APX3330 / Apexian, Opus Genetics - LARVOL DELTA

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

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

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

New Ref-1/APE1 targeted inhibitors demonstrating improved potency for clinical applications in multiple cancer types. (PubMed, Pharmacol Res) - "To characterize the effects of Ref-1 inhibition in vivo, global proteomics was used following treatment with the top four analogs. This study identified and characterized more potent inhibitors of Ref-1 redox function (that outperformed APX3330 by 5-10-fold) with PK studies demonstrating efficacious doses for translation to clinic."

Journal • Oncology • Sarcoma • Solid Tumor • HIF1A • STAT3

Activation of APE1 modulates Nrf2 protected against acute liver injury by inhibit hepatocyte ferroptosis and promote hepatocyte autophagy. (PubMed, Int Immunopharmacol) - "The data suggest that APE1 is a pivotal player in ALI, closely linked to its regulation of Nrf2. Strategies involving APE1 activation to modulate Nrf2, thereby inhibiting hepatocyte ferroptosis and promoting autophagy, may represent innovative therapeutic approaches for ALI. Additionally, tert-butylhydroquinone (TBHQ) holds significant promise in the treatment of acute liver injury."

Journal • Acute Myelogenous Leukemia • Hepatology • Liver Failure • ATG3 • ATG5 • GPX4 • NFE2L2

Ocuphire Pharma Announces Presentation at Ophthalmology Innovation Summit (OIS) XIII (GlobeNewswire) - "Ocuphire Pharma, Inc...today announced that the Company’s CEO, George Magrath M.D., M.B.A., M.S., will deliver a presentation at the Ophthalmology Innovation Summit (OIS XIII), to take place in San Diego, CA on December 1-2, 2023....Dr. Magrath will also host a conference call for the investment community on Tuesday, December 5, 2023. During this call he will provide a strategic update, including the company's plans to advance APX3330 into registrational trials in diabetic retinopathy in 2024."

New trial • Diabetic Retinopathy • Ophthalmology • Retinal Disorders

Oral APX3330 Prevents DR Progression: Efficacy and Safety Results of the ZETA-1 Phase 2 Trial in DR (AAO 2023) - "Across treatment arms, 211 adverse events were reported, most considered mild and unrelated to the study medication. Conclusion APX3330 demonstrated a favorable safety profile and significant prevention of DR progression, representing a new oral option for DR patients."

Clinical • P2 data • Diabetic Retinopathy • Ophthalmology • Retinal Disorders

Bridging population pharmacokinetic and semimechanistic absorption modeling of APX3330. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Delayed APX3330 absorption with food may be related to higher conversion to the more soluble but less permeable hydroquinone form in the gastrointestinal tract. Future work should address pharmacokinetic differences between APX3330 quinone and hydroquinone forms."

Journal • PK/PD data • Diabetic Retinopathy • Gastrointestinal Disorder • Hepatitis C • Hepatology • Macular Edema • Oncology • Ophthalmology • Retinal Disorders

Oral Apx3330 Reduces The Drss Worsening After 24-Weeks Of Daily Treatment: Efficacy And Safety Results Of The Zeta-1 Phase 2 Trial In Diabetic Retinopathy (ESCRS 2023) - P2 | "The ZETA-1 Phase 2 trial of APX3330 demonstrated a statistically significant prevention of DR progression as measured by ≥ 3 step binocular DRSS worsening compared to placebo and a favorable safety and tolerability profile. The safety profile in diabetic patients is consistent with that observed in hundreds of patients of hepatitis, cancer, and healthy. APX3330 may represent a promising oral treatment option for preventing risk of disease progression in NPDR patients who otherwise are monitored and untreated."

Clinical • P2 data • Diabetic Macular Edema • Diabetic Retinopathy • Ophthalmology • Retinal Disorders

Reflux conditions induce E-cadherin cleavage and EMT via APE1 redox function in oesophageal adenocarcinoma. (PubMed, Gut) - "Reflux conditions promote EMT via APE1 redox-dependent E-cadherin cleavage. APE1-redox function inhibitors can have a therapeutic role in EAC."

Journal • Esophageal Adenocarcinoma • Esophageal Cancer • Gastroenterology • Gastroesophageal Reflux Disease • Gastrointestinal Cancer • Oncology • Solid Tumor • CDH1 • IL1B • MMP14 • VIM

Ocuphire Pharma to Present at ESCRS 2023 and MODLive! Conferences in September (GlobeNewswire) - "Ocuphire Pharma, Inc...today announced that it will present clinical data on APX3330 and Nyxol at the 41st Congress of the European Society of Cataract and Refractive Surgeons (ESCRS) to take place September 8th - 11th, in Vienna, Austria."

Clinical data • P2 data • P3 data • Diabetic Retinopathy • Ophthalmology • Retinal Disorders

Aristolochic acid I aggravates oxidative stress-mediated apoptosis by inhibiting APE1/Nrf2/HO-1 signaling. (PubMed, Toxicol Mech Methods) - "In the presence of a low concentration of the APE1 inhibitor E3330, expression of Nrf2 and HO-1 proteins in HK-2 cells was decreased and AAI-induced apoptosis was aggravated...The collective findings demonstrate that AAI can inhibit the induction of oxidative stress and apoptosis by the APE1/Nrf2/HO-1 axis, leading to AAI renal injury. Targeting APE1 may be an effective therapeutic strategy to treat AA nephrotoxicity."

Journal • Renal Disease • HMOX1 • NFE2L2

Ocuphire Pharma Announces Financial Results for Second Quarter 2023 and Provides Corporate Update (Yahoo Finance) - "Research and development expenses for the three and six months ended June 30, 2023 were $4.7 million and $10.3 million, respectively, compared to $3.2 million and $7.9 million, respectively, for the three and six months ended June 30, 2022. The increases from the comparable periods in 2022 were primarily attributable to increased clinical costs of for Nyxol and APX3330 period over period as well as increased consulting and other costs during the current period."

Commercial • CNS Disorders • Diabetic Macular Edema • Diabetic Retinopathy • Inflammatory Bowel Disease • Ophthalmology • Pain • Peripheral Neuropathic Pain

Quinones as Neuroprotective Agents. (PubMed, Antioxidants (Basel)) - "Additional neuroprotective quinones that can be regarded as coenzyme Q analogues are idobenone, mitoquinone and plastoquinone. Other endogenous quinones with neuroprotective activities include tocopherol-derived quinones, most notably vatiquinone, and vitamin K. A final group of non-endogenous quinones with neuroprotective activity is discussed, comprising embelin, APX-3330, cannabinoid-derived quinones, asterriquinones and other indolylquinones, pyrroloquinolinequinone and its analogues, geldanamycin and its analogues, rifampicin quinone, memoquin and a number of hybrid structures combining quinones with amino acids, cholinesterase inhibitors and non-steroidal anti-inflammatory drugs."

Journal • Review • Alzheimer's Disease • CNS Disorders • Movement Disorders • Parkinson's Disease

ZETA-1 Phase 2 Trial Efficacy Results for APX3330: a Novel, Oral Ref-1 Inhibitor for the Treatment of Diabetic Retinopathy (ASRS 2023) - No abstract available

Clinical • P2 data • Diabetic Retinopathy • Retinal Disorders