Therapeutics

Exenatide

Tools

Back to the Top

Overview

Name: Exenatide
Synonyms: Exendin-4, 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 3)
Company: AstraZeneca, Eli Lilly & Co.
Approved for: Diabetes mellitus in US

Background

Exenatide is an analog of the hormone 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., 2012; Talbot, 2014).

The short-acting form of exenatide is administered by twice-daily subcutaneous self-injection; a long-acting preparation is injected just once a week. In mice, exenatide readily crossed the blood-brain barrier, while other GLP-1 mimetics liraglutide and semaglutide did not (Salameh et al., 2020).

In animal models of Parkinson’s disease, exenatide dampens inflammation and protects dopaminergic neurons, which were reported to express GLP-1 receptor (Perry et al., 2002; Bertilsson et al., 2008; Cao et al., 2016; Jan 2009 news). It also had beneficial effects in a mouse model of the rapidly progressing α-synucleinopathy multiple systems atrophy (Bassil et al., 2017). Potential mechanisms of neuroprotection by GLP-1 mimetics are reviewed in Reich and Hölscher, 2022.

In mouse models of AD, exendin-4 was reported to lower amyloid plaque load and protect against Aβ oligomers (Li et al., 2010; Gengler et al., 2012; Bomfim et al., 2012). The related GLP-1 analog liraglutide was reported to have similar effects (Dec 2010 news). Exenatide also enhanced cognition in insulin-resistant rats (Gad et al., 2016), and improved 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 Parkinson's disease 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 and cognitive scores were reported to have improved in participants on drug, and declined in those on L-dopa only (Aviles-Olmos et al., 2013; Jun 2013 news). The drug was well-tolerated, although many participants lost weight. Gains in movement and cognitive skills persisted for one year after treatment ended (Aviles-Olmos et al., 2014).

From 2014 to 2016, UCL researchers ran a placebo-controlled Phase 2 trial of 2 milligrams extended-release exendin-4 administered subcutaneously once weekly for 48 weeks. This trial enrolled 60 people with moderate Parkinson's. Motor symptoms were reported to have improved in those on drug, with gains persisting for three months past dosing, whereas the placebo group declined (Athuada et al., 2017, Aug 2017 news). Again, the drug was well-tolerated, although treated patients lost more weight on average than those in the placebo group. Exenatide levels in CSF were about 2 percent of serum levels. Secondary outcomes related to cognition, or quality of life, showed no benefit. A post hoc analysis claimed some potential advantage in mood and well-being subdomains of the assessments (Athauda et al., 2018). Analysis of insulin signaling markers in neuronally-derived blood exosomes confirmed target engagement of brain insulin pathways (Athauda et al., 2019).

From 2016 through 2019, the University of Parma, Italy, ran a trial comparing a 36-week course of once-weekly subcutaneous injection of 2 mg long-acting exenatide to placebo for its effect on cognitive decline in 40 prediabetic patients; the primary outcome was decline on the ADAD-cog.

In June 2018, a Phase 1 open-label study sponsored by the University of Florida started recruiting what was to be 20 participants with Parkinson's to evaluate a one-year course of 2 mg subcutaneous exenatide. The outcomes were imaging measures of free water in the substantia nigra and blood oxygenation in multiple brain regions. This trial stopped enrolling after five patients, and completed treatment in October 2020.

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 Alzheimer's disease 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 results posted on clinicaltrials.gov indicate more cases of nausea in the drug than placebo group, and no statistically significant treatment benefit.

In January 2020, a trial in Stockholm began enrolling 60 people with Parkinson's disease to receive 2 mg once weekly for 18 months, with a primary outcome of changes in brain glucose uptake on FDG-PET. As of September 2022, this trial was listed as fully recruited and active, and was to be completed in October 2023.

