agonist, IRX4204, increases the anti-tumor activity of HER2-targeted therapies in HER2-amplified breast cancer (SABCS 2021) - " In vitro cell growth assays were conducted to evaluate the efficacy of IRX4204 alone and in combination with trastuzumab, tucatinib, neratinib or T-DM1, using a panel of breast cancer cell lines expressing various levels of HER2. These data demonstrate a novel use of an RXR agonist, IRX4204, to inhibit the growth of HER2-amplified breast cancer cell lines and to enhance the activity of anti-HER2 therapy in vitro . These results also demonstrate that IRX4204 can overcome anti-HER2 resistance to inhibit the growth of HER2-positive cells. These data demonstrate that IRX4204 can enhance the anti-cancer activity of anti-HER2 therapies even in TKI-resistant cells."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Repurposing a novel anti-cancer RXR agonist to attenuate acute GVHD and maintain graft-versus-leukemia responses. (PubMed, Blood) - "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 used as a novel approach to prevent acute GVHD in the clinic."

Journal • Graft versus Host Disease • Hematological Malignancies • Immune Modulation • Immunology • Inflammation • Leukemia • Oncology • FOXP3 • IFNG • TNFA

Study of IRX4204 With Erlotinib in Previously Treated Advanced NSCLC (clinicaltrials.gov) - P1; N=12; Recruiting; Sponsor: Io Therapeutics; Trial completion date: Dec 2019 ➔ Dec 2021; Trial primary completion date: Jul 2019 ➔ Jul 2021

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor