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

Decoding resistance to trastuzumab deruxtecan in metastatic breast cancer: S100P signaling and immune-niche barriers (SABCS 2025) - "Functional validation included CRISPR-Cas9–mediated knockout and lentiviral overexpression of S100P, RAGE inhibition with azeliragon, and in vivo xenograft models. T-DXd response was not associated with HER2 (p=0.128), ER (p=0.832), PR (p=0.617), or Ki-67 (p=0.212). Prior T-DM1 exposure predicted improved response (OR=5.27, p=0.048)... Resistance to T-DXd is driven by tumor-intrinsic S100P-RAGE signaling and reinforced by niche-specific microenvironments—particularly in the brain—characterized by immunosuppressive astrocyte and macrophage programs. These findings nominate S100P, RAGE, and brain niche-derived stromal pathways as actionable targets to overcome resistance and extend the efficacy of T-DXd in MBC."

Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CD163 • FABP4 • HER-2 • S100P

A phase II study of azeliragon in combination with radiation therapy in newly diagnosed patients with MGMT-unmethylated glioblastoma. (SNO 2025) - P2 | " In this multi-institutional, single-arm, open-label phase II trial, patients with unmethylated GBM received azeliragon with RT (60 Gy/30 fractions) without temozolomide or tumor-treating fields. The combination of azeliragon and RT was well tolerated but did not improve PFS. Patients with lower baseline ALC may benefit from MDSC modulation, warranting further investigation."

Clinical • Combination therapy • P2 data • Brain Cancer • Glioblastoma • Solid Tumor • MGMT

Trial in progress: phase IB study of concurrent Azeliragon, a RAGE inhibitor, with craniospinal irradiation in patients with leptomeningeal metastases (SNO 2025) - P1 | "Patient and disease characteristics will be analyzed descriptively. This study was activated on 2/19/2025 with 6 patients (2 patients with metastatic solid tumors and 4 patients with high grade gliomas) enrolled at time of submission."

Clinical • P1 data • Brain Cancer • Glioma • High Grade Glioma • Solid Tumor

Development of New Benzo[b]Thiophene-2-Carboxamide Derivatives as Advanced Glycation End-Products Receptor (RAGE) Antagonists. (PubMed, ChemMedChem) - "In light of LCMS, NMR, X-ray, and DFT studies, a mechanism for this reaction was proposed. This novel strategy enabled us to synthesize analogs whose best molecule 3t', with an IC50 of 13.2 µM, shows similar interactions with RAGE as the reference molecule Azeliragon (13.0 µM)."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Diabetes • Metabolic Disorders • Oncology

A phase II study of azeliragon in combination with radiation therapy in newly diagnosed patients with MGMT-unmethylated glioblastoma. (WFNOS 2025) - P1, P2 | " In this multi-institutional, single-arm, open-label phase II trial, patients with unmethylated GBM received azeliragon with RT (60 Gy/30 fractions) without temozolomide or tumor-treating fields. The combination of azeliragon and RT was well tolerated but did not improve PFS. Patients with lower baseline ALC may benefit from MDSC modulation, warranting further investigation."

Clinical • Combination therapy • P2 data • Brain Cancer • Glioblastoma • Glioma • High Grade Glioma • Solid Tumor • MGMT

Trial in progress: phase IB study of concurrent Azeliragon, a RAGE inhibitor, with craniospinal irradiation in patients with leptomeningeal metastases (WFNOS 2025) - P1 | "Patient and disease characteristics will be analyzed descriptively. This study was activated on 2/19/2025 with 6 patients (2 patients with metastatic solid tumors and 4 patients with high grade gliomas) enrolled at time of submission."

Clinical • P1 data • Brain Cancer • Glioma • High Grade Glioma • Solid Tumor

ADORATION: Effect of Azeliragon Combined With Stereotactic Radiation Therapy in Patients With Brain Metastases (clinicaltrials.gov) - P1/2 | N=46 | Recruiting | Sponsor: Baptist Health South Florida | Trial primary completion date: Oct 2025 ➔ Mar 2027

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

Hyperglycaemic Stress Due to Age/Rage Pathway Increases Dipeptidyl-Peptidase 4 and Extracellular Vesicle (EV) Release in Human Proximal Tubule Cells (KIDNEY WEEK 2025) - "50µM of TTP488 (Azeliragon) inhibited the receptor for AGE (RAGE)'s function...This aligns with our previous in-vivo data in DKD-patients. The DPP4/MME positive EVs, elevated in our in vitro and patient samples, could represent a novel tool to detect DKD earlier in disease-course than currently employed strategies."

Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • DPP4

Neoadjuvant Chemoradiotherapy With or Without Concurrent Azeliragon in Patients With Newly Diagnosed Glioblastoma (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: Washington University School of Medicine | Not yet recruiting ➔ Recruiting

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

RAGE signaling pathway in glioblastoma and cognitive decline: Insights into inflammatory mechanisms and therapeutic implications. (PubMed, Brain Res) - "Small-molecule inhibitors such as FPS-ZM1 and Azeliragon, biologics including sRAGE and RAGE antagonistic peptides, and phytochemicals such as curcumin, Tanshinone IIA, and berberine demonstrate the feasibility of modulating this pathway in preclinical models. Collectively, the evidence highlights the RAGE signaling as one of the central modulators of GBM progression and RT-induced cognitive decline through NF-κB, JAK/STAT, and MAPK activation. Future strategies that selectively disrupt pathological RAGE signaling, while sparing physiological functions, may provide transformative therapeutic avenues for patients facing the dual burden of glioblastoma and radiation-induced neurotoxicity."

Journal • Brain Cancer • CNS Disorders • Glioblastoma • Glioma • Oncology • Solid Tumor • HMGB1

HMGB1-Induced Neurite Outgrowth in the Dorsal Root Ganglion Neurons and Regeneration Priming after their Axonal Injury by Sciatic Nerve Crush. (PubMed, J Neuroimmune Pharmacol) - "However, the neurite regeneration priming of DRG neurons by SNC in mice was prevented by daily treatment with HMGB1-Ab, minocycline, a macrophage/microglia inhibitor, ethyl pyruvate capable of inhibiting HMGB1 release from macrophages, and azeliragon, a RAGE antagonist. Our data suggest that extracellular at-HMGB1 causes RAGE-dependent acceleration of neuritogenesis in cultured DRG neurons, which is suppressed synergistically by thrombin and TMα. Nonetheless, neurite regeneration priming of DRG neurons by SNC is considered to involve HMGB1 derived from macrophages recruited to the damaged axon, but is not mediated by HMGB1 released from cultured DRG cells."

Journal • ANGPT1 • HMGB1

AZELIRAGON ATTENUATES AGGRAVATION OF CEREBRAL INFARCTION IN DIABETIC RATS: RECEPTOR FOR ADVANCED GLYCATION END-PRODUCT AS A NOVEL THERAPEUTIC TARGET (WSC 2025) - "The ratio of phosphorylated to total NF-κB p65 decreased significantly in the azeliragon group compared to the vehicle group (P < 0.05). The increased levels of both TNF-α and IL-1β following cerebral ischemia were significantly reduced in the azeliragon group compared to the vehicle group (P < 0.05 for each).ConclusionsThese findings suggest that RAGE antagonism can ameliorate ischemic brain damage and neuroinflammation in diabetic stroke, offering a promising therapeutic strategy."

Metastases • Preclinical • Cardiovascular • CNS Disorders • Diabetes • Inflammation • Ischemic stroke • Metabolic Disorders • Vascular Neurology • IL1B • NFKB1 • TNFA

RAGE antagonism restores immune homeostasis and improves kidney function in an outbred CD-1 mouse model of diabetic kidney disease (EASD 2025) - "In this study, we investigated the efficacy of targeting RAGE in diabetic kidney disease, by specifically evaluating its effects on the immune cell compartment in a novel outbred preclinical model.Materials and Diabetes was induced in groups (n=12) of outbred male CD-1 mice (6-8 weeks old) followed by intragastric therapy at 10 weeks age: (i) RAGE antagonist Azeliragon (Az) (3 mg/kg/day, 3x per week), (ii) Ramipril (ACE inhibitor; 3mg/kg/day, 5x per week) and (iii) Placebo (3x per week) for a duration of 12 weeks... Taken together, these findings suggest that RAGE antagonism may improve kidney function, mitigate kidney inflammation and enhance immune regulation via Treg-mediated mechanisms. Further studies will investigate the mechanisms by which kidney and immune cell interactions contribute to inflammation in DKD and are alleviated by Az, a RAGE antagonist known to have a good safety profile in humans in previous Phase II clinical trials."

Preclinical • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus • CD4 • CD8 • CST3 • FOXP3 • IL2RA • ITGAM

Unravelling Neuronal Death Mechanisms: The Role of Cytokines and Chemokines in Immune Imbalance in Alzheimer's Disease Progression. (PubMed, Ageing Res Rev) - "Therapeutic drugs such as Magnolol, Necrostatin-1, Salidroside, Azeliragon, DNL788, Baricitinib, Sargramostim, etc. targeting neuroinflammation-associated signaling pathways, have shown efficacy in preclinical and clinical studies mitigating AD pathology. Enhancing our comprehension of neuronal death mechanisms could elucidate disease pathogenesis, offer insights for therapeutic approaches, and aid in developing modified animal models of AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Inflammation • AMPK • GPX4 • NLRP3 • RIPK1 • STING

Mechanisms of Pain Hypersensitivity in a Human Skin Inflammation Model (clinicaltrials.gov) - P1 | N=42 | Completed | Sponsor: Stefan Heber

New P1 trial • Dermatitis • Immunology • Inflammation • Pain

The RAGE Inhibitor TTP488 (Azeliragon) Improves Diabetic Bladder Dysfunction in Leptin-Deficient Obese Mice. (PubMed, Antioxidants (Basel)) - "TTP488 reduced total void volume, volume per void, and ex vivo bladder contractility in response to electrical-field stimulation and carbachol. Our finding that TTP488 mitigates DBD in ob/ob mice supports the proposal that RAGE blockade could serve as a promising therapeutic strategy for managing DBD."

