Therapeutics

Lixisenatide

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Overview

Name: Lixisenatide
Synonyms: Adlyxin, Lyxumia
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 2)
Company: Sanofi
Approved for: Type 2 diabetes

Background

Lixisenatide is an analog of the hormone glucagon-like peptide-1. GLP-1 stimulates the pancreas to release insulin in response to food intake. GLP-1 mimetics resensitize cells to insulin signaling and are used to treat Type 2 diabetes. Several GLP-1 mimetics are also approved for weight loss. The FDA approved Adlyxin for Type 2 diabetes in 2016, but Sanofi discontinued marketing it for this disease in 2023, citing business reasons. Lixisenatide is taken as a once-daily self-injection under the skin.

Lixisenatide is one of four GLP-1 mimetics being tested for Alzheimer’s or Parkinson’s diseases. It is a 44-amino acid peptide closely related to exenatide (Leon et al., 2017). Lixisenatide appears to cross the blood-brain barrier better than liraglutide and semaglutide (Hunter and Hölscher, 2012; Salameh et al., 2020).

The rationale of using GLP-1 receptor agonists for neurodegeneration stems from observations of insulin resistance in some cases of Alzheimer's disease (e.g. Talbot et al., 2012; Talbot, 2014). Type 2 diabetes raises the risk of Parkinson’s, and in some studies, the prevalence of Parkinson’s was lower in people with diabetes who were treated with GLP-1 receptor agonists compared to those taking other diabetes medications (Brauer et al., 2020; Svenningsson et al., 2016).

GLP-1 mimetics are neuroprotective in preclinical models of Alzheimer’s and Parkinson’s (e.g. Perry et al., 2002; Bertilsson et al., 2008; Li et al., 2010). Potential mechanisms of neuroprotection by GLP-1 mimetics include reduced inflammation (reviewed in Reich and Hölscher, 2022). 

Preclinically, lixisenatide reduced Aβ-induced impairments in spatial learning and memory in rats, and was neuroprotective in APP/PS1/tau mice (Cai et al., 2014; Cai et al., 2017; Cai et al., 2018). In the APPswe/PS1Δe9 mouse line, it improved object recognition and synaptic plasticity, prevented synapse loss, reduced amyloid load and microglial activation, and increased neurogenesis, all at lower doses than liraglutide (McClean and Hölscher, 2014; Hölscher, 2014). In the MPTP toxin-induced mouse model of Parkinson's lixisenatide prevented motor impairment and dopamine neuron loss (Liu et al., 2015).

For a review of the development of GLP-1 class drugs for Parkinson’s and Alzheimer’s, see Hölscher, 2024.

Findings

In June 2018, French researchers started a Phase 2 study to evaluate the effect of lixisenatide in people with early Parkinson’s disease. The LixiPark trial enrolled 156 participants, with a target dose of 20 μg daily for one year, or a matched placebo, in addition to their usual Parkinson's medications. The primary outcome was motor function, as measured by the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part 3. Conducted at 20 sites in France, the trial ended in April 2021. Results are published (see Apr 2024 news on Meissner et al., 2024). After 12 months, the lixisenatide group had improved by 0.04 points on the primary outcome, compared to a decline of 3.04 points in the placebo group, a statistically significant difference. A difference favoring treatment remained after two months off drug. Secondary outcomes including non-motor symptoms, activities of daily living, and need for levodopa were not different between the groups. One third of participants had to limit their dose to 10 μg due to side effects, mainly nausea, as well as vomiting and acid reflex. A post hoc analysis suggested greater benefit for people under 60.

For details on the LixiPark trial, see clinicaltrials.gov.

