Trial finds benefit for GLP-1 agonist in Parkinson’s

A small study of Sanofi’s lixisenatide has suggested that the GLP-1 agonist could slow down the progression of Parkinson’s disease, pointing to another potential use for the fast-growing drug class.

If borne out in additional, larger trials, the finding could see the end of a decades-long effort to find a therapy for Parkinson’s that could offer a neuroprotective effect, rather than simply treating symptoms like muscle tremors.

Lixisenatide is an older drug in the same class as Novo Nordisk’s big-selling Ozempic/Wegovy (semaglutide), used to treat type 2 diabetes and obesity, as well as to reduce the risk of cardiovascular disease in some overweight patients.

It has also been shown to reduce kidney disease-related events in people with type 2 diabetes and chronic kidney disease (CKD), and Novo Nordisk is also exploring additional applications, including Alzheimer’s disease.

Lixisenatide requires daily injections, while newer GLP-1-targeting drugs like Ozempic and Wegovy, as well as Eli Lilly’s tirzepatide-based Mounjaro and Zepbound, only need to be given once a week, and orally-active formulations are also coming through the pipeline.

Given the huge unmet need for new Parkinson’s therapies, the new study looks likely to encourage additional studies, at least for GLP-1 compounds that, like lixisenatide, can cross the blood-brain barrier. It is thought that neither semaglutide nor tirzepatide are very good at penetrating the central nervous system.

The investigator-led phase 2 LixiPark trial of lixisenatide looked at the progression of motor symptoms in 156 people living with Parkinson’s whose symptoms had been stabilised using standard antiparkinsonian drugs.

The study has been running since 2018, comparing once-daily subcutaneous injections with lixisenatide to a placebo shot, with the primary endpoint the change from baselines in MDS-UPDRS III motor scores over 12 months.

The group taking lixisenatide saw no worsening of their motor symptoms over that period, with a reduction of just 0.04 points, while those on placebo experienced a 3.04-point decline. Use of the GLP-1 agonist was associated, however, with an increased risk of side effects, particularly gastrointestinal symptoms such as nausea, which occurred in nearly half of patients. The results have been published in the New England Journal of Medicine.

Professors Wassilios Meissner and Olivier Rascol of Toulouse University Hospital, who led the trial, said the findings “constitute a significant step forward in the future management of the disease,” adding that they "look forward to confirming these encouraging results in the future in order to translate such findings into clinical practice.”

According to neurology specialist Professor Tom Foltynie of University College London – who was not involved in the study – the new study is an “important publication” that replicates the findings of an earlier study in Parkinson’s of a similar GLP-1 agonist, exenatide, which was published in The Lancet in 2017.

“This cumulative clinical data […] strongly supports the earlier laboratory and epidemiological data, that GLP-1 receptor stimulation in the brain has neuroprotective effects relevant to the neurodegenerative processes of Parkinson’s,” he said.

Another consideration is that the effect on disease progression was pretty small at 12 months, so it will be important to run longer studies to see if it is sustained and will be clinically meaningful for patients, according to the Parkinson’s UK charity.

Two-year data from a phase 3 trial of exenatide in Parkinson’s is due later this year and could help answer that question, said Prof Foltynie.

Image by Annick Vanblaere via Pixabay