APX3330 / Apexian, Opus Genetics - LARVOL DELTA

APE1/Ref-1: multifunctional biology, selective inhibition, and the path to clinical translation. (PubMed, Expert Opin Ther Targets) - "Small-molecule inhibitors such as APX3330 and new-generation analogs like APX2009 and APX2014 have advanced into therapeutic applications spanning cancer, inflammatory disorders, and ocular diseases. Continued investigation into the context-dependent and multifunctional roles of APE1/Ref-1, together with the progression of mechanism-informed therapeutic design, is steadily strengthening the translational potential of APE1/Ref-1-directed therapies."

Journal • Review • Diabetic Retinopathy • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Oncology • Ophthalmology • Retinal Disorders

NANOPARTICLE DELIVERY OF OXALIPLATIN AND APX3330 REDUCES DOSING FREQUENCY AND ENHANCES TREATMENT EFFICACY IN A PRE-CLINICAL MODEL OF COLORECTAL CANCER (MASCC-ISOO 2026) - "Conclusions This pre-clinical study shows that nanoparticle co-delivery of oxaliplatin and APX3330 reduces administration frequency while enhancing anti-tumour efficacy. By lowering dosing burden and limiting off-target exposure, this approach supports improved tolerability and practical feasibility for the treatment of CRC and other cancers."

Preclinical • Colorectal Cancer • Oncology • Solid Tumor

Ref-1 drives ulcerative colitis induced systemic defects in hematopoietic cells. (PubMed, Commun Biol) - "Blockade of the redox-activity of APE1/Ref-1 with APX3330 inhibits the elevated expression of HIF-1α in HSPCs and reverses the aberrant HSPC dynamics under the inflammatory milieu of UC, including suppression of pro-inflammatory Ly6Chi monocytes. Using echinomycin, we pharmacologically blocked HIF-1α activity and found that HIF-1α mediates inflammatory responses via downstream IL-1r1 signaling. Blockade of the redox activity of ref-1 rescues the abnormal HSPC function. Our data highlight the significance of the APE1/Ref-1/HIF-1α/IL-1r1 signaling cascade in aberrant hematopoiesis that contributes to the pathophysiology of chronic UC through a feed-forward loop."

Journal • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • HIF1A • IL1R1

Targeting the redox transcriptional regulator Ref-1 for inhibition of retinoblastoma cell growth (ARVO 2026) - "In humans, non-ocular tumors and diabetic retinopathy respond to the oral Ref-1 inhibitor APX3330, with a strong safety record...We have found compounds inhibiting a promising new drug target that are well tolerated when delivered systemically and inhibit retinoblastoma cell growth. We hope these can be the basis for new treatments for patients with retinoblastoma."

Diabetic Retinopathy • Ophthalmology • Retinal Disorders

Targeted combination nano-drug delivery system to enhance anti-cancer efficacy and reduce side effects (AACR 2024) - "Oxaliplatin (OXL) is a common treatment for CRC but its effectiveness is hampered by side effects, including gastrointestinal and neurotoxic effects. APX3330 exerts anti-angiogenic and neuroprotective effects... This study demonstrates the potential of NPs with improved retention and encapsulation efficiency for effective drug delivery. Our research validates our novel method for creating NPs with mAb conjugation, enhancing cytotoxicity against CRC cell lines. In conclusion, the designed NPs+mAb formulation improves OXL treatment efficacy, providing targeted delivery of anti-cancer drugs to the tumor site and reducing tumor size while minimizing side effects."

Adverse events • Clinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Inflammatory Bowel Disease-induced Inflammation Augments Clonal Hematopoiesis of Indeterminate Potential through Ref-1. (PubMed, Blood) - "In a mouse model of CHIP-IBD, HSC/Ps with Dnmt3a mutation demonstrated significantly worse pathophysiology compared to controls, due in part to heightened expression of Apurinic/apyrimidinic endonuclease 1 (APE1) in the bone marrow and colon. Treatment with the APE1/Ref-1 inhibitor APX3330 ameliorated CHIP-IBD driven by the Dnmt3a mutation."

