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

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 | "Clinical Trial Registration Number: NCT05789589 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • P1/2 data • 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 | "Clinical Trial Registration Number: NCT05635734 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

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

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

The RAGE antagonist Azeliragon prevents adiposity and metaflammation in diet-induced obese mice (EASD 2024) - "The results of the present project provide new knowledge on the benefits of RAGE antagonism in obesity and metaflammation and suggest the potential efficacy of Azeliragon treatment in humans as strategy to prevent type 2 diabetes."

Preclinical • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • CSF2 • CXCL1 • IL10 • IL6 • LEP • RETN

Microbiota-induced S100A11-RAGE axis underlies immune evasion in right-sided colon adenomas and is a therapeutic target to boost anti-PD1 efficacy. (PubMed, Gut) - "Our findings unravelled that dysfunctional goblet cells and consequential bacterial translocation activated the S100A11-RAGE axis in right-sided colon ADs, which recruits MDSCs to promote immune evasion. Targeting this axis by Azeliragon improves the efficacy of immunotherapy in colon cancer."

IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD8 • S100A11

Azeliragon in MGMT Unmethylated Glioblastoma (clinicaltrials.gov) - P2 | N=30 | Active, not recruiting | Sponsor: Cantex Pharmaceuticals | Recruiting ➔ Active, not recruiting

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

Study of Effect of Azeliragon in Patients Refractory to Prior Treatment of Metastatic Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=30 | Recruiting | Sponsor: Cantex Pharmaceuticals | N=18 ➔ 30 | Trial completion date: Nov 2024 ➔ May 2025 | Trial primary completion date: Oct 2024 ➔ Feb 2025

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

RAGE inhibition to decrease cancer therapy related cardiotoxicity in women with early breast cancer (RAGE). (ASCO 2024) - P1/2 | "In Cohort 1, 6 patients will receive dose dense paclitaxel (ddT). In Cohort 2, 6 patients will receive docetaxel and cyclophosphamide (TC). In Cohort 3, 6 patients will receive docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP). In Cohort 4, 6 patients will receive dose dense doxorubicin and cyclophosphamide (ddAC)...As of 2/1/24, 4 patients have been enrolled, with 4 undergoing screening. At the completion of this trial, we plan a randomized trial to evaluate the role of TTP488 to decrease cardiotoxicity, cancer related cognitive decline and disease recurrence."

Clinical • Breast Cancer • Cardiovascular • Oncology • Solid Tumor

A phase I/II open label study to assess safety and preliminary evidence of a therapeutic effect of azeliragon in patients refractory to first-line treatment of metastatic pancreatic cancer. (ASCO 2024) - P1/2 | "RAGE interaction with its ligands, including S100 proteins and HMGB1 released from PDAC cells, promotes PDAC invasion, metastasis, and resistance to 5 FU and Gemcitabine...Secondary endpoints include disease control, overall survival, changes in pain as determined by the Brief Pain Inventory, and changes in ECOG performance status, weight, and serum albumin. The study received regulatory approval and accrual started in June 2023."

Clinical • Metastases • P1/2 data • Alzheimer's Disease • CNS Disorders • Gastrointestinal Cancer • Hepatology • Neuralgia • Oncology • Pain • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • HMGB1

Azeliragon, a RAGE inhibitor, in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Phase Ib/II CAN-201 NDG trial design. (ASCO 2024) - P1/2 | "The study received regulatory approval and accrual started in September 2023. As of January 2024, recruitment in dose level 1 was completed with 6 patients and 3 patients were already included in dose level 2."

Clinical • Combination therapy • P1/2 data • Alzheimer's Disease • Brain Cancer • CNS Disorders • CNS Tumor • Fatigue • Glioblastoma • Infectious Disease • Oncology • Solid Tumor • HMGB1 • MGMT • S100A9

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 2024) - P1/2 | "Neurocognitive batteries, symptom inventories, and quality-of-life questionnaires will also be administered. Three participants have been enrolled in the starting cohort and are pending DLT assessment."

Clinical • P1/2 data • Oncology • Solid Tumor • S100A9

Involvement of RAGE in radiation-induced acquisition of malignant phenotypes in human glioblastoma cells. (PubMed, Biochim Biophys Acta Gen Subj) - "Both phenotypes were suppressed by specific inhibitors of RAGE (FPS-ZM1 and TTP488) or by knockdown of RAGE...In addition, γ-irradiation-induced phosphorylation of STAT3 was suppressed by RAGE inhibitors, and a STAT3 inhibitor suppressed γ-irradiation-induced enhancement of cell migration, indicating that STAT3 is involved in the migration enhancement downstream of RAGE. Our results suggest that HMGB1-RAGE-STAT3 signaling is involved in radiation-induced enhancement of GBM cell migration, and may contribute to GBM recurrence by promoting metastasis and invasion."

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