Phase 2 trial reveals Lixisenatide may reduce motor disability in Parkinson’s patients

By Tarun Sai LomteReviewed by Lily Ramsey, LLMApr 18 2024

A recent study published in the New England Journal of Medicine conducted a trial of lixisenatide to assess its effects in early Parkinson’s disease.

Study: Trial of Lixisenatide in Early Parkinson’s Disease. Image Credit: create jobs 51/Shutterstock.com

Background

Current treatments for Parkinson’s disease are primarily based on dopaminergic replacement therapy and have not convincingly demonstrated effects on disease progression. Further, epidemiological studies have observed increased Parkinson’s disease risk in individuals with type 2 diabetes.

Moreover, some studies have shown a lower prevalence of Parkinson’s disease among diabetes patients treated with dipeptidyl peptidase-4 inhibitors or glucagon-like peptide (GLP)-1 receptor agonists compared to recipients of other medications.

Lixisenatide is a GLP-1 receptor agonist used to treat type 2 diabetes. Its neuroprotective actions have been demonstrated in animal models of Parkinson’s disease and Alzheimer’s disease.

About the study

In the present study, researchers evaluated the disease-modifying effect of lixisenatide in individuals with early Parkinson’s disease. This phase 2, double-blind, randomized, multicenter, placebo-controlled trial was performed in France.

People aged 40–75 diagnosed with Parkinson’s disease within the past three years were recruited. Eligible subjects were treated with a stable, optimized dopaminergic medication regimen for at least a month before starting trial agents.

Participants were randomized to receive lixisenatide or placebo in addition to their standard treatment for Parkinson’s disease.

The trial agent was initially administered at 10 μg/day for 14 days and 20 μg/day for the remainder of 12 months. Subjects continued their existing medication for Parkinson’s disease for the first six months at least.

Clinical assessments were performed at baseline, six-month, and 12-month visits. Subjects were evaluated in an on-medication state based on scores on the Parkinson’s Disease Questionnaire summary index, Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson’s Disease Rating Scale (UPDRS) parts I–IV, and Montreal Cognitive Assessment.

Besides, subjects were assessed in an off-medication state after a two-month washout period at 14 months.

Fasting blood glucose and insulin levels were measured. Vital signs and adverse events were recorded at visits. The primary efficacy endpoint was the MDS-UPDRS part III scores change from baseline to 12 months.

Secondary efficacy endpoints were the change in scores on MDS-UPDRS part III at six months, change in scores on MDS-UPDRS parts I, II, and IV at six and 12 months, and change in total MDS-UPDRS score at 12 months. Efficacy was assessed using Student’s t-test.

Linear regression analyses investigated the potential effects of baseline levels of fasting blood glucose and insulin on the primary endpoint.

Findings

The study enrolled 156 subjects; seventy-eight were assigned to receive lixisenatide, and the remainder were assigned to the placebo group. In the lixisenatide arm, 28 subjects were switched back to the 10 μg/day dose due to side effects at the 20 μg/day dose.

Further, dose reduction was required for three placebo recipients. Adherence to the trial agent was over 92% at all visits.

Participants’ baseline clinical and demographic characteristics were similar between groups. In both groups, the average time from diagnosis was 1.4 years.

The average baseline MDS-UPDRS motor score was 14.8 in lixisenatide subjects and 15.5 in placebo recipients. At 12 months, these scores were 14.9 and 18.8 in the lixisenatide and placebo groups, respectively.

Lixisenatide recipients improved their score by 0.04 points from baseline, while placebo subjects had worsened it by 3.04 points. At 14 months, these scores were 17.7 and 20.7 in the lixisenatide and placebo groups, respectively.

Results for secondary/exploratory measures were similar between groups at six and 12 months. No associations were observed between fasting blood glucose and insulin levels at baseline and MDS-UPDRS part III score at 12 months.

Most participants had at least one adverse event. Gastrointestinal side effects were more prevalent with lixisenatide.

The two groups had a similar incidence of serious adverse events. One serious adverse event, syncope in placebo recipients and pancreatitis in the lixisenatide group was deemed treatment-related.

Conclusions

In sum, this phase 2 trial showed that lixisenatide, administered in an on-medication state, had a three-point improvement on a motor disability scale over 12 months compared to baseline.

This difference was driven by an increase in scores in placebo recipients. Further, a three-point between-group difference in the motor score was observed after the two-month washout period, favoring active treatment.

Notably, the trial involved subjects with early disease; as such, it has to be investigated whether drug effects persist at other stages of the disease.

Moreover, secondary endpoints did not definitively support primary endpoint results; therefore, longer washout periods may be necessary to test if the drug has long-lasting effects.