azeliragon (TTP488) / vTv Therapeutics, Cantex Pharma - LARVOL DELTA

The Brown Algal Phlorotannin Dieckol Attenuates Amyloid-β Oligomer-Induced Oxidative DNA Damage and Senescence-like Stress in Human Neuron-like Cells. (PubMed, Mar Drugs) - "Differentiated SH-SY5Y cells were pretreated with dieckol (10-50 μmol/L) or the receptor for advanced glycation end products (RAGE) antagonist azeliragon (100 μmol/L) for 24 h, followed by AβO (20 μmol/L) exposure for 24 h. Dieckol concentration-dependently preserved cell viability, as indirectly assessed by the MTT assay and reduced mitochondrial superoxide accumulation...Collectively, dieckol concurrently attenuated mitochondrial oxidative stress, DNA damage response signaling, and senescence-associated alterations. Although these parallel effects support a possible relationship among these processes, their causal and temporal relationships remain to be established."

Journal • Alzheimer's Disease • CNS Disorders • Oncology • CHEK2 • IL1B • IL6 • TNFA

Early experience with azeliragon, a RAGE inhibitor, in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Phase Ib/II CAN-201 NDG trial (ESMO 2024) - P1/2 | "AZE was safely administered in the first two dose levels. Recruitment continues in the higher dose level."

Clinical • Combination therapy • P1/2 data • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • MGMT

Azeliragon, a RAGE inhibitor, in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Preliminary results of phase Ib/II CAN-201 NDG trial. (ASCO 2025) - P1/2 | "Azeliragon in combination with standard RT and TMZ is safe, with no dose-limiting toxicities reported so far at the initial three dose levels. To further explore the safety and efficacy profile of azeliragon, we are now expanding the study to include two additional dose levels of 30 mg/day (L4) and 50 mg/day (L5). Enrollment is currently open for level L4."

Clinical • Combination therapy • P1/2 data • Alzheimer's Disease • Brain Cancer • CNS Disorders • CNS Tumor • Epilepsy • Glioblastoma • Oncology • Solid Tumor • MGMT

RAGE Antagonist Azeliragon Modulates Adipose Tissue Mitochondrial Metabolism in Obese Mice (OBESITY WEEK 2026) - No abstract available

Preclinical • Obesity

Rage inhibition suppresses immune cell infiltration and antigen presentation in an outbred model of diabetic kidney disease (EASD 2026) - "Materials and Diabetes was induced using multiple-low-dose streptozotocin in male (n=12) outbred CD-1 mice (6-8 weeks old) followed by intragastric therapy from 10 weeks age: (i) RAGE antagonist Azeliragon (AZ) (3 mg/kg/day, 3x per week), (ii) Placebo (3x per week) for 12 weeks... RAGE signaling in PTECs promotes dendritic cell and macrophage infiltration which enhances tubular antigen presentation that drives inflammation in DKD."

Immune cell • Diabetes • Metabolic Disorders • ANPEP • CD8

Immune profiling a CD-1 mouse model of diabetes complications following RAGE antagonism therapy following RAGE antagonism therapy (EASD 2026) - "Groups of mice with/without diabetes (n=7-12) were treated from 10-22 weeks of age with the RAGE antagonist Azeliragon (Az) or placebo (intragastrically, 3 mg/kg/day, 3x per week)... Diabetes specific immune changes were seen in splenic and mesenteric immune compartments but not in the blood. RAGE antagonism showed immunomodulatory effects, increasing Tregs and attenuating diabetes associated increases in moDCs and RAGE expression on T cells."

Preclinical • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus • CD4 • CD8 • FOXP3 • IL2RA • ITGAM • ITGAX

The RAGE antagonism with azeliragon prevents MASLD and hepatic insulin resistance by modulating glycolipid metabolism and dicarbonyl stress in diet-induced dysmetabolic mice (EASD 2026) - "Pharmacological antagonism of RAGE with AZ reprograms hepatic substrate utilization and reduces carbonyl stress in western diet-induced obesity independently of caloric intake. Targeting the AGE-RAGE axis may represent an effective novel therapeutic strategy for MASLD and hepatic insulin resistance."