In 2020, four new efficacy trials began. In January, University College London began a Phase 3 trial in 200 people with Parkinson's, who will receive 2 mg extended-release exenatide once weekly for two years. The protocol has been published (Vijiaratnam et al., 2021); the trial will finish in mid-2024. In September, another trial at UCL began enrolling 50 people with multiple system atrophy for a 12-month course of once-weekly exenatide. This study was anticipated to be completed in 2022. In February, a multicenter trial in Korea started enrolling 99 people with early PD to test PT320, an extended-release form of exendin-4 that is claimed to have better blood-brain barrier penetration (Li et al., 2019). This trial will compare PT320 to placebo, given by subcutaneous injection once per week for 48 weeks. The current status of this trial is unknown. In preclinical studies in PD mouse models, PT320 was reported to delay dopamine neuron degeneration, disease progression, and lessen L-DOPA-induced dyskinesias (Yu et al., 2020; Wang et al., 2021; Kuo et al., 2023; Wang et al., 2024).

Also in February, a multicenter trial in the U.S. began comparing placebo to two doses of NLY01, Neuraly’s pegylated formulation of exendin-4, in 240 people with early PD. In preclinical pharmacokinetic studies, NLY01 did not enter the brain (Lv et al., 2021). The trial finished in March 2023, after 36 weeks treatment. According to published results, 2.5 or 5 mg NLY01 failed to change the primary endpoint of the MDS-UPRDS parts II and III, compared to placebo (McGarry et al., 2024). Younger patients showed a possible benefit on motor symptoms.

Exendin-4 is also being evaluated in stroke, and brain and spinal cord injury.

For a review of exenatide’s development for Parkinson’s and Alzheimer’s, see Hölscher, 2024.

For details on trials of exendin-4 in neurodegenerative diseases, see clinicaltrials.gov.

