Diabetes Drug Shows Promise for Parkinson’s Disease

A new study adds to the evidence that a class of diabetes drugs could help Parkinson’s patients, even if only a little. In the April 4 New England Journal of Medicine, researchers led by Olivier Rascol at Toulouse University Hospital, France, reported that PD patients taking the GLP-1 analogue lixisenatide maintained their motor abilities over the course of a year in a small Phase 2 trial, while patients on placebo declined. This follows reports that a similar GLP-1 analogue, exenatide, also halted decline in Phase 2. Together, the studies suggest this class of drugs is worth continuing to explore in larger Phase 3 studies.

  • Lixisenatide stabilized motor abilities in Parkinson’s patients over one year.
  • The small benefit versus placebo was maintained two months later.

Nigel Greig at the National Institutes of Health, Bethesda, Maryland, called the clinical effect small but meaningful, and said it supports prior findings with exenatide. He was a co-author on the exenatide study. “A valuable aspect of GLP-1 receptor agonists is that multiple potentially efficacious cascades are selectively triggered … to provide neuroprotective, neurotrophic, anti-neuroinflammatory, and reversal of brain insulin resistance actions,” he noted (comment below).

These beneficial brain effects were first shown in rodent models of PD two decades ago (Perry et al., 2002; Bertilsson et al., 2008; Harkavyi et al., 2008). The data led to clinical studies with exenatide. Like other glucagon-like peptide-1 receptor agonists, exenatide boosts insulin release, revving up glucose metabolism. In small studies, the drug stabilized motor abilities in people with moderate PD, but only in their “off-medication” state, i.e., when they had not yet taken their dopaminergic medications for the day (Jun 2013 news; Aug 2017 news).

In the new study, Rascol and colleagues tested lixisenatide, a GLP-1 mimic made by Sanofi. It was marketed under the brand name Adlyxin but has since been discontinued, for what the company said were business reasons. The Lixipark trial in France enrolled 156 participants with mild Parkinson’s disease. They were 60 years old on average and had been diagnosed about 1.5 years earlier. Participants injected themselves daily with 10 or 20 μg lixisenatide or placebo.

After 12 months, people on drug had notched a small numerical improvement of 0.04 points on the primary outcome measure, the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part 3, which assesses motor abilities. This compared with a decline of 3.04 points for people on placebo, a statistically significant difference. Unlike in the exenatide trial, this difference was apparent while participants were taking dopaminergic drugs. The three-point difference between treatment and placebo groups was maintained after two months off lixisenatide and was seen in the off-medication state as well.

Lixisenatide did not demonstrate any benefit on secondary outcome measures. These included other parts of the MDS-UPDRS, which reflect non-motor symptoms and activities of daily living. Exenatide likewise had no effect on these measures.

The treatment group was twice as likely as the placebo group to experience side effects. These were mostly gastrointestinal, with almost half of people on lixisenatide having nausea, 13 percent vomiting, and 8 percent with acid reflux. A total of seven people dropped out of the study, four from the treatment group and three from placebo.

Greig noted that the lixisenatide study extends the benefits of GLP-1 analogues from moderate to mild PD. Recent mouse studies indicate that these medications may have greater benefits the earlier in disease they are started (Wang et al., 2021; Wang et al., 2024). In a similar vein, post hoc analysis from a trial of an exenatide variant, NLY01, found greater benefits in PD patients younger than the age of 60 (McGarry et al., 2024). In the lixisenatide trial, post hoc analysis likewise showed greater benefit for people under 60. They notched a five-point difference from the placebo group, compared with one point for those older than 60.

Exenatide is now in a Phase 3, 96-week trial of 200 mild-to-moderate PD patients in the U.K. (Vijiaratnam et al., 2021). A Phase 3 trial of lixisenatide is planned.

Also in Parkinson’s news, exploratory analyses from the Phase 2 Pasadena study of Roche’s anti-α-synuclein antibody prasinezumab are now published. In the April 15 Nature Medicine, researchers led by Gennaro Pagano at Roche in Basel, Switzerland, reported that a subgroup of participants with more rapidly progressing disease maintained their motor abilities better on prasinezumab (Apr 2021 conference news). Overall, the trial had been negative (Apr 2020 conference news). A new Phase 2 trial, Padova, is testing prasinezumab in patients with faster-progressing disease.—Madolyn Bowman Rogers

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Therapeutics Citations

  1. Exenatide
  2. Prasinezumab

News Citations

  1. Single-Blind Trial: Diabetes Drug Helps Parkinson’s, Maybe
  2. Diabetes Drug Improves Parkinson’s Motor Symptoms in Small Trial
  3. For α-Synuclein Immunotherapy, Is Going Later the Key?
  4. α-Synuclein Antibody Misses Primary, May Have Signal on Secondaries

Paper Citations

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.

External Citations

  1. Padova

Further Reading

Primary Papers

  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.

Annotate

To make an annotation you must Login or Register.