Azeliragon

Overview

Azeliragon (TTP488; PF‑04494700) is an oral small‑molecule antagonist of the receptor for advanced glycation end products (RAGE) originally developed for Alzheimer’s disease (AD). After mixed Phase 2 results and two negative Phase 3 trials in mild AD, development in AD was discontinued. Since 2023, the drug has been repurposed by Cantex Pharmaceuticals for oncology and other indications, with FDA Orphan Drug Designations for glioblastoma (January 9, 2023), pancreatic cancer (May 20, 2024), and brain metastasis from breast cancer (December 9, 2024); human efficacy results in these indications have not yet been reported. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

• Target: RAGE, a multiligand pattern‑recognition receptor expressed on neurons, microglia, and brain endothelium. RAGE binds Aβ, HMGB1, and S100 proteins, promoting neuroinflammation, oxidative stress, and Aβ influx across the blood–brain barrier (BBB). Blocking RAGE can reduce Aβ transport into brain and downstream inflammatory signaling in preclinical models. (pubmed.ncbi.nlm.nih.gov)
• Azeliragon is a small‑molecule RAGE antagonist designed to inhibit these ligand–receptor interactions. Reviews and preclinical work support RAGE as a disease‑relevant target in AD. (pmc.ncbi.nlm.nih.gov)

Efficacy (Alzheimer’s disease)

• Phase 2b (ADCS; 18 months; n=399): Two doses were tested. The high dose (20 mg/day after loading) was stopped at 6 months due to more confusion, falls, and faster cognitive decline; the low dose (5 mg/day after loading) later met futility criteria but post‑hoc analyses suggested a possible benefit on ADAS‑Cog at 18 months (Class IV evidence). (pubmed.ncbi.nlm.nih.gov)
• On‑treatment analyses and subgroup analyses (mild AD) favored 5 mg/day (e.g., nominal ADAS‑Cog differences of about 2.7–4.0 points at 18 months), underpinning subsequent low‑dose studies. (pubmed.ncbi.nlm.nih.gov)
• Phase 3 STEADFAST (two parallel, 18‑month, double‑blind trials in mild AD; 5 mg/day): Both Part A and Part B failed to meet co‑primary endpoints (ADAS‑Cog and CDR‑SB). In Part A, mean decline from baseline on ADAS‑Cog was 4.4 points with azeliragon vs 3.3 with placebo; CDR‑SB declines were 1.6 vs 1.6. Similar negative results were reported for Part B. The trials were terminated in 2018. Tabulated results were later posted. (ir.vtvtherapeutics.com)
• Elevage study (mild AD with type 2 diabetes/IGT; Phase 2, 6 months; n=43): Did not meet the primary endpoint; LS‑mean ADAS‑Cog14 decline was 1.8 with azeliragon vs 0.35 with placebo (difference 1.45 points; p=0.17). (cslide.ctimeetingtech.com)

Interpretation: Across controlled trials, azeliragon has not demonstrated reproducible clinical efficacy in mild AD at the studied 5‑mg dose. Signals in post‑hoc or subgroup analyses did not translate into success in Phase 3. (pubmed.ncbi.nlm.nih.gov)

Safety

• In the 18‑month ADCS Phase 2b trial, the high dose (20 mg/day) was associated with increased adverse events (notably confusion and falls) and greater cognitive decline, leading to early discontinuation of that arm. The 5‑mg dose had a “good safety profile” in that study. (pubmed.ncbi.nlm.nih.gov)
• In Phase 3 STEADFAST, top‑line communications and posted results reported no efficacy and did not identify new major safety concerns at 5 mg/day. (ir.vtvtherapeutics.com)
• A pooled exposure–response analysis (711 participants across multiple studies) found no clinically meaningful effect of azeliragon on QTc at therapeutic or supratherapeutic exposures. (accp1.onlinelibrary.wiley.com)

Other development

• Oncology: FDA Orphan Drug Designations have been granted for glioblastoma (2023), pancreatic cancer (2024), and brain metastasis from breast cancer (2024). A Phase 2 glioblastoma study was authorized to proceed by FDA in February 2023. As of October 7, 2025, peer‑reviewed human efficacy results in oncology have not been published. (cantex.com)

Further reading

• Phase 2b ADCS randomized trial (methods and outcomes): Galasko et al., Neurology 2014. (pubmed.ncbi.nlm.nih.gov)
• Phase 2 safety run‑in trial: Sabbagh et al., Alzheimer Disease & Associated Disorders 2011 (author manuscript). (pmc.ncbi.nlm.nih.gov)
• Development overview and Phase 2b summary: Burstein et al., Journal of Prevention of Alzheimer’s Disease 2018. (pmc.ncbi.nlm.nih.gov)
• STEADFAST Part A and Part B top‑line disclosures (negative): vTv Therapeutics press releases, April 9, 2018, and June 12, 2018; results tables later posted. (ir.vtvtherapeutics.com)
• Elevage (AD with diabetes) 6‑month results (negative): AD/PD 2021 abstract; trial record. (cslide.ctimeetingtech.com)
• QTc analysis: Burstein et al., Clinical Pharmacology in Drug Development 2019. (accp1.onlinelibrary.wiley.com)
• RAGE biology in AD and BBB transport: Deane et al., 2003; reviews on RAGE signaling in neurodegeneration. (pubmed.ncbi.nlm.nih.gov)

Notes: Names/aliases include azeliragon, TTP488, and PF‑04494700. Current oncology programs are ongoing; efficacy data will need confirmation in peer‑reviewed publications as they emerge. (cantex.com)

Last updated: Oct 2025