Last Updated: 14 May 2024

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

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
  2. Semaglutide

Paper Citations

  1. Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, Whitton P, Wyse R, Isaacs T, Lees A, Limousin P, Foltynie T. Exenatide and the treatment of patients with Parkinson's disease. J Clin Invest. 2013 Jun 3;123(6):2730-6. PubMed.
  2. Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Kahan J, Fmedsci PE, Whitton P, Wyse R, Isaacs T, Lees A, Limousin P, Foltynie T. Motor and Cognitive Advantages Persist 12 Months After Exenatide Exposure in Parkinson's Disease. J Parkinsons Dis. 2014 Mar 24; PubMed.
  3. Athauda D, Maclagan K, Skene SS, Bajwa-Joseph M, Letchford D, Chowdhury K, Hibbert S, Budnik N, Zampedri L, Dickson J, Li Y, Aviles-Olmos I, Warner TT, Limousin P, Lees AJ, Greig NH, Tebbs S, Foltynie T. Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017 Aug 3; PubMed.
  4. Athauda D, Maclagan K, Budnik N, Zampedri L, Hibbert S, Skene SS, Chowdhury K, Aviles-Olmos I, Limousin P, Foltynie T. What Effects Might Exenatide have on Non-Motor Symptoms in Parkinson's Disease: A Post Hoc Analysis. J Parkinsons Dis. 2018;8(2):247-258. PubMed.
  5. Athauda D, Gulyani S, Karnati HK, Li Y, Tweedie D, Mustapic M, Chawla S, Chowdhury K, Skene SS, Greig NH, Kapogiannis D, Foltynie T. Utility of Neuronal-Derived Exosomes to Examine Molecular Mechanisms That Affect Motor Function in Patients With Parkinson Disease: A Secondary Analysis of the Exenatide-PD Trial. JAMA Neurol. 2019 Apr 1;76(4):420-429. PubMed.
  6. Vijiaratnam N, Girges C, Auld G, Chau M, Maclagan K, King A, Skene S, Chowdhury K, Hibbert S, Morris H, Limousin P, Athauda D, Carroll CB, Hu MT, Silverdale M, Duncan GW, Chaudhuri R, Lo C, Del Din S, Yarnall AJ, Rochester L, Gibson R, Dickson J, Hunter R, Libri V, Foltynie T. Exenatide once weekly over 2 years as a potential disease-modifying treatment for Parkinson's disease: protocol for a multicentre, randomised, double blind, parallel group, placebo controlled, phase 3 trial: The 'Exenatide-PD3' study. BMJ Open. 2021 May 28;11(5):e047993. PubMed.
  7. Li Y, Vaughan KL, Tweedie D, Jung J, Kim HK, Choi HI, Kim DS, Mattison JA, Greig NH. Pharmacokinetics of Exenatide in nonhuman primates following its administration in the form of sustained-release PT320 and Bydureon. Sci Rep. 2019 Nov 20;9(1):17208. PubMed.
  8. Yu SJ, Chen S, Yang YY, Glotfelty EJ, Jung J, Kim HK, Choi HI, Choi DS, Hoffer BJ, Greig NH, Wang Y. PT320, Sustained-Release Exendin-4, Mitigates L-DOPA-Induced Dyskinesia in a Rat 6-Hydroxydopamine Model of Parkinson's Disease. Front Neurosci. 2020;14:785. Epub 2020 Aug 11 PubMed.
  9. Wang V, Kuo TT, Huang EY, Ma KH, Chou YC, Fu ZY, Lai LW, Jung J, Choi HI, Choi DS, Li Y, Olson L, Greig NH, Hoffer BJ, Chen YH. Sustained Release GLP-1 Agonist PT320 Delays Disease Progression in a Mouse Model of Parkinson's Disease. ACS Pharmacol Transl Sci. 2021 Apr 9;4(2):858-869. Epub 2021 Mar 16 PubMed.
  10. Kuo TT, Chen YH, Wang V, Huang EY, Ma KH, Greig NH, Jung J, Choi HI, Olson L, Hoffer BJ, Tseng KY. PT320, a Sustained-Release GLP-1 Receptor Agonist, Ameliorates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson's Disease. Int J Mol Sci. 2023 Feb 28;24(5) PubMed.
  11. Wang V, Tseng KY, Kuo TT, Huang EY, Lan KL, Chen ZR, Ma KH, Greig NH, Jung J, Choi HI, Olson L, Hoffer BJ, Chen YH. Attenuating mitochondrial dysfunction and morphological disruption with PT320 delays dopamine degeneration in MitoPark mice. J Biomed Sci. 2024 Apr 17;31(1):38. PubMed.
  12. Lv M, Xue G, Cheng H, Meng P, Lian X, Hölscher C, Li D. The GLP-1/GIP dual-receptor agonist DA5-CH inhibits the NF-κB inflammatory pathway in the MPTP mouse model of Parkinson's disease more effectively than the GLP-1 single-receptor agonist NLY01. Brain Behav. 2021 Aug;11(8):e2231. Epub 2021 Jun 14 PubMed.
  13. McGarry A, Rosanbalm S, Leinonen M, Olanow CW, To D, Bell A, Lee D, Chang J, Dubow J, Dhall R, Burdick D, Parashos S, Feuerstein J, Quinn J, Pahwa R, Afshari M, Ramirez-Zamora A, Chou K, Tarakad A, Luca C, Klos K, Bordelon Y, St Hiliare MH, Shprecher D, Lee S, Dawson TM, Roschke V, Kieburtz K. Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2024 Jan;23(1):37-45. PubMed.
  14. Hölscher C. Glucagon-like peptide-1 class drugs show clear protective effects in Parkinson's and Alzheimer's disease clinical trials: A revolution in the making?. Neuropharmacology. 2024 Aug 1;253:109952. Epub 2024 Apr 25 PubMed.
  15. Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Wilson RS, Arvanitakis Z, Schneider JA, Wolf BA, Bennett DA, Trojanowski JQ, Arnold SE. 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;122(4):1316-38. PubMed.
  16. Talbot K. 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.
  17. Salameh TS, Rhea EM, Talbot K, Banks WA. Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer's and Parkinson's disease therapeutics. Biochem Pharmacol. 2020 Oct;180:114187. Epub 2020 Aug 2 PubMed. Correction.
  18. Perry T, Haughey NJ, Mattson MP, Egan JM, Greig NH. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther. 2002 Sep;302(3):881-8. PubMed.
  19. Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, Kortesmaa J, Mercer A, Nielsen E, Rönnholm H, Wikström L. 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.
  20. Cao L, Li D, Feng P, Li L, Xue GF, Li G, Hölscher C. 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.
  21. Bassil F, Canron MH, Vital A, Bezard E, Li Y, Greig NH, Gulyani S, Kapogiannis D, Fernagut PO, Meissner WG. Insulin resistance and exendin-4 treatment for multiple system atrophy. Brain. 2017 Mar 14; PubMed.
  22. Reich N, Hölscher C. The neuroprotective effects of glucagon-like peptide 1 in Alzheimer's and Parkinson's disease: An in-depth review. Front Neurosci. 2022;16:970925. Epub 2022 Sep 1 PubMed.
  23. Li Y, Duffy KB, Ottinger MA, Ray B, Bailey JA, Holloway HW, Tweedie D, Perry T, Mattson MP, Kapogiannis D, Sambamurti K, Lahiri DK, Greig NH. 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.
  24. Gengler S, McClean PL, McCurtin R, Gault VA, Hölscher C. 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.
  25. Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, Silverman MA, Kazi H, Melo HM, McClean PL, Holscher C, Arnold SE, Talbot K, Klein WL, Munoz DP, Ferreira ST, De Felice FG. 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.
  26. Gad ES, Zaitone SA, Moustafa YM. 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.
  27. Robinson A, Lubitz I, Atrakchi-Baranes D, Licht-Murava A, Katsel P, Leroith D, Liraz-Zaltsman S, Haroutunian V, Beeri MS. 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. clinicaltrials.gov

