Therapeutics

Exendin-4

Overview

Name: Exendin-4
Synonyms: Exenatide, Byetta, Bydureon
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Inactive), Parkinson's Disease (Phase 2)
Approved for: Diabetes mellitus in US

Background

Exendin-4 is a long-acting analog of glucagon-like peptide-1. GLP-1 stimulates the pancreas to release insulin in response to food intake. It resensitizes cells to insulin signaling and is used to treat Type 2 diabetes. The rationale of this approach is that counteracting the insulin resistance that accompanies some cases of Alzheimer's disease might confer a therapeutic benefit (e.g. Talbot et al., 2012Talbot 2014).

In animal models of PD, the compound dampens inflammation and protects dopaminergic neurons, which were reported to express GLP-1 receptor (Bertilsson et al., 2008Cao et al., 2016Jan 2009 news).

In mouse models of AD, exendin-4 was reported to lower amyloid plaque load and protect against Aβ oligomers (Li et al., 2010Gengler et al., 2012Bomfim et al., 2012). The related GLP-1 analogue liraglutide was reported to have similar effects (Dec 2010 news). Exenatide was also reported to enhance cognition in insulin-resistant rats (Gad et al., 2016), and to enhance insulin receptor signaling and learning in Tg2576 mice (Robinson et al., 2019).

Findings

In 2010, an investigator-sponsored trial at University College London enrolled 44 people with moderate PD into an open-label study. Half the cohort injected themselves with 10 micrograms of exendin-4 twice daily for a year, in addition to taking L-dopa, while the other half took only L-dopa. Movement abilities were reported to have improved in participants on drug, and declined in those on L-dopa only (Jun 2013 news).

From 2014 to 2016, UCL researchers ran a placebo-controlled Phase 2 trial of 2 milligrams exendin-4 administered subcutaneously once per week for 48 weeks. This trial enrolled 60 people with moderate PD. Motor symptoms were reported to have improved in those on drug, with improvement persisting for three months past dosing, whereas the placebo group declined (Aug 2017 news).

In June 2018, a phase 1 open-label study sponsored by the University of Florida started recruiting 20 people with PD 1 to evaluate a one-year course of 2 milligram subcutaneous exendin-4.

From 2010 to November 2016, the NIA ran a single-center Phase 2 Alzheimer’s disease trial. The study compared 5 or 10 micrograms exendin-4 or placebo, taken twice daily for 18 months, in people with a clinical diagnosis of prodromal or mild AD ascertained by cerebrospinal fluid Aβ42 of below 192 pg/ml, indicating amyloid buildup in the brain. The trial originally aimed to enroll 230 participants and was to run until January 2013, but randomized only 27 participants. After AstraZeneca withdrew its support, it was terminated in November 2016 with 18 participants remaining. Findings have not been published in a peer-reviewed journal, but study data are posted on clinicaltrials.gov indicate more cases of nausea in the drug than placebo group, and no statistically significant treatment benefit.

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References

News Citations

  1. Single-Blind Trial: Diabetes Drug Helps Parkinson’s, Maybe
  2. Diabetes Drug Improves Parkinson’s Motor Symptoms in Small Trial
  3. Type 2 Diabetes and Neurodegeneration—The Plot Caramelizes
  4. San Diego: A New Tack on Insulin-Based Therapies?

Therapeutics Citations

  1. Liraglutide

Paper Citations

  1. . Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012 Apr 2;122(4):1316-38. PubMed.
  2. . Brain insulin resistance in Alzheimer's disease and its potential treatment with GLP-1 analogs. Neurodegener Dis Manag. 2014 Feb;4(1):31-40. PubMed.
  3. . Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson's disease. J Neurosci Res. 2008 Feb 1;86(2):326-38. PubMed.
  4. . A novel dual GLP-1 and GIP incretin receptor agonist is neuroprotective in a mouse model of Parkinson's disease by reducing chronic inflammation in the brain. Neuroreport. 2016 Apr 13;27(6):384-91. PubMed.
  5. . GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer's disease. J Alzheimers Dis. 2010;19(4):1205-19. PubMed.
  6. . Val(8)GLP-1 rescues synaptic plasticity and reduces dense core plaques in APP/PS1 mice. Neurobiol Aging. 2012 Feb;33(2):265-76. PubMed.
  7. . An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers. J Clin Invest. 2012 Apr 2;122(4):1339-53. PubMed.
  8. . Pioglitazone and exenatide enhance cognition and downregulate hippocampal beta amyloid oligomer and microglia expression in insulin-resistant rats. Can J Physiol Pharmacol. 2016 Aug;94(8):819-28. Epub 2015 Dec 16 PubMed.
  9. . Combination of Insulin with a GLP1 Agonist Is Associated with Better Memory and Normal Expression of Insulin Receptor Pathway Genes in a Mouse Model of Alzheimer's Disease. J Mol Neurosci. 2019 Apr;67(4):504-510. Epub 2019 Jan 11 PubMed.

External Citations

  1. open-label study
  2. Phase 2 trial
  3. phase 1 open-label study
  4. Phase 2 Alzheimer’s disease trial

Further Reading

Papers

  1. . Exenatide as a potential treatment for patients with Parkinson's disease: first steps into the clinic. Alzheimers Dement. 2014 Feb;10(1 Suppl):S38-46. PubMed.
  2. . Parkinson's disease, insulin resistance and novel agents of neuroprotection. Brain. 2012 Feb 17; PubMed.
  3. . A New Treatment Strategy for Parkinson's Disease Through the Gut-Brain Axis: The Glucagon-like Peptide-1 Receptor Pathway. Cell Transplant. 2017 Apr 26; PubMed.
  4. . The extra-pancreatic effects of GLP-1 receptor agonists: a focus on the cardiovascular, gastrointestinal and central nervous systems. Diabetes Obes Metab. 2013 Dec 24; PubMed.
  5. . Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. Lancet Neurol. 2011 Feb;10(2):187-98. PubMed.
  6. . Glucagon-like Peptide-1 and the Central/Peripheral Nervous System: Crosstalk in Diabetes. Trends Endocrinol Metab. 2017 Feb;28(2):88-103. Epub 2016 Oct 27 PubMed.
  7. . Exenatide and the treatment of patients with Parkinson's disease. J Clin Invest. 2013 Jun 3;123(6):2730-6. PubMed.