Preclinical • Diabetes • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus • PDHA1 • PDK4

Study of Trastuzumab Deruxtecan (T-DXd) in Combination With a RAGE Inhibitor in Patients With T-DXd-Resistant HER2-Positive or HER2-Low Metastatic Breast Cancer (clinicaltrials.gov) - P1/2 | N=27 | Not yet recruiting | Sponsor: The Methodist Hospital Research Institute

New P1/2 trial • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Targeting the S100A2-RAGE Pathway Restores AT2 Cell Identity and Mitigates Lung Fibrosis. (PubMed, Am J Respir Cell Mol Biol) - "We demonstrate that pharmacologic inhibition of RAGE using Azeliragon preserves AT2 cell populations, associated with reduced oxidative stress in iAT2 cells, and significantly attenuates collagen deposition in bleomycin-induced lung fibrosis models. Collectively, our results indicate that S100A2 is a key driver of epithelial dysfunction in lung fibrosis, promoting loss of AT2 identity, aberrant basal fate acquisition, and persistent epithelial injury. Targeting the unrecognized S100A2-RAGE pathway may offer a new therapeutic strategy to restore epithelial homeostasis in lung fibrosis."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases

Targetable S100-RAGE signaling mediates intrinsic trastuzumab deruxtecan resistance in metastatic breast cancer. (PubMed, Clin Cancer Res) - "Spatial proteogenomics identifies a conserved S100-RAGE-driven survival state coupled to immune-excluded tumor architecture as a mechanism of intrinsic T-DXd resistance across metastatic niches. Targeting this pathway with an orally available RAGE antagonist restores T-DXd responsiveness and offers an immediately translatable strategy to overcome resistance in metastatic breast cancer."

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

Steroid Avoidance, Dexamethasone, and RAGE Inhibition for Perioperative Cerebral Edema Management in High-Grade Gliomas (clinicaltrials.gov) - P2 | N=80 | Not yet recruiting | Sponsor: Akshitkumar MIstry

New P2 trial • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor

ADORATION: Effect of Azeliragon Combined With Stereotactic Radiation Therapy in Patients With Brain Metastases (clinicaltrials.gov) - P1/2 | N=46 | Suspended | Sponsor: Baptist Health South Florida | Recruiting ➔ Suspended

Trial suspension • Brain Cancer • Oncology • Solid Tumor

Azeliragon, a RAGE inhibitor, plus temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Final results from a dose-finding phase in the CAN-201 NDG trial. (ASCO 2026) - P1/2 | "Azeliragon at 50 mg/day in combination with standard RT / TMZ is safe, with no DLTs reported. More mature OS data will be presented. Further follow-up with a larger number of pts is required to assess preliminary efficacy."

Clinical • Alzheimer's Disease • Anorexia • Brain Cancer • CNS Disorders • Glioblastoma • Hematological Disorders • Solid Tumor • Thrombocytopenia • MGMT

CAN-201 NDG: Azeliragon and Chemoradiotherapy in Newly Diagnosed Glioblastoma (clinicaltrials.gov) - P1/2 | N=33 | Completed | Sponsor: Cantex Pharmaceuticals | Active, not recruiting ➔ Completed | N=18 ➔ 33 | Trial completion date: Dec 2026 ➔ Apr 2026 | Trial primary completion date: Dec 2026 ➔ Apr 2026

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • S100A9

Concurrent Azeliragon With Craniospinal Irradiation (clinicaltrials.gov) - P1 | N=21 | Active, not recruiting | Sponsor: NYU Langone Health | Recruiting ➔ Active, not recruiting | N=32 ➔ 21

Enrollment change • Enrollment closed • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor

Cancer-associated fibroblast-derived protein S100-A11 influences the response to anti-HER2 therapies in HER2-positive breast cancer. (PubMed, Neoplasia) - "In this study, we investigated the role of stromal/CAF-derived S100-A11 in the response to trastuzumab, pertuzumab, and docetaxel (TPD) therapy...In a reductionist xenograft model, RAGE inhibition with azeliragon attenuated the effect of exogenous S100-A11 on tumour response to TPD...Moreover, the partial reversibility of this phenotype through pharmacological inhibition of RAGE or STAT3 suggests that stromal signalling pathways may represent potential targets for therapeutic intervention. Overall, these findings expand current perspectives on resistance by incorporating the contribution of therapy-associated stromal responses and support further investigation into combinatorial strategies targeting both tumour cells and their TME."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CAFs • S100A11

Repurposing Azeliragon as a novel antibacterial agent against methicillin-resistant Staphylococcus aureus via combined membrane phospholipids and cell wall targeting. (PubMed, Commun Biol) - "In a murine wound model Azeliragon reduced local bacterial burden and accelerated healing to levels comparable with vancomycin. Azeliragon is a repurposable antibacterial agent that perturbs membrane phospholipid homeostasis and engages MurA-dependent peptidoglycan synthesis. These findings support further preclinical development of Azeliragon or optimized derivatives as potential therapeutics against MRSA and other gram-positive pathogens."