Last Updated: 14 May 2024

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References

News Citations

  1. Diabetes Drug Shows Promise for Parkinson’s Disease

Therapeutics Citations

  1. Exenatide
  2. Liraglutide
  3. Semaglutide

Paper Citations

  1. Meissner WG, Remy P, Giordana C, Maltête D, Derkinderen P, Houéto JL, Anheim M, Benatru I, Boraud T, Brefel-Courbon C, Carrière N, Catala H, Colin O, Corvol JC, Damier P, Dellapina E, Devos D, Drapier S, Fabbri M, Ferrier V, Foubert-Samier A, Frismand-Kryloff S, Georget A, Germain C, Grimaldi S, Hardy C, Hopes L, Krystkowiak P, Laurens B, Lefaucheur R, Mariani LL, Marques A, Marse C, Ory-Magne F, Rigalleau V, Salhi H, Saubion A, Stott SR, Thalamas C, Thiriez C, Tir M, Wyse RK, Benard A, Rascol O, LIXIPARK Study Group. Trial of Lixisenatide in Early Parkinson's Disease. N Engl J Med. 2024 Apr 4;390(13):1176-1185. PubMed.
  2. Leon N, LaCoursiere R, Yarosh D, Patel RS. Lixisenatide (Adlyxin): A Once-Daily Incretin Mimetic Injection for Type-2 Diabetes. P T. 2017 Nov;42(11):676-711. PubMed.
  3. Hunter K, Hölscher C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci. 2012;13:33. PubMed.
  4. 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.
  5. 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.
  6. 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.
  7. Brauer R, Wei L, Ma T, Athauda D, Girges C, Vijiaratnam N, Auld G, Whittlesea C, Wong I, Foltynie T. Diabetes medications and risk of Parkinson's disease: a cohort study of patients with diabetes. Brain. 2020 Oct 1;143(10):3067-3076. PubMed.
  8. Svenningsson P, Wirdefeldt K, Yin L, Fang F, Markaki I, Efendic S, Ludvigsson JF. Reduced incidence of Parkinson's disease after dipeptidyl peptidase-4 inhibitors-A nationwide case-control study. Mov Disord. 2016 Sep;31(9):1422-3. Epub 2016 Jul 19 PubMed.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. Cai HY, Hölscher C, Yue XH, Zhang SX, Wang XH, Qiao F, Yang W, Qi JS. Lixisenatide rescues spatial memory and synaptic plasticity from amyloid β protein-induced impairments in rats. Neuroscience. 2014 Feb 27;277C:6-13. PubMed.
  14. Cai HY, Wang ZJ, Hölscher C, Yuan L, Zhang J, Sun P, Li J, Yang W, Wu MN, Qi JS. Lixisenatide attenuates the detrimental effects of amyloid β protein on spatial working memory and hippocampal neurons in rats. Behav Brain Res. 2017 Feb 1;318:28-35. Epub 2016 Oct 21 PubMed.
  15. Cai HY, Yang JT, Wang ZJ, Zhang J, Yang W, Wu MN, Qi JS. Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP/PS1/tau mouse model of Alzheimer's disease. Biochem Biophys Res Commun. 2018 Jan 1;495(1):1034-1040. Epub 2017 Nov 22 PubMed.
  16. McClean PL, Hölscher C. Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer's disease. Neuropharmacology. 2014 Nov;86:241-58. Epub 2014 Aug 8 PubMed.
  17. Hölscher C. The incretin hormones glucagonlike peptide 1 and glucose-dependent insulinotropic polypeptide are neuroprotective in mouse models of Alzheimer's disease. Alzheimers Dement. 2014 Feb;10(1 Suppl):S47-54. PubMed.
  18. Liu W, Jalewa J, Sharma M, Li G, Li L, Hölscher C. Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Neuroscience. 2015 Sep 10;303:42-50. Epub 2015 Jul 2 PubMed.
  19. 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.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Chen SD, Chuang YC, Lin TK, Yang JL. Alternative role of glucagon-like Peptide-1 receptor agonists in neurodegenerative diseases. Eur J Pharmacol. 2023 Jan 5;938:175439. Epub 2022 Dec 2 PubMed.
  2. Gad SN, Nofal S, Raafat EM, Ahmed AA. Lixisenatide Reduced Damage in Hippocampus CA1 Neurons in a Rat Model of Cerebral Ischemia-Reperfusion Possibly Via the ERK/P38 Signaling Pathway. J Mol Neurosci. 2020 Jul;70(7):1026-1037. Epub 2020 Feb 10 PubMed.