Therapeutics

TTP488

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Overview

Name: TTP488
Synonyms: PF-04494700 , RAGE Inhibitor
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Inactive)
Company: Pfizer, TransTech Pharma, Inc.

Background

TTP488 is a small-molecule inhibitor of RAGE, a cell-surface receptor of the immunoglobulin superfamily that 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 receptor, 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 (see related news story). RAGE is upregulated in astrocytes and microglia in the hippocampus of people with AD (Lue et al., 2005and is thought to mediate amyloid transport into the brain. The RAGE antagonist TTP488 blocks this interaction; hence its rationale was that it would 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 originally 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 (see Nov 2011 conference news story). 

Pfizer discontinued its work with this compound in 2011. Previously PF-04494700 had been developed for diabetic neuropathy, but it has been discontinued for this indication. In July 2013, TransTech Pharma announced in a press release that it had met with the Food and Drug Administration and was planning to conduct a pivotal Phase 3 trial in patients with mild to moderate AD (see company release). In a personal communication to AlzForum, Transtech Pharma’s president and CEO, Adnan Mjalli, said the company intends to fund the trial, and start it in 2014.  For clinical trials of PF-04494700, see clinicaltrials.gov.

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References

News Citations

  1. Door Slams 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. . RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature. 1996 Aug 22;382(6593):685-91. PubMed.
  3. . 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.

Other Citations

  1. related news story

External Citations

  1. company release
  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.