Journal • Infectious Disease • Targeted Protein Degradation

Protective effects of the RAGE inhibitor azeliragon as a potential anti-Streptococcus pneumoniae therapeutic in sepsis models. (PubMed, Front Med (Lausanne)) - "Collectively, these findings provide the first systematic evidence that the RAGE inhibitor azeliragon exerts direct anti-S. pneumoniae activity and affords in vivo protection, supporting its potential as a novel antibacterial candidate for pneumococcal infections."

Journal • Infectious Disease • Pneumococcal Infections • Pneumonia • Septic Shock • IL6 • TNFA

Deconstructing the RAGE signaling maze: the molecular key to opening a new dimension of ovarian anti-aging. (PubMed, Exp Mol Med) - "We highlight therapeutic strategies targeting RAGE, including small-molecule inhibitors (Azeliragon and FPS-ZM1), soluble RAGE decoys and natural compounds, which show promise in restoring ovarian reserve and hormonal balance in preclinical models...Beyond reproductive health, RAGE's role in aging and metabolic disorders underscores its potential as a cross-disciplinary biomarker and therapeutic target. By bridging molecular mechanisms with clinical applications, this work provides a framework for developing precision therapies to combat ovarian aging, with implications for endocrinology, oncology and geroscience."

Journal • Review • Endocrine Disorders • Metabolic Disorders • Oncology • Ovarian Cancer • Polycystic Ovary Syndrome • Solid Tumor • Women's Health

Azeliragon in MGMT Unmethylated Glioblastoma (clinicaltrials.gov) - P2 | N=30 | Active, not recruiting | Sponsor: Cantex Pharmaceuticals | Trial completion date: Jun 2025 ➔ Dec 2026 | Trial primary completion date: Sep 2024 ➔ Sep 2026

Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • MGMT

RAGE Inhibition Reduces Surgery-Induced Cerebral Edema After Glioma Resection. (PubMed, Neurosurgery) - "RAGE inhibitors effectively reduced postoperative CE to a degree comparable with dexamethasone, without compromising the efficacy of immunotherapy or wound healing. These findings suggest that RAGE inhibition may offer a promising steroid-sparing strategy for perioperative management of CE in patients with brain tumor undergoing immunotherapy."

IO biomarker • Journal • Brain Cancer • CNS Disorders • Glioblastoma • Glioma • Oncology • Solid Tumor • Vascular Neurology

CAN-201 NDG: Azeliragon and Chemoradiotherapy in Newly Diagnosed Glioblastoma (clinicaltrials.gov) - P1/2 | N=18 | Recruiting | Sponsor: Cantex Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • S100A9

Phycocyanobilin as a Functional Food-Derived Nutraceutical Candidate for Modulating the RAGE/NOX4 Axis in Neurodegenerative Disorders. (PubMed, Nutrients) - "The overall protective profile of PCB was comparable to that observed with TTP488 at the level of downstream pathway modulation. These findings suggest that PCB mitigates glycation-associated neuronal injury through coordinated regulation of oxidative, ER stress, and mitochondrial apoptotic pathways linked to RAGE/NOX4 signaling, supporting further investigation of PCB as a functional food-derived bioactive in metabolic stress-related neurodegeneration."

Journal • CNS Disorders • Diabetes • Metabolic Disorders • ATF4 • NOX4

CAN-201 NDG: Azeliragon and Chemoradiotherapy in Newly Diagnosed Glioblastoma (clinicaltrials.gov) - P1/2 | N=18 | Active, not recruiting | Sponsor: Cantex Pharmaceuticals | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2026

Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • S100A9

Identification of RAGE Inhibitors from Curcuma caesia Roxb: Implications in Treatment against Diabetic Complications. (PubMed, Curr Diabetes Rev) - "These natural compounds exhibited promising drug-like characteristics against the target protein RAGE and may serve as lead compounds for the development of RAGE inhibitors. The study recommends further in vitro and in vivo investigations to assess the therapeutic potential of these identified compounds in the treatment of diabetic nephropathy."

Journal • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Inflammation • Nephrology • Pain • Renal Disease • Retinal Disorders