FDA Grants Orphan Drug Designation to Azeliragon for Patients with Glioblastoma


Azeliragon has been granted an orphan drug designation by the FDA for patients with glioblastoma after previous trials demonstrated the agent to be well-tolerated in Alzheimer’s disease.

The FDA has granted orphan drug designation to azeliragon (formerly TTP488) as a treatment for patients with glioblastoma (GBM), according to Cantex Pharmaceuticals.1

Azeliragon is a well-tolerated, once-a-day pill, which is orally administered. The agent is a small molecule antagonist of the receptor for advanced glycation endproducts (RAGE), andinhibits RAGE interactions with certain ligands, including HMGB1 and S100 proteins in the GBM microenvironment. Through preventing interaction of RAGE with these ligands, azeliragon may inhibit GBM and overcome its resistance to effective treatment.

Cantex Pharmaceuticals licensed the drug from vTv Therapeutics Inc, which had originally been under development for patients with Alzheimer’s disease.

“Receiving FDA orphan drug status for azeliragon highlights the significant unmet need for novel treatment options for patients with GBM, the most common and lethal primary brain cancer,” said Stephen G. Marcus, MD, chief executive officer of Cantex, in a press release. “This designation validates our continued commitment to developing new treatment options for patients with GBM, as well as for other cancers and their complications, including breast cancer, cancer chemotherapy–related cognitive decline, pancreatic cancer, and cancers such as breast and lung that have metastasized to the brain.”

In previous trials which evaluated azeliragon in over 2000 patients with Alzheimer’s, clinical safety data were promising and showed the agent to be well-tolerated. These patients with Alzheimer’s who were enrolled in the studies received up to 18 months of treatment with azeliragon.2

Patients with Alzheimer’s were administered 5 mg/day of azeliragon. Findings showed that this dose delayed the time to cognitive deterioration (7-point change in ADAS-cog from baseline, log rank P = .0149).

Based on these promising results from this phase 2b study, the registrational, phase 3 STEADFAST trial (NCT02080364) was initiated under a Special Protocol Assessment from FDA. The study aimed to evaluate the efficacy and safety of azeliragon in patients with mild Alzheimer's disease. Those enrolled were given either azeliragon or placebo for approximately 18 months. However, the trial was ultimately terminated due to lack of efficacy at the 5 mg/kg dose.3

In addition to GBM, Cantex is working on developing azeliragon for the treatment of other cancers where RAGE-mediated resistance and treatment-related complications have resulted in poor outcomes for patients.

Cantex Pharmaceuticals receives FDA orphan drug designation for azeliragon for the treatment of glioblastoma. News release. Cantex Pharmaceuticals. January 9, 2023. Accessed January 10, 2023. https://prn.to/3CCF5w2
Burstein AH, Sabbagh M, Andrews R, et al. Development of azeliragon, an oral small molecule antagonist of the receptor for advanced glycation endproducts, for the potential slowing of loss of cognition in mild Alzheimer’s disease. J Prev Alzheimers Dis. 2018;5(2):149-154. doi:10.14283/jpad.2018.18
Evaluation of the efficacy and safety of azeliragon (TTP488) in patients with mild Alzheimer’s disease (STEADFAST). ClinicalTrials.gov. Updated May 7, 2021. Accessed January 10, 2023. https://clinicaltrials.gov/ct2/show/NCT02080364
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