Exenatide Once Weekly in the Treatment of Patients with Multiple System Atrophy.

OBJECTIVE: Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of multiple system atrophy (MSA). We investigated these effects in a proof-of-concept clinical trial. METHODS: In this single-center, randomized, open label trial, participants with MSA were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg weekly for 48 weeks, or as controls, followed by a 48-week washout period. The primary outcome was the Unified Multiple System Atrophy Rating Scale (UMSARS) parts I + II combined score at 48 weeks. Objective secondary outcome measures included the numbers of participants losing ambulation; scoring ≥ 3 on UMSARS part I items for falls, speech, swallowing, as well as timed walking and measures of quality of life and cognition. RESULTS: Between September 23, 2020, and May 6, 2022, 50 participants were recruited (25 in each group). At 48 weeks, UMSARS parts I + II scores had worsened by 6.1 points (95% confidence interval [CI] = 3.0 to 9.3, SD = 6.9) in the exenatide group and by 13 3 points (95% CI = 9.2 to 17.3, SD = 9.4) in the control group, an adjusted mean difference of -7.4 points (-11.3 to -3.6, p = 0.0003). There were no statistically significant differences at either 48 or 96 weeks in the secondary outcome measures. Biomarker analysis of neurofilament light chain and cerebral spinal fluid (CSF) alpha-synuclein oligomer load, sensor-derived gait measures, and imaging findings were also similar between groups. INTERPRETATION: Exenatide was associated with positive effects on participant-reported symptoms and clinician-rated MSA severity. In contrast, none of the objective comparisons differed according to randomization. Given the open label trial design, the discrepancy between the primary outcome and the objective measures may be explicable as placebo effects/observer bias. ANN NEUROL 2025;98:991-1003.