By Harini Sarva, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College
This paper demonstrated that after one year of treatment, lixisenatide resulted in less progression of motor disability. Longer studies are needed to determine if this represents true disease modification.
Meissner WG, Remy P, Giordana C, et al. Trial of lixisenatide in early Parkinson’s disease. N Engl J Med 2024;390:1176-1185.
This was a one-year study comparing 156 individuals with early Parkinson’s disease (PD) on stable doses of medications who received either lixisenatide or placebo. The primary endpoint was change from baseline to month 12 on the International Parkinson and Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part 3 (motor scores in the on-medication state). Secondary measures included individual MDS-UPDRS motor scores in the off-medication state after a two-month washout period, Montreal Cognitive Assessment (MOCA) scores, and the 39-item Parkinson’s Disease Questionnaire (PDQ-39) scores.
Comparable doses given to diabetes patients were chosen as the dose to be tested in this population. Thirty-six percent of the lixisenatide group had intolerable side effects at the goal of 20 mcg per day dosing and had to switch to a half dose for the duration of the study. Improvement in MDS-UPDRS Part 3 scores was by 0.04 points from baseline in the treatment arm and worsened by 3.04 points in the placebo arm. Secondary endpoint measures generally were similar in the two groups at both six and 12 months. Post-hoc subgroup analysis suggested greater efficacy in those younger than 60 years of age in the treatment group, but no significant conclusions could be drawn from this analysis. Gastrointestinal side effects were most common in the treatment arm. Six subjects lost weight in the lixisenatide group.
COMMENTARY
Studies have suggested an increased incidence of PD in people with diabetes. There is an association between alpha-synuclein aggregation and insulin resistance in the brain. Other studies have suggested a lower incidence of PD among people taking glucagon-like peptide 1 (GLP-1) receptor agonists. Preclinical models have suggested that this class of medications is protective against cytokine-mediated apoptopsis, thus the interest in their neuroprotective potential.
To date, none of the studies using this class of medications has significantly demonstrated disease modification. Despite the improvement in MDS-UPDRS Part 3 scores in the treated group, there were no changes in nonmotor symptoms, thus the underlying mechanisms involved in PD leading to its diverse manifestations have not entirely been targeted with this drug class. Previous studies of pegylated exenatide failed to meet their primary endpoints as well.
Whether this drug class is sufficient in disease modification needs greater assessment in preclinical models. Perhaps it needs to be combined with another drug class to reach full effect. How effectively this and other drugs in this class penetrate the blood-brain barrier has not entirely been elucidated. No radiographic or cerebrospinal fluid (CSF) analysis was performed in this study to assess this effect. Ultimately, in disease-modifying trials, choosing the correct biomarker is vital to establish efficacy. Other than the DATSCAN, CSF synuclein-seeding assays and skin biopsy assays have demonstrated good sensitivities and specificities but were not used in this study.
Although the MDS-UPDRS motor score is a validated clinical scale, it, along with other parts of the UPDRS, does not adequately capture long-term facets of PD but rather snapshots of symptoms and signs. Although greater inclusion of digital biomarkers is occurring in clinical trials, the validity of their data has not been established.
Lastly, the duration of the study was only one year. It is unclear if that is a sufficient timeline to establish disease modification. Despite some disease-modifying trials being longer than one year, study retention may be an issue in trial design. Thus, while GLP-1 agonists hold promise, improvements in the selection of biomarkers and endpoints, in addition to determining the appropriate length of trial design, will greatly enhance our ability to study these medications in disease modification for PD.
