A diabetes drug may improve Parkinson's disease symptoms
Lixisenatide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) for the treatment of diabetes, slows dyskinesia in patients with early Parkinson's disease, according to the results of a phase 2 clinical trial published in the New England Journal of Medicine (NEJM) on 4 April 2024.
The study, led by the University Hospital of Toulouse (France), recruited 156 subjects, equally divided between a lixisenatide treatment group and a placebo group. The researchers measured the effect of the drug using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score, with higher scores on the scale indicating more severe movement disorders. The results showed that at month 12, the MDS-UPDRS part III score decreased by 0.04 points (indicating slight improvement) in the lixisenatide group and increased by 3.04 points (indicating worsening of the disease) in the placebo group.
A contemporaneous NEJM editorial noted that, on the surface, these data suggest that lixisenatide completely prevented the worsening of Parkinson's disease symptoms over a 12-month period, but this may be an overly optimistic view. All of the MDS-UPDRS scales, including Part III, are composite scales consisting of many parts, and improvement in one part may counteract deterioration in another. In addition, both trial groups may have benefited simply by participating in the clinical trial. However, the differences between the two trial groups appear to be real, and the results support the effect of lixisenatide on Parkinson's disease symptoms and potential disease course.
In terms of safety, 46 percent of subjects treated with lixisenatide experienced nausea and 13 per cent experienced vomiting.The NEJM editorial suggests that the incidence of side effects may hinder the widespread use of lixisenatide in the treatment of Parkinson's disease, and therefore further exploration of dose reduction and other methods of relief would be valuable.
"In this trial, the difference in MDS-UPDRS scores was statistically significant but small after 12 months of treatment with lixisenatide. The importance of this finding lies not in the magnitude of the change, but in what it portends." The aforementioned editorial writes, "The biggest concern for most Parkinson's patients is not their current condition, but the fear of disease progression. If lixisenatide improves MDS-UPDRS scores by at most 3 points, then the therapeutic value of the drug may be limited (especially given its adverse effects). On the other hand, if the efficacy of lixisenatide is cumulative, increasing the score by another 3 points per year over a period of 5 to 10 years or more, then this could be a truly transformative treatment. The next step is obviously to conduct trials of longer duration."
Developed by French drugmaker Sanofi (SNY.US), lixisenatide was approved by the U.S. Food and Drug Administration (FDA) for the treatment of type 2 diabetes in 2016, making it the 5th GLP-1RA to be marketed globally.Judging from the data from the clinical trials, it is not as effective in lowering glucose as its counterparts liraglutide and Exendin-4, and its entry into the U.S. market came later than theirs, making it difficult for the product to gain a foothold. In 2023, lixisenatide was withdrawn from the US market. Sanofi explains that this was due to commercial reasons rather than safety or efficacy issues with the drug.
Parkinson's disease is a neurodegenerative disorder that occurs mostly in middle-aged and older adults, most notably characterised by resting tremor, rigidity and slowed movements, with an undetermined cause. Currently, the mainstay of treatment for Parkinson's disease is dopaminergic replacement therapy, which primarily works to improve symptoms and has no convincing evidence of affecting disease progression.
Several previous studies have found that GLP-1 receptor agonists reduce brain inflammation. Neuroinflammation leads to a progressive loss of dopamine-producing brain cells, a core pathological feature of Parkinson's disease. However, only GLP-1 receptor agonists that have access to the brain are effective in Parkinson's disease, and recently semaglutide and liraglutide, which are well known for their weight loss effects, have not shown potential for treating Parkinson's disease.
Previously, a trial conducted by a team of researchers at the Institute of Neurology at the University of London (UK) found that exenatide, which is structurally similar to lixisenatide, improved Parkinson's disease symptoms. The results of the trial showed that at 60 weeks, patients treated with exenatide had a 1-point reduction in their MDS-UPDRS scores, while those treated with a placebo had a 2.1-point improvement. Co-developed by Eli Lilly (LLY.US), a major U.S. pharmaceutical company, exenatide is the world's first GLP-1 receptor agonist, which had monopolised the market for five years.
According to statistics, at least six GLP-1 receptor agonists have been or are currently being tested for their effectiveness in treating Parkinson's disease.
According to the World Parkinson's Association, there are currently 5.7 million Parkinson's disease patients worldwide, with about 2.7 million in China. By 2030, China will have half of the world's total Parkinson's population. The global Parkinson's disease drug market will have sales of RMB 38.2 billion in 2023 and is expected to reach RMB 61.24 billion in 2030, according to DIResaerch (DIResaerch).
Post time: Apr-24-2024
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