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.
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National Institute on Aging, National Institutes of Health
It is wonderful to see a treatment strategy, proposed by my collaborators and me in 2002 in publications describing the neuroprotective/neurotrophic actions of GLP-1 receptor agonists, demonstrating efficacy in Parkinson’s disease (Perry et al., 2002; Perry et al., 2002). New effective treatment approaches remain a significant unmet need for PD. We first presented our work relating to the efficacy of GLP-1 receptor agonists in preclinical PD models in 2005 and this triggered a flurry of supportive publications in 2008/2009 (Bertilsson et al., 2008; Harkavyi et al., 2008; Li et al., 2009).
This lixisenatide PD study of Wassilios Meissner and collaborators is impressive, elegant, and provides a balanced evaluation of the primary and secondary measures of the trial, putting them into context with the current literature. The primary outcome measure (MDS-UPDRS Part III) relates to motor examination, and showed a small but statistically significant and meaningful separation from the placebo group after 12 months in this Phase 2, double-blind, randomized, placebo-controlled trial. Importantly, this difference remained following a two-month washout period when measured in the off-medication state. In this regard, this study nicely supports the exenatide PD trials of Foltynie and collaborators (Athauda et al., 2017; Aviles-Olmos et al., 2013) and, importantly, extended these beyond patients with moderate PD to those with milder disease—diagnosed less than three years earlier.
Our recent collaborative studies with a sustained release form of exenatide (PT320) in the mitoPark mouse—which provides a valuable, slowly progressive model of PD—indicate that earlier treatment with a GLP-1 receptor agonist is preferential (Wang et al., 2021; Wang et al., 2024). A valuable aspect of GLP-1 receptor agonists is that multiple potentially efficacious cascades are selectively triggered by receptor activation, with the potential to positively impact a broad spectrum of PD patients to provide neuroprotective, neurotrophic, anti-neuroinflammatory and reversal of brain insulin resistance actions that have been described in recent reviews (Athauda and Foltynie, 2018; Glotfelty et al., 2020; Holscher, 2022; Kopp et al., 2022; Kalinderi et al., 2024).
Meissner et al. provide thoughtful insight into potential future directions. Furthermore, the availability of clinically available, dual, and triple agonists from the diabetes/obesity field that can trigger GLP-1, GIP, and glucagon receptor stimulation may offer the PD field more than does a single GLP-1 receptor agonist. Other outcome measures of relevance to PD may, likewise, benefit from a GLP-1 receptor agonist approach—for example, our recent collaborative studies have demonstrated a mitigation of L-DOPA-induced dyskinesia across two different PD preclinical animal models using a clinically translatable dose of exenatide (PT320) (Yu et al., 2020; Kuo et al., 2023).
Importantly, Meissner et al.’s trial and the exenatide studies by Foltynie and colleagues demonstrate that successful clinical translation can be achieved for neurodegenerative disorders—as it has for cancer and for cardiovascular disorders. This keeps our spirits alive and strong that, together, we can positively impact diseases such as Alzheimer’s, traumatic brain injury, tauopathies, multiple system atrophy, ALS, and others.
References:
Perry T, Lahiri DK, Chen D, Zhou J, Shaw KT, Egan JM, Greig NH. A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. J Pharmacol Exp Ther. 2002 Mar;300(3):958-66. PubMed.
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.
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.
Harkavyi A, Abuirmeileh A, Lever R, Kingsbury AE, Biggs CS, Whitton PS. Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease. J Neuroinflammation. 2008;5:19. PubMed.
Li Y, Perry T, Kindy MS, Harvey BK, Tweedie D, Holloway HW, Powers K, Shen H, Egan JM, Sambamurti K, Brossi A, Lahiri DK, Mattson MP, Hoffer BJ, Wang Y, Greig NH. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1285-90. PubMed.
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.
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.
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.
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.
Athauda D, Foltynie T. Protective effects of the GLP-1 mimetic exendin-4 in Parkinson's disease. Neuropharmacology. 2018 Jul 1;136(Pt B):260-270. Epub 2017 Sep 18 PubMed.
Glotfelty EJ, Olson L, Karlsson TE, Li Y, Greig NH. Glucagon-like peptide-1 (GLP-1)-based receptor agonists as a treatment for Parkinson's disease. Expert Opin Investig Drugs. 2020 Jun;29(6):595-602. Epub 2020 May 15 PubMed.
Hölscher C. Glucagon-like peptide 1 and glucose-dependent insulinotropic peptide hormones and novel receptor agonists protect synapses in Alzheimer's and Parkinson's diseases. Front Synaptic Neurosci. 2022;14:955258. Epub 2022 Jul 27 PubMed.
