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Name: Azeliragon
Synonyms: PF-04494700, TTP488
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Pfizer, TransTech Pharma, Inc., vTv Therapeutics LLC


Azeliragon is an oral, small-molecule inhibitor of RAGE, a cell-surface receptor of the immunoglobulin superfamily. Expressed on multiple cell types, RAGE binds advanced glycation end products (AGEs); these are modified forms of lipids and proteins that become glycated when exposed to sugars. AGEs form during normal aging and in higher amounts in patients with diabetes. When bound to their receptors, AGEs cause inflammation and oxidative damage. RAGE also binds Aβ (Yan et al., 1996), and has been reported to mediate toxic effects of Aβ oligomers in neurons (Mar 2008 news). RAGE is upregulated in astrocytes and microglia in the hippocampi of people with AD (Lue et al., 2005) and is thought to mediate amyloid transport into the brain.

The RAGE antagonist azeliragon blocks this interaction; hence the rationale is that it could provide a combined treatment effect across glial inflammatory and amyloid-related processes. In preclinical studies, the compound decreased brain Aβ load in transgenic mice and improved their performance on behavioral assays.


This compound was discovered by TransTech Pharma as TTP488 and licensed to Pfizer as PF-04494700. In 2005, Pfizer ran a 10-week Phase 2 trial in 67 people with mild to moderate AD. This trial compared two doses—15 mg for six days followed by daily dosing of 5 mg, and 60 mg for six days followed by daily dosing of 20 mg—against placebo for safety and tolerability. Both doses were reported to be safe and well-tolerated, with more people in the treatment groups completing the trial than people in the placebo group (Sabbagh et al., 2011).

In 2007, Pfizer and the National Institute on Aging jointly funded a larger, 18-month Phase 2 trial run via the Alzheimer's Disease Cooperative Study (ADCS). This trial recruited 399 people with mild to moderate AD and evaluated the same doses for safety and efficacy as measured by the ADAS-cog. The higher dose was dropped after a six-month interim analysis flagged both safety signals and faster deterioration. The low dose was halted before its intended conclusion following a futility analysis that indicated no benefit; however, follow-up examination conducted after treatment was suspended did suggest a possible belated clinical benefit for the low dose (Nov 2011 conference newsGalasko et al., 2014). A subgroup analysis reported numerical group differences in mild AD, favoring the low dose over placebo, and linked higher plasma levels of TTP488 to slower cognitive decline (Burstein et al., 2014Burstein et al., 2018).

Pfizer terminated its work with TTP488 in 2011. Pfizer had previously been developing this compound for diabetic neuropathy but discontinued this program as well. 

In March 2013, TransTech Pharma announced in a press release that it had received fast-track designation from the Food and Drug Administration for this compound in Alzheimer's disease, and in July it announced that it had met with the FDA and was planning a pivotal trial in patients with mild to moderate AD.

In May 2015, TransTech Pharma became vTv Therapeutics.

One month before the name change, a Phase 3 trial of azeliragon began; it ran at 115 study locations in North America, Australia, New Zealand, South Africa, the U.K., and Ireland. Called STEADFAST, this study compared an 18-month course of the 5 mg daily dose to placebo in 880 people who have a clinical diagnosis of mild probable Alzheimer's disease and an MRI consistent with this diagnosis. The trial did not use CSF or amyloid PET to ascertain that Alzheimer's underlies the clinical symptoms. The twin primary outcomes were the ADAS-cog and CDR-sum of boxes; secondary outcomes included MRI and FDG-PET, plasma Aβ levels, and neuropsychiatric, functional, and cognitive measures.

In April 2018, vTv announced that STEADFAST had failed to meet its co-primary endpoint (April 2018 news). The trial was set to run until June 2019 but was terminated in June 2018. A two-year, open-label extension study to evaluate continued safety parameters and progression slopes had been projected to enroll 640 STEADFAST completers and run through 2020; however, in June 2018, with 298 people enrolled, it was terminated as well.

At subsequent conferences, the investigators reported subgroup analyses claiming a benefit on both the ADAS-cog and CDR-sum of boxes in participants with Type 2 diabetes and elevated concentrations of acetylated hemoglobin (HBA1c), a RAGE ligand (Nov 2018 conference news, AD/PD slide set; AAIC 2019 abstract).

