Trial of Lixisenatide in Early Parkinson’s Disease (LIXIPARK)

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LIXIPARK¹ was an investigator-initiated randomised, double-blind, placebo-controlled trial involving 21 centers of the French NS-Park/F-CRIN network trial². The study, sponsored by the Toulouse University Hospital, was funded by the French Ministry of Health and Cure Parkinson, while Sanofi provided active treatment and placebo. Lixisenatide is a glucagon-like peptide (GLP-1) receptor agonist, approved for type 2 diabetes, that crosses the blood-brain barrier. LIXIPARK was conducted following several lines of evidence suggesting: 

1. A link between diabetes and Parkinson’s disease (PD) 

2. A lower prevalence of PD in diabetic patients taking GLP-1 receptor agonists 

3. An association between α-synuclein aggregates and abnormal brain insulin signalling 

4. Results from preclinical PD models and an open-label single-centre trial with the GLP-1 agonist exenatide, suggesting possible beneficial effects on disease progression  

The results of a single-centre, randomised trial with exenatide reporting positive effects on motor function sustained beyond exposure provided additional evidence while LIXIPARK was ongoing.³ 

The primary objective of LIXIPARK was to assess the effect of lixisenatide on the progression of motor disability in people with early PD. One-hundred and fifty-six participants within three years of PD diagnosis on stable symptomatic medications and without motor complications were randomised (1:1) to lixisenatide or placebo once daily for 12 months, followed by a 2-month wash-out. 

At month 12, MDS-UPDRS Part-III ON-state scores (primary endpoint) had worsened by 3.04 points [95% CI, 1.46, 4.62] in the placebo group and remained at baseline (change of -0.04 [-1.62, 1.54] points) in the lixisenatide group. The difference between groups (3.08 [0.86, 5.30]) was significant (p=0.0068). A post-hoc analysis showed a higher effect on motor progression in participants below 60 receiving lixisenatide. Mean MDS-UPDRS motor scores in the practically defined OFF-state following washout were lower on lixisenatide than placebo (17.7 [15.7, 19.7] vs 20.7 [18.5, 22.8]), supporting a potentially neuroprotective mechanism. There were no significant changes between groups in other secondary endpoints (LEDD at Month-12, MDS-UPDRS Parts-I, II and III scores at Month-6, and Part-I and II scores at Month-12). The safety profile was similar to that of diabetes patients, the most common being GI side effects in around 50% of the lixisenatide group. Participants with significant GI side effects were allowed to reduce the daily dose from 20 µg (the usual dose in type 2 diabetes) to 10 µg. This allowed no trial participant to be lost because of GI side effects. Weight remained stable in the lixisenatide group, bearing in mind that weight loss is a classical feature of GLP-1 agonists. 

Taken together, lixisenatide reduced motor disability progression in patients with early PD, suggesting a disease-modifying effect that warrants further investigation in larger trials.  In the meantime, we don’t recommend off-label use of GLP-1 agonists for PD until larger trials have confirmed our results, bearing in mind that Sanofi removed lixisenatide from markets for the treatment of diabetes mellitus in 2023 and that the drug currently only exists in fixed combination with insulin, which is not suitable for PD patients. 

References 

1. Meissner WG, Remy P, Maltête D, et al. Trial of Lixisenatide in Early Parkinson’s Disease. N Eng J Med 2024;390:1176-85. 
2. https://parkinson.network/ 
3. Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet 2017;390:1664-75. 

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