Kopp KO, Glotfelty EJ, Li Y, Greig NH. Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment. Pharmacol Res. 2022 Dec;186:106550. Epub 2022 Nov 11 PubMed.
Kalinderi K, Papaliagkas V, Fidani L. GLP-1 Receptor Agonists: A New Treatment in Parkinson's Disease. Int J Mol Sci. 2024 Mar 29;25(7) PubMed.
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.
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.
View all comments by Nigel GreigUCL Institute of Neurology
This is an important publication, given it essentially replicates the findings of Athauda et al., who reported positive Phase 2 data of a very similar GLP-1 receptor agonist drug, exenatide, when given to patients with Parkinson’s disease (Athauda et al., 2017).
This cumulative clinical data, therefore, strongly supports the earlier laboratory and epidemiological data that GLP1 receptor stimulation in the brain has neuroprotective effects relevant to the neurodegenerative processes of Parkinson’s disease. Importantly, the beneficial effects seen are likely to be restricted to those GLP1 receptor agonists which can effectively access the brain, as has been demonstrated for exenatide (and are likely for the closely structurally related lixisenatide), but do not occur with liraglutide or semaglutide, while it remains unclear for the PEGylated formulation of exenatide, NLY01.
The French lixisenatide trial was well-conducted and the results appear robust, although there remains a small risk of bias resulting from unblinding, given the same investigator was recording adverse events (weight loss and GI upset which occur in the lixisenatide patients) and rating the primary outcome. The authors are correct that further trial replication is necessary before any shift in clinical practice should be sought.
While these findings are encouraging in the search for neuroprotective effects in Parkinson’s disease, there will remain speculation whether the mechanism of action of GLP-1 receptor drugs solely improves dopaminergic signaling (and therefore helps in the relief of symptoms), or whether they suppress the unfavorable neuroinflammatory state in PD, allowing cells to resume their normal neurotransmitter functions, and ultimately avoid premature cell death. Phase 3 trial data of the effects of two years’ exposure to exenatide in patients with Parkinson’s disease will hopefully address this question, and will be available in the second half of 2024.
References:
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.
View all comments by Thomas FoltynieHenan University of Chinese Medicine
The lixipark study is great news for PD patients as it shows halt of disease progression and confirms earlier clinical trials testing exenatide (Athauda et al., 2017; Aviles-Olmos et al., 2014) as well as a small Phase 2 trial testing the GLP-1 analogue liraglutide, which also showed some improvements (Hogg et al., 2023). We are at the verge of a new dawn where drugs of this type can make a real difference in the clinic (see Hölscher, 2024, for a review).
We had tested lixisenatide in different preclinical models of AD and PD and found it to be very effective (Cai et al., 2014; Cai et al., 2017; Liu et al., 2015; McClean and Holscher, 2014). An important aspect is how well the drug can cross the blood-brain barrier. A recent study showed that there are large differences between the ability of GLP-1 class drugs and dual GLP-1/GIP receptor-agonist-type drugs to protect the brain (Rhea et al., 2023). Intriguingly, a recent Phase 2 trial testing a pegylated version of exenatide (NLY01) that does not enter the brain readily (Lv et al., 2021) did not show any improvements in primary and secondary readouts (McGarry et al., 2024). We therefore developed novel dual GLP-1/GIP receptor agonists that can enter the brain at an accelerated level (Hölscher, 2021; Rhea et al., 2023; Zhang et al., 2023).
This research area certainly deserves a lot more attention and support than it currently enjoys. Perhaps the positive results of the lixipark trial will shift opinions toward this promising direction.
References:
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.
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.
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.
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.
Hölscher C. Protective properties of GLP-1 and associated peptide hormones in neurodegenerative disorders. Br J Pharmacol. 2021 Apr 26; PubMed.
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.
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.
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.
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.
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.
Rhea EM, Babin A, Thomas P, Omer M, Weaver R, Hansen K, Banks WA, Talbot K. Brain uptake pharmacokinetics of albiglutide, dulaglutide, tirzepatide, and DA5-CH in the search for new treatments of Alzheimer's and Parkinson's diseases. Tissue Barriers. 2023 Dec 14;:2292461. PubMed.
Zhang Z, Shi M, Li Z, Ling Y, Zhai L, Yuan Y, Ma H, Hao L, Li Z, Zhang Z, Hölscher C. A Dual GLP-1/GIP Receptor Agonist Is More Effective than Liraglutide in the A53T Mouse Model of Parkinson's Disease. Parkinsons Dis. 2023;2023:7427136. Epub 2023 Sep 25 PubMed.
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