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

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

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

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

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

New P1 trial • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

The RAGE Inhibitor TTP488 (Azeliragon) Demonstrates Anti-Tumor Activity and Enhances the Efficacy of Radiation Therapy in Pancreatic Cancer Cell Lines. (PubMed, Cancers (Basel)) - "Additionally, Azeliragon modulated the immune suppressive tumor microenvironment in pancreatic cancer by reducing immunosuppressive cells, including M2 macrophages, regulatory T cells, and myeloid-derived suppressor cells, while enhancing CD8+ T cell infiltration. These findings suggest that Azeliragon, by inhibiting RAGE-mediated signaling and modulating immune response, may serve as an effective anti-cancer agent in pancreatic cancer."

Journal • Preclinical • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CD8

RAGE Inhibition to Decrease Cardiotoxicity in Women With Early Breast Cancer (clinicaltrials.gov) - P1/2 | N=48 | Recruiting | Sponsor: Georgetown University | Trial completion date: Nov 2024 ➔ Apr 2025 | Trial primary completion date: Nov 2024 ➔ Mar 2025

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

The RAGE Inhibitor TTP488 (Azeliragon) Demonstrates Anti-Tumor Activity and Enhances the Efficacy of Radiation Therapy in Pancreatic Cancer Cell Lines (Multidisciplinary Digital Publishing Institute) - "Azeliragon demonstrated significant growth delay in mouse models of pancreatic cancer and additive effects when combined with RT. Additionally, Azeliragon modulated the immune suppressive tumor microenvironment in pancreatic cancer by reducing immunosuppressive cells, including M2 macrophages, regulatory T cells, and myeloid-derived suppressor cells, while enhancing CD8+ T cell infiltration."

Preclinical • Pancreatic Cancer

CANTEX PHARMACEUTICALS RECEIVES FDA ORPHAN DRUG DESIGNATION FOR AZELIRAGON FOR THE TREATMENT OF BRAIN METASTASIS FROM BREAST CANCER (PRNewswire) - "Cantex Pharmaceuticals, Inc...announced today that the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to Cantex's azeliragon for the treatment of brain metastasis from breast cancer."

Orphan drug • Brain Cancer • Breast Cancer • Oncology • Solid Tumor

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

New P1 trial • Brain Cancer • CNS Tumor • Glioma • Malignant Glioma • Oncology • Solid Tumor

Orphan Designation: treatment of breast cancer brain metastases (FDA) - Date Designated: 11/20/2024

Orphan drug • Breast Cancer

Phase II study of azeliragon in combination with radiation therapy in newly diagnosed patients with MGMT-unmethylated glioblastoma (SNO 2024) - P2 | "Azeliragon at 20 mg per day with concurrent RT is well tolerated in patients with GBM. The phase II study is currently enrolling across 8 institutions in the United States (NCT05986851)."

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

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

Enrollment closed • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Dexamethasone and Azeliragon for Management of Post-Resection Cerebral Edema in Patients with Glioblastoma (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: City of Hope Medical Center | N=21 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Ultrasound-Assisted Synthesis of Pyrazoline Derivatives as Potential Antagonists of RAGE-Mediated Pathologies: Insights from SAR Studies and Biological Evaluations. (PubMed, ChemMedChem) - "Our investigation identifies phenylurenyl-pyrazoline 2g as a promising candidate, demonstrating superior efficiency compared to the reference antagonist Azeliragon (IC50 = 13 µM). Compound 2g exhibits potent inhibition of the AGE2-BSA/sRAGE interaction (IC50 = 22 µM) and favorable affinity in Microscale Thermophoresis (MST) assays (Kd = 17.1 µM), along with a favorable safety profile, with no apparent cytotoxicity observed in vitro in the MTS assay. These findings underscore the potential of pyrazoline-derived RAGE antagonists as therapeutic agents for addressing age-related disorders."

Journal • Inflammation

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