Journal • Cardiovascular • Chronic Kidney Disease • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Immunology • Inflammation • Inflammatory Bowel Disease • Nephrology • Oncology • Renal Disease • Ulcerative Colitis • DNMT3A • TET2

APX3330 reverses the immunosuppressive tumor microenvironment during colorectal carcinogenesis. (PubMed, Cancer Cell Int) - No abstract available

Biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor

Oral therapies for diabetic retinopathy: Addressing an unmet need or a distant prospect? (PubMed, J Int Med Res) - "We appraised the following key therapeutic oral classes: (a) peroxisome proliferator-activated receptor alpha agonists (fenofibrate), which consistently demonstrate prevention-of-worsening signals; (b) protein kinase C beta inhibitors (ruboxistaurin), showing mixed efficacy but reduced vision-threatening outcomes in specific subsets; (c) redox transcription modulators (APX3330/Ref-1), exhibiting binocular prevention-of-worsening signals; (d) vascular adhesion protein-1/ amine oxidase copper-3 inhibitors, with variable phase-2 results; and (e) rho kinase inhibitors (OPL-0401), which have shown neutral primary endpoints to date. Finally, we outlined current gaps-such as limited phase-3 data beyond fenofibrate, endpoint heterogeneity, and the need for robust prevention trials-and proposed a concise research agenda. As a narrative synthesis, this review emphasizes clinical interpretation rather than quantitative meta-analytic estimation."

Journal • Diabetic Retinopathy • Retinal Disorders • AOC3 • PPARA • PRKCB • PRKCH

A Phase I study targeting the APE1/ref-1 redox signaling protein with APX3330: First clinical agent targeting APE1/ref-1 in Cancer. (PubMed, Oncologist) - P1 | "APX3330 showed preliminary signals of disease control and on-target pharmacology in this first-in-human study. Based on safety and PD, the RP2D is 600 mg/day. Given the small sample size, efficacy conclusions are exploratory (ClinicalTrials.gov Identifier: NCT03375086)."

Journal • P1 data • Oncology • Solid Tumor • CTCs

Redox regulation of memory formation by Rrp1 in Drosophila. (PubMed, Proc Natl Acad Sci U S A) - "Pharmacological inhibition of Rrp1 redox activity with E3330 suppresses Period and CaMKII expression, disrupting LTM formation...Moreover, Rrp1 is required for CREBA-mediated LTM acceleration, revealing a redox-dependent link between transcriptional regulation and memory persistence. These findings establish Rrp1 as a critical modulator of LTM in Drosophila and highlight redox regulation as a conserved mechanism underlying memory formation."

Journal

Targeting APE1/Ref-1 to alleviate formalin-induced pain and spinal neuro-inflammation in rats: a promising therapeutic approach. (PubMed, Front Neurosci) - "These findings suggest that E3330 may modulate pain signaling pathways from the periphery to the spinal cord, offering a novel approach for the management of inflammatory pain conditions, potentially through the modulation of the dopaminergic signaling pathway. Further research is warranted to elucidate E3330's role in regulating central nervous system pain signal transmission, as it emerges as a promising therapeutic candidate in clinical contexts."

Journal • Preclinical • Inflammation • Pain • DRD2 • DRD5

APE1/Ref-1 inhibition via APX3330 lowers monocyte/macrophage infiltration without ameliorating the structure and function of dystrophic mdx hindlimb muscles. (PubMed, Physiol Rep) - "APX3330 treatment neither improve force output and fatiguability of isolated hindlimb muscles, nor affect muscle pathology. As APE1/Ref-1 inhibition modestly lowered inflammation, with no improved contractile function, targeting solely inflammation and oxidative stress in 6-week-old mdx mice appears insufficient."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Inflammation • Muscular Dystrophy • CD68 • KEAP1

Chemically induced partial unfolding of the multifunctional apurinic/apyrimidinic endonuclease 1. (PubMed, Protein Sci) - "APX3330 significantly decreases the melting temperature of APE1 but has no effect on endonuclease activity using a standard assay in either co-solvent. Our results provide insights on reversible partial unfolding of APE1 relevant for its redox function as well as the mechanism of redox inhibition by APX3330."

Journal • Review • HIF1A

APE1/REF-1 REDOX ACTIVITY INHIBITOR AS A NOVEL ORAL TREATMENT FOR INFLAMMATORY BOWEL DISEASE (DDW 2025) - "APX3330, a novel small-molecule compound, directly and specifically inhibits APE1/Ref-1's redox signaling domain, creating a dual positive effect reducing inflammation and enhancing DNA repair...These are unique findings that distinguish our target/compound from other IBD treatments, proposing a novel highly effective oral treatment for IBD. Hence, this study may result in significant outcomes that will lead to the improvement of IBD treatment and clinical practice."

Diabetic Retinopathy • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • Retinal Disorders • Ulcerative Colitis • STAT3

Ref-1 redox activity modulates canonical Wnt signaling in endothelial cells. (PubMed, Redox Biol) - "Ref-1 redox inhibitors APX3330 and APX2009 reduced Wnt3a-induced nuclear β-catenin levels, decreased Wnt transcriptional activity by TOPFlash luciferase assay, and blocked hypoxia-induced Wnt/β-catenin activation in HRECs. In the oxygen-induced retinopathy mouse model of retinal neovascularization, Ref-1 specific inhibitor APX2009 reduced the expression of Wnt-related genes at sites of neovascularization. These findings reveal a novel role for Ref-1 redox activity in modulating Wnt/β-catenin signaling in endothelial cells and highlight the potential of Ref-1 redox activity targeted inhibitors as a novel therapeutic approach for retinal neovascular diseases by modulating multiple disease-relevant pathways."

Journal • Age-related Macular Degeneration • Diabetic Retinopathy • Ophthalmology • Retinal Disorders • Retinopathy of Prematurity • WNT3A

A Phase I study targeting the APE1/Ref-1 redox signaling protein with APX3330: First clinical agent targeting APE1/Ref-1 in Cancer. (PubMed, medRxiv) - P1 | "Ref-1 target engagement was confirmed via biomarker analyses, with reduced serum Ref-1 and circulating tumor cells. The RP2D is 600 mg daily, with APX3330 showing a favorable safety profile and target-mediated effects."

Journal • P1 data • Oncology • Solid Tumor • CTCs

The Potential of Targeting APE1/Ref-1 as a Therapeutic Intervention for Duchenne Muscular Dystrophy. (PubMed, Antioxid Redox Signal) - "Numerous studies have reported increased expression of APE1/Ref-1 in various disorders and have demonstrated the beneficial effects of inhibiting its redox function using the small molecular inhibitor, APX3330...Redox Signal. 00, 000-000."

Journal • Review • CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Inflammation • Muscular Dystrophy • Myositis

Overtaking the Oxidative Stress Pathway: The Therapeutic Benefit of Intraperitoneal APX3330 in Experimental Necrotizing Enterocolitis (ACS-CLINCON 2024) - "Our findings suggest improvement in murine NEC outcomes when mice are treated with APX3330, a novel Ref-1 inhibitor. Subsequent studies that examine downstream mechanisms are needed prior to widespread therapeutic use."

Oxidative stress • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease

APEX1 in intestinal epithelium triggers neutrophil infiltration and intestinal barrier damage in Ulcerative colitis. (PubMed, Free Radic Biol Med) - "Studies related to the redox activity of APEX1 have shown that the combination of the redox inhibitor E3330 with 5-aminosalicylic acid (5-ASA) can effectively alleviate colitis, indicating that APEX1 has promising prospects for clinical treatment of IBD. APEX1 is required for interactions between neutrophil and intestinal epithelial cells. This study provided a mechanism demonstrating that APEX1 protein triggered the risk of UC by promoting neutrophil infiltration and compromising intestinal epithelial barrier function."

Journal • Colon Cancer • Colorectal Cancer • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Oncology • Solid Tumor • Ulcerative Colitis • APEX1 • CXCL1 • IL1B

Effect of Oral APX3330 on Slowing Progression of DR Using a Binocular DRSS Person-Level Scale (AAO 2024) - "Conclusion Fewer subjects treated with APX3330 had worsening on the binocular ≥3-step and ≥4-step DRSS compared to placebo. These data support the evaluation of APX3330 using the validated binocular DRSS person-level scale as a registration endpoint in future studies."

Diabetic Retinopathy • Ophthalmology • Retinal Disorders

REF-1 INHIBITORS FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASE: EFFICACY, MECHANISMS OF ACTION, AND CLINICAL APPLICATIONS (DDW 2024) - "The anti-inflammatory effects of 14-day treatment with APX3330 and APX 009 were comparable with 8-day treatment with a corticosteroid dexamethasone. APX3330 and APX 009 produce positive effects by reducing inflammation oxidative stress and enteric neuropathy enhancing DNA repair and restoring anti-microbial defense. Given the current data on safety and lack of toxicity for orally administered APX3330 in Phase I trial in cancer patients and Phase IIb diabetic retinopathy patients our findings can be quickly translated into a clinical trial for IBD patients. The results of our studies will allow us to design phase I/II clinical trials using APX3330 and with the potential development of APX 009 as a second-generation compound for IBD."

Clinical • Diabetic Retinopathy • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • Pain • Retinal Disorders • Ulcerative Colitis

Oral APX3330, a Ref-1 Inhibitor, Slows Progression of Diabetic Retinopathy on a Binocular DRSS Person-Level Scale (ARVO 2024) - "A clinically meaningful reduction in binocular ≥ 3 step and ≥ 4 step worsening in APX3330 treated subjects compared to placebo was observed in this trial. APX3330 may represent a promising oral treatment option for delaying or preventing disease progression in NPDR patients who otherwise are monitored and untreated until they progress to sight-threatening disease. These Phase 2 data support further evaluation of APX3330 in Phase 3 registration trials."

Diabetic Macular Edema • Diabetic Retinopathy • Ophthalmology • Retinal Disorders

Ref-1 redox activity modulates canonical Wnt signaling in human retinal endothelial cells (ARVO 2024) - "An oral Ref-1 inhibitor APX3330 will be entering phase III clinical trials for DR and diabetic macular edema (DME)... Ref-1 redox activity modulates canonical Wnt signaling in HRECs via regulating levels of Wnt3a receptors and nuclear localization of β-catenin. These results provide evidence of novel targets regulated by Ref-1 redox activity, building a foundation of knowledge of new molecular targets modulating retinal neovascular disease. Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand."

Age-related Macular Degeneration • Diabetic Macular Edema • Diabetic Retinopathy • Ophthalmology • Retinal Disorders • TCF7 • WNT3A

Ref-1 inhibitor APX2009 regulates hypoxia signaling in murine subretinal neovascularization and human retinal endothelial cells (ARVO 2024) - "Ref-1 inhibitor APX3330 has been approved for a Phase III clinical trial for diabetic retinopathy and diabetic macular edema... Ref-1 inhibition markedly downregulated expression of CA9 in HRECs under hypoxia and APX2009 decreased neovascularization and CA9 expression in Vldlr-/- mouse eyes, suggesting regulation of hypoxia-driven angiogenesis in SRN. Together, this study validates APX2009 as a potent candidate for further exploration in nAMD treatment. Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand."

Preclinical • Age-related Macular Degeneration • Diabetic Macular Edema • Diabetic Retinopathy • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration • CA9 • HIF1A • LDLR • STAT3

APE-1/Ref-1 Inhibition Blocks Malignant Pleural Mesothelioma Cell Proliferation and Migration: Crosstalk between Oxidative Stress and Epithelial Mesenchymal Transition in Carcinogenesis and Metastasis (EACR-AACR 2024) - "Material and Methods After confirming Ref-1 overexpression in MPM (MSTO-211H) and NSCLC (A549) cells towards the not transformed ones, we started to inhibit Ref-1 by incubating cells with different concentrations of E3330 (a Ref-1 inhibitor) and Ref-1 siRNA transfection...Moreover, we found in Ref-1 deficient cells we showed a strong inhibition of cellular proliferation and migration, thus suggesting Ref-1 as a potential pharmacological target in MPM therapy. Conclusion Taken as a whole, these results show a new molecular mechanism involved in MPM carcinogenesis and invasiveness, thus improving the knowledge to better address a preventive and therapeutic approach against this aggressive cancer."

Oxidative stress • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PCNA • ZEB1