In June 2019, vTv began a Phase 2/3 trial of azeliragon in a planned 300 participants with a clinical diagnosis of mild Alzheimer’s disease and high HbA1c. In the first phase, approximately 100 volunteers were to receive 5 mg drug, once a day, or placebo, for six months; the primary outcome is change from baseline in ADAS-Cog. Results from this group were expected by the end of 2020. In a second phase, an additional 200 were to be randomized to treatment or placebo for 18 months, with the primary endpoints of ADAS-Cog and CDR-sum of boxes at the end of treatment. The study was being conducted at 31 sites in the U.S. and Canada, and slated to end in 2023. At the end of 2020, the company announced azeliragon had missed its endpoint of slowing decline on the ADAS-Cog in 43 participants after six months (Dec 2020 news). The trial was terminated, and development of azeliragon for Alzheimer’s stopped.

For all trials of azeliragon, see and

Clinical Trial Timeline

  • Phase 2/3
  • Phase 3
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034
vTv Therapeutics LLC NCT02080364
vTv Therapeutics LLC NCT03980730

Last Updated: 02 Feb 2021


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News Citations

  1. Door Slams on RAGE
  2. Fighting RAGE No Help to Alzheimer’s Disease Patients
  3. Trials of Diabetes-Related Therapies: Mainly a Bust
  4. Positive Phase 2 Results Claimed for Masitinib in Alzheimer’s
  5. Aβ Oligomers and Synaptic Dysfunction—Blame It on RAGE?

Paper Citations

  1. . PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease. Alzheimer Dis Assoc Disord. 2011 Jul-Sep;25(3):206-12. PubMed.
  2. . Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease. Neurology. 2014 Apr 29;82(17):1536-42. Epub 2014 Apr 2 PubMed.
  3. . Effect of TTP488 in patients with mild to moderate Alzheimer's disease. BMC Neurol. 2014 Jan 15;14:12. PubMed.
  4. . 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. PubMed.
  5. . RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature. 1996 Aug 22;382(6593):685-91. PubMed.
  6. . Preventing activation of receptor for advanced glycation endproducts in Alzheimer's disease. Curr Drug Targets CNS Neurol Disord. 2005 Jun;4(3):249-66. PubMed.

External Citations

  1. AD/PD slide set
  2. AAIC 2019 abstract

Further Reading


  1. . Synthesis and structure-activity relationships of tri-substituted thiazoles as RAGE antagonists for the treatment of Alzheimer's disease. Bioorg Med Chem Lett. 2012 Dec 15;22(24):7555-61. PubMed.
  2. . Hypertension induces brain β-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature. Hypertension. 2012 Jul;60(1):188-97. PubMed.
  3. . Hypertension induces brain β-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature. Hypertension. 2012 Jul;60(1):188-97. PubMed.
  4. . RAGE: a potential target for Abeta-mediated cellular perturbation in Alzheimer's disease. Curr Mol Med. 2007 Dec;7(8):735-42. PubMed.
  5. . RAGE and amyloid beta interactions: atomic force microscopy and molecular modeling. Biochim Biophys Acta. 2005 Jun 30;1741(1-2):199-205. PubMed.
  6. . RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. EMBO J. 2004 Oct 13;23(20):4096-105. PubMed.
  7. . Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer's disease: identification of a cellular activation mechanism. Exp Neurol. 2001 Sep;171(1):29-45. PubMed.
  8. . Assessment of Azeliragon QTc Liability Through Integrated, Model-Based Concentration QTc Analysis. Clin Pharmacol Drug Dev. 2019 May;8(4):426-435. Epub 2019 Apr 1 PubMed.
  9. . Short-term pharmacologic RAGE inhibition differentially affects bone and skeletal muscle in middle-aged mice. Bone. 2019 Jul;124:89-102. Epub 2019 Apr 24 PubMed.
  10. . Activation of the receptor for advanced glycation end products and consequences on health. Diabetes Metab Syndr. 2017 Oct - Dec;11(4):305-309. Epub 2016 Sep 4 PubMed.