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Lixisenatide slows motor disability progression in early PD

Lixisenatide slows motor disability progression in early PD

By Lucy Piper, medwireNews Reporter

medwireNews: The glucagon-like peptide-1 receptor agonist lixisenatide slows motor disability progression in patients with early Parkinson’s disease (PD), suggest findings from the LIXIPARK trial.

The phase 2, multicentre trial, conducted in France, showed that 12 months of treatment with lixisenatide alongside existing dopamine therapy was associated with a 0.04-point reduction in scores on the Movement Disorder Society–Unified PD Rating Scale (MDS-UPDRS) part III, whereby a higher score indicates greater motor disability.

This compared with a worsening of 3.04 points among patients given placebo, corresponding to a 3.08-point difference in favour of lixisenatide.

Oliver Rascol (University of Toulouse, France) and colleagues note, however, that gastrointestinal adverse events were more common in people taking lixisenatide than placebo, specifically nausea (46 vs 12%), vomiting (13 vs 3%) and gastroesophageal reflux (8 vs 1%).

Commenting on the findings in a related editorial in The New England Journal of Medicine, David Standaert, from the University of Alabama in Birmingham, USA, says: “The importance of this finding is not the magnitude of the change but what it portends.”

He continues: “If a three-point improvement in scores on the MDS-UPDRS is the most that can be achieved with lixisenatide, then the value of the treatment with the drug may be limited (especially in view of the adverse events). On the other hand, if the benefit of lixisenatide is cumulative, adding another three points each year over a period of 5 to 10 years or more, then this could be a truly transformative treatment.”

The study involved 149 patients aged a mean of 60 years (40–75 years) who were diagnosed with PD no more than 3.0 years earlier (mean 1.4 years) and had been receiving optimized stable dopaminergic treatment for at least a month.

The participants were randomly assigned to receive either subcutaneous lixisenatide, at an initial dose of 10 µg/day for 14 days and increased to 20 µg/day for the remainder of the 12-month trial, or placebo. Existing treatment could be continued for at least 6 months. The mean baseline MDS-UPDRS part III score was 14.8 points for patients in the lixisenatide group and 15.5 for those in the placebo group.

The researchers report that 36% of patients in the lixisenatide-treatment group had “unacceptable side effects” at the maximum dose and were switched to the lower dose.

At 12 months, patients receiving lixisenatide had a mean MDS-UPDRS part III score of 14.9 points, compared with 18.8 points for patients given placebo. And by month 14, following a 2-month washout period of lixisenatide and placebo and an overnight washout of dopaminergic medication, the mean scores were 17.7 points and 20.6 points, respectively, giving a 3-point difference in favour of lixisenatide.

Rascol and colleagues say that the findings “suggest an effect on motor disability progression that is potentially related to a neuroprotective mechanism”, but they add that “an effect of lixisenatide on symptoms cannot be ruled out”, suggesting the drug may “enhance synaptic dopamine levels.”

Secondary endpoints, such as changes from baseline in scores on the MDS-UPDRS parts I, II and IV, and changes in levodopa equivalent daily dose, were similar between the lixisenatide and placebo treatment groups.

Serious adverse events occurred in five patients in each group, only two of which were considered related to treatment: one case of pancreatitis in the lixisenatide group and one of syncope in the placebo group. Six patients taking lixisenatide reported weight loss, which was not reported for any patients taking placebo.

The researchers conclude that larger and longer trials are now needed to determine whether “the apparent effect of the drug on motor scores persists with longer exposure and other stages of Parkinson’s disease.”

This independent news story was supported by an educational grant from L’Institut Servier, Suresnes, France.

N Engl J Med 2024; 390: 1176–1185