Objective: To explore if the glucagon-like peptide-1 (GLP-1) receptor agonist, exenatide could modify the course of Parkinson’s disease (PD) and if peripheral insulin resistance (IR) mightdifferentially impact on this.

Background: Exenatide has neuroprotective effects in preclinical models of PD. Two phase 2 clinical trials have suggested that exenatide modifies the course of PD. In post-hoc analysis of one of these trials (ExPD2), IR predicted better treatment response.

Method: We performed a phase 3 trial of exenatide once weeklyover 96 weeks in non-diabetic patients with PD (ExPD3). The primary outcome was the difference in MDS UPDRS part III OFF scores at 96 weeks. Secondary outcomes included several motor, non-motor and quality of life rating scales. We explored biomarker changes over 96 weeks by measuring 120 proteins in plasma and cerebrospinal fluid using a novel Nucleic acid Linked Immuno-Sandwich Assay (NULISA) multi-biomarker panel and striatal dopamine transporter imaging signal (DAT-SBR). We determined target engagement by exploring panel plasma C-reactive protein (CRP) change. We also tested exenatide levels in CSF and plasma to assess compliance and brain penetration. We measured HbA1C levels at baseline and used a validated cut-off level of ≥39 mmol/mol to demarcate peripheral insulin resistance (IR+). Intention to treat analyses using linear mixed modelling was performed to examine drug effects on the outcomes. This was repeated for IR status as a post hoc analysis.

Results: Exenatide did not alter the progression of clinical outcomemeasures or biomarkers over 96 weeks. Blood exenatide levels confirmed compliance and CSF levels confirmed low levels of CNSpenetration. 19.8% of patients treated with exenatide were IR+. A non-significant advantage of exenatide compared to placebo was identified on MDS UPDRS 3 OFF score, DAT-SBR signal and plasma CRP in IR+ patients.

Conclusion: Exenatide did not influence PD progression in the overall ExPD3 trial cohort. In ExPD2, there were a larger number of IR+ patients included, which may explain why exenatide was found to have positive effects overall. Although a non-significant trend towards potential benefit was noted in the small subgroup ofIR+ patients in ExPD3, the hypothesis that IR underpins responsiveness to exenatide would require further trial evaluation of a centrally penetrant GLP1 agonist in PD enriching for IR to formally evaluate this possibility.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/peripheral-insulin-resistance-may-predict-exenatide-treatment-response-in-parkinsons-disease/