Diabetes drug trial sparks hope GLP-1s could slow Parkinson's progression

2024-04-04

临床2期临床结果

GLP-1 agonists have flipped the script when it comes to managing diabetes and obesity, and appear to be making headway on heart health as well. But one small study has now revealed promising results for slowing the progression of motor disability in early Parkinson's disease.

A growing body of evidence suggests GLP-1 agonists have neuroprotective properties that could benefit these patients. For example, some studies point to a lower risk of Parkinson's among diabetics treated with GLP-1s or DPP-4 inhibitors DPP-4 inhibitors, which increase GLP-1 levels. Another consistent physiological finding of GLP-1 receptor activation has been reduced inflammation in the brain, a key pathological process in Parkinson's.

A new paper published in the NEJM evaluated Sanofi's diabetes drug lixisenatide, marketed under the trade names Adlyxin in the US and Lyxumia in Europe, in a randomised Phase II trial of 156 patients with early Parkinson's. Subjects had already begun receiving standard therapy and were in the "on-medication" state. The primary endpoint was change from baseline on a 132-point scale measuring motor disability.

Small, but significant difference

At 12 months, patients on lixisenatide experienced less decline in their motor symptoms, with essentially no change in scores on the Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III. By contrast, those in the placebo group saw their Parkinson's symptoms get worse, with an increase of 3.04 points on MDS-UPDRS, where higher scores reflect greater motor disability. The difference was small, but statistically significant.

After a 2-month washout period, the mean MDS-UPDRS motor scores in the "off-medication" state were 17.7 with lixisenatide and 20.6 for placebo; that compares to baseline motor scores of approximately 15 in both groups. Secondary endpoints, which assessed scores at 6 and 12 months on different parts of the MDS-UPDRS scale including non-motor measures, did not differ substantially between the groups.

"It remains to be determined whether the apparent effect of the drug on motor scores persists with longer exposure and at other stages of Parkinson's disease," the study authors said.

Looking beyond motor scores

In an accompanying editorial, neurologist David Standaert of the University of Alabama's Heersink School of Medicine cautioned against drawing "overly optimistic" conclusions that lixisenatide may have completely prevented disease worsening. However, the difference between the two groups nonetheless "appears genuine and supports an effect of lixisenatide on the symptoms, and potentially the course, of Parkinson's disease," he said.

Trial participants did encounter adverse effects of treatment. Researchers aimed to give the highest approved dose of lixisenatide for diabetes, but 36% of patients had side effects that were too severe at that level. Even with a lower dose, many still experienced adverse effects, with 46% reporting nausea and 13% reporting vomiting in the lixisenatide group, compared to 12% and 3%, respectively, in the placebo arm.

Standaert suggested the main takeaway of the study is not so much the extent of the motor score change, but what it might signify. "The primary concern of most patients with Parkinson's disease is not their present condition — it is the fear of progression… If a three-point improvement in score on the MDS-UPDRS is the most that can be achieved with lixisenatide, then the value of treatment with the drug may be limited, especially in view of the adverse effects."

"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," he said, adding "the next step is clearly trials of longer duration."

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