Further Reading

Papers

  1. Foltynie T, Aviles-Olmos I. 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. Aviles-Olmos I, Limousin P, Lees A, Foltynie T. Parkinson's disease, insulin resistance and novel agents of neuroprotection. Brain. 2012 Feb 17; PubMed.
  3. Kim DS, Choi HI, Wang Y, Luo Y, Hoffer BJ, Greig NH. 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. Seufert J, Gallwitz B. 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. Kapogiannis D, Mattson MP. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. Lancet Neurol. 2011 Feb;10(2):187-98. PubMed.
  6. Muscogiuri G, DeFronzo RA, Gastaldelli A, Holst JJ. 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. Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, Whitton P, Wyse R, Isaacs T, Lees A, Limousin P, Foltynie T. Exenatide and the treatment of patients with Parkinson's disease. J Clin Invest. 2013 Jun 3;123(6):2730-6. PubMed.
  8. Athauda D, Maclagan K, Budnik N, Zampedri L, Hibbert S, Aviles-Olmos I, Chowdhury K, Skene SS, Limousin P, Foltynie T. Post hoc analysis of the Exenatide-PD trial-Factors that predict response. Eur J Neurosci. 2019 Feb;49(3):410-421. Epub 2018 Oct 6 PubMed.
  9. Athauda D, Maclagan K, Budnik N, Zampedri L, Hibbert S, Skene SS, Chowdhury K, Aviles-Olmos I, Limousin P, Foltynie T. What Effects Might Exenatide have on Non-Motor Symptoms in Parkinson's Disease: A Post Hoc Analysis. J Parkinsons Dis. 2018;8(2):247-258. PubMed.
  10. Labandeira CM, Fraga-Bau A, Arias Ron D, Muñoz A, Alonso-Losada G, Koukoulis A, Romero-Lopez J, Rodriguez-Perez AI. Diabetes, insulin and new therapeutic strategies for Parkinson's disease: Focus on glucagon-like peptide-1 receptor agonists. Front Neuroendocrinol. 2021 Jul;62:100914. Epub 2021 Apr 15 PubMed.
  11. Bergkvist L, Johnson ME, Mercado G, Steiner JA, Meyerdirk L, Schulz E, Madaj Z, Ma J, Becker K, Li Y, Brundin P. An extended release GLP-1 analogue increases α-synuclein accumulation in a mouse model of prodromal Parkinson's disease. Exp Neurol. 2021 Jul;341:113693. Epub 2021 Mar 13 PubMed.
  12. Mulvaney CA, Duarte GS, Handley J, Evans DJ, Menon S, Wyse R, Emsley HC. GLP-1 receptor agonists for Parkinson's disease. Cochrane Database Syst Rev. 2020 Jul 23;7:CD012990. PubMed.
  13. Yu SJ, Chen S, Yang YY, Glotfelty EJ, Jung J, Kim HK, Choi HI, Choi DS, Hoffer BJ, Greig NH, Wang Y. PT320, Sustained-Release Exendin-4, Mitigates L-DOPA-Induced Dyskinesia in a Rat 6-Hydroxydopamine Model of Parkinson's Disease. Front Neurosci. 2020;14:785. Epub 2020 Aug 11 PubMed.