April 3, 2024

expert reaction to phase II trial of Lixisenatide in Early Parkinson’s Disease

A study published in The New England Journal of Medicine looks at a trial of Lixisenatide in early Parkinson’s Disease.

Professor Tom Foltynie, Professor of Neurology, UCL Queen Square Institute of Neurology, University College London (UCL), said:

“This is an important publication given it essentially replicates the findings reported by Athauda et al Lancet 2017, which reported positive phase 2 data of a very similar GLP-1 receptor agonist drug, Exenatide, when given to patients with Parkinson’s disease.

“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 very 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 signalling, (and therefore helps in the relief of symptoms), or whether they suppress the unfavourable 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 2 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.”

Prof Masud Husain, Professor of Neurology, University of Oxford, said:

“The results of this trial are really encouraging for people with Parkinson’s disease. After a year, patients who were on the drug were significantly better off in their movements than those who weren’t on the medication. However, the findings do not provide conclusive evidence that the drug has a protective effect on the brain to effectively slow down disease progression. We also have to bear in mind the side effects. Nausea occurred in nearly half and vomiting in 13% of people on the medication.”

Prof Michele Vendruscolo, Co-Director, Centre for Misfolding Diseases, University of Cambridge, said:

“GLP-1 agonists are widely used to treat type 2 diabetes, and are among the leading repurposed drugs being tested for disease-modifying effects in Parkinson’s disease. A recent Phase II clinical trial has indicated that one of these drugs, lixisenatide, can slow down to some extent the progression of motor disability. In addition to prompting longer and larger clinical trials, these results show that a more quantitative understanding of the mechanism of action of GLP-1 agonists may reveal one or more therapeutic targets for the development of more potent drugs to treat Parkinson’s disease.”

‘Trial of Lixisenatide in Early Parkinson’s Disease’ by W.G. Meissner et al. was published in The New England Journal of Medicine at 22:00 UK time on Wednesday 3 April 2024.

DOI: 10.1056/NEJMoa2312323

Declared interests

Prof Masud Husain: I don’t have any conflict of interest related to this work.

Prof Michele Vendruscolo: founder of WaveBreak Therapeutics (formerly Wren Therapeutics).

Prof Tom Foltynie: Chief Investigator for a series of trials investigating the potential neuroprotective effects of Exenatide in patients with Parkinson’s disease. He is employed by Queen Square Institute of Neurology, London, UK and has had funding for this work from Cure Parkinson’s, Michael J Fox Foundation, National Institute for Health Research, and provision of drug and placebo from Astra Zeneca & Bristol Myers Squibb.