Journal • Preclinical • Leptin Receptor Deficiency Obesity • Obesity • Urology • LEP

Neoadjuvant Chemoradiotherapy With or Without Concurrent Azeliragon in Patients With Newly Diagnosed Glioblastoma (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: Washington University School of Medicine | Trial completion date: May 2029 ➔ Apr 2030 | Trial primary completion date: Oct 2027 ➔ Oct 2028

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

RAGE Is Essential for Subretinal Fibrosis in Laser-Induced Choroidal Neovascularization: Therapeutic Implications. (PubMed, Invest Ophthalmol Vis Sci) - "The role of RAGE in EMT was studied in cells pretreated with RAGE antagonists (FPS-ZM1 or azeliragon), followed by cotreatment with TGF-β2 for 48 hours...FPS-ZM1 blocked TGF-β2-induced Smad2-dependent signaling and EMT without affecting the extracellular signal-regulated kinase (ERK) pathway. Our findings indicate that RAGE plays a role in RPE cell EMT in subretinal fibrosis and that RAGE antagonists attenuate this process, making RAGE a promising therapeutic target for subretinal fibrosis in nAMD."

Journal • Age-related Macular Degeneration • Fibrosis • Immunology • Inflammation • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration • TGFB1 • TGFB2

A phase I/II study to assess safety and preliminary evidence of a therapeutic effect of azeliragon combined with stereotactic radiation therapy in patients with brain metastases (ADORATION). (ASCO 2025) - P1/2 | "Azeliragon was safely substituted for corticosteroids in this phase 1 study with no DLTs observed. The early response rate appears encouraging and accrual to the phase II expansion cohort (n = 40) with a primary endpoint of objective response rate is ongoing."

Clinical • P1/2 data • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

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

The Receptor for Advanced Glycation Endproducts (RAGE) Mediates Bacterial Second Messenger-skewed Allergen and IL-33 Driven Neutrophilic Airway Inflammation in Mice (ATS 2025) - "Additional studies were performed using the RAGE-specific small molecule antagonist Azeliragon (AZR)... Overall, these studies demonstrate that RAGE is a critical mediator of the innate immune response to allergen or IL-33 driven neutrophilic airway inflammation associated with the presence of bacterial components, making RAGE an intriguing therapeutic target to reduce aberrant neutrophilia in airway diseases such as severe asthma."

Metastases • Preclinical • Asthma • Infectious Disease • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • CXCL1 • ELANE • IFNG • IL1B • IL33 • IL6 • TNFA

RAGE Inhibition to Decrease Cardiotoxicity in Women With Early Breast Cancer (clinicaltrials.gov) - P1/2 | N=48 | Recruiting | Sponsor: Georgetown University | Trial completion date: Apr 2025 ➔ Oct 2025 | Trial primary completion date: Mar 2025 ➔ Oct 2025

Trial completion date • Trial primary completion date • Breast Cancer • Cardiovascular • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Miami Cancer Institute to Present Latest Research at 2025 Annual Meeting of the American Society of Clinical Oncology (Baptist Health South Florida) - "Miami Cancer Institute, part of Baptist Health South Florida, today announced its presentations at this year’s annual meeting of the American Society of Clinical Oncology (ASCO), May 30 – June 3, at McCormick Place in Chicago, Illinois. Miami Cancer Institute’s presentations this year include advances in the treatment of glioblastoma, brain metastases, breast cancer, as well as testicular and bladder cancer....'The research presented covers a study into liquid biopsy in glioblastoma patients, a new approach using transcranial ultrasound to treat brain metastases, and results from a trial studying a combination immunotherapy in patient with rare tumor brain cancer metastases, among many others.'"

Clinical data • Diagnostic • Bladder Cancer • Breast Cancer • Glioblastoma • HER2 Positive Breast Cancer • Non Small Cell Lung Cancer • Testicular Cancer

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

Enrollment open • Brain Cancer • CNS Tumor • Glioma • Malignant Glioma • Oncology • Solid Tumor

A Randomized, Double-Blind, Placebo-Controlled Phase 2/3 Study to Determine the Safety and Effectiveness of Azeliragon in the Treatment of Patients Hospitalized for Coronavirus Disease 2019 (COVID-19) or Pneumonia (clinicaltrials.gov) - P2/3 | N=144 | Active, not recruiting | Sponsor: The University of Texas Medical Branch, Galveston | Recruiting ➔ Active, not recruiting

Enrollment closed • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases