Therapeutics

Azeliragon

Overview

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 (Inactive)
Company: Pfizer, TransTech Pharma, Inc., vTv Therapeutics LLC

Background

Azeliragon is an oral, small-molecule inhibitor of RAGE. This cell-surface receptor of the immunoglobulin superfamily is 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.

Findings

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 news story). 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, 2014).

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.

For all trials of azeliragon, see clinicaltrials.gov and clinicaltrials.gov.

Clinical Trial Timeline

  • 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
vTv Therapeutics LLC NCT02080364
N=800

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References

News Citations

  1. Door Slams on RAGE
  2. Fighting RAGE No Help to Alzheimer’s Disease Patients
  3. 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. . Effect of TTP488 in patients with mild to moderate Alzheimer's disease. BMC Neurol. 2014 Jan 15;14:12. PubMed.
  3. . RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature. 1996 Aug 22;382(6593):685-91. PubMed.
  4. . 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. clinicaltrials.gov
  2. clinicaltrials.gov

Further Reading

Papers

  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.