Therapeutics

Thalidomide

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Overview

Name: Thalidomide
Synonyms: Thalomid®
Therapy Type: Small Molecule
Target Type: Amyloid-Related (timeline), Inflammation
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2/3)
Company: Celgene Corporation

Background

Thalidomide is an immunomodulatory agent with a spectrum of activity that is only partly characterized. Originally introduced as a nonbarbiturate hypnotic, it was used to treat morning sickness, but numerous instances of severe birth defects led to its withdrawal from the market. Thalidomide has been reintroduced and used for a number of immunological and inflammatory disorders, as well as multiple myeloma and other types of cancer. Thalidomide displays anti-angiogenic and immunosuppressive activity.  It modulates various cytokines, including inhibiting release of tumor necrosis factor-alpha (TNFβ) from monocytes.

Preclinical data suggests that chronic thalidomide treatment reduces amyloid pathology and gliosis in APP23 transgenic mice by way of inhibiting expression of the Aβ-generating secretase enzyme BACE1 (see He et al., 2013). This followed prior studies reporting preclinical efficacy of thalidomide in AD mouse models (e.g. Gabbita et al., 2012; Alkam et al., 2008; Greig et al., 2004; see also further reading). This literature prompted interest in a clinical evaluation of thalidomide in Alzheimer's disease.

Findings

A 24-week trial of the effect of thalidomide and placebo on CSF and plasma biomarkers including BACE1 in patients with mild to moderate Alzheimer's disease is ongoing at Banner Sun Health Research Institute in Sun City, Arizona. As of summer 2013, 25 patients had been randomized. More than 120 potential participants refused participation (AAIC 2013). Improvement of cognition will be assessed at two years.

Clinical Trial Timeline

  • Phase 2/3
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024
Banner Sun Health Research Institute NCT01094340
N=20

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References

Paper Citations

  1. . Restraining tumor necrosis factor-alpha by thalidomide prevents the amyloid beta-induced impairment of recognition memory in mice. Behav Brain Res. 2008 May 16;189(1):100-6. Epub 2007 Dec 27 PubMed.
  2. . Thalidomide-based TNF-alpha inhibitors for neurodegenerative diseases. Acta Neurobiol Exp (Wars). 2004;64(1):1-9. PubMed.

Other Citations

  1. He et al., 2013

Further Reading

Papers

  1. . Thalidomide attenuates learning and memory deficits induced by intracerebroventricular administration of streptozotocin in rats. Biotech Histochem. 2013 May;88(3-4):145-52. Epub 2012 Dec 17 PubMed.
  2. . Tumor necrosis factor-α synthesis inhibitor 3,6'-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer's disease. J Neuroinflammation. 2012 May 29;9:106. PubMed.
  3. . Are anti-angiogenic drugs useful in neurodegenerative disorders?. CNS Neurol Disord Drug Targets. 2010 Dec;9(6):807-12. PubMed.
  4. . Thalidomide inhibition of perturbed vasculature and glial-derived tumor necrosis factor-alpha in an animal model of inflamed Alzheimer's disease brain. Neurobiol Dis. 2008 Feb;29(2):254-66. Epub 2007 Sep 15 PubMed.