GLP1-R agonist improves Parkinson disease symptoms in early disease
Presenter: Wassilios G. Meissner, MD, PhD, University Hospital Bordeaux, France
Multicenter, randomized, placebo-controlled, double-blind, parallel-group proof-of-concept study of lixisenatide in patients with early Parkinson’s disease (PD): the LIXIPARK trial. Abstract 94. Presented August 29, 2023.
Lixisenatide, a glucagon-like peptide 1 receptor (GLP1-R) agonist approved for the treatment of type 2 diabetes, has potential disease-modifying effects when used an adjunction to antiparkinsonian medications, according to a multicenter phase II clinical trial.
Lixisenatide can cross the blood-brain barrier and is known to have neuroprotective properties in preclinical models of Parkinson disease (PD), note the study’s investigators, led by Wassilios G. Meissner, MD, PhD, University Hospital Bordeaux, France. Further, two single-center phase II pilot trials with other GLP1-R agonists (exenatide, liraglutide) have already shown beneficial effects on motor and nonmotor outcomes in advanced PD,1-3 they noted, leading to this clinical trial, called LixiPark, designed to evaluate the disease-modifying effect of lixisenatide when used as an adjunct to antiparkinsonian medications in patients with early PD.
Results from LixiPark showed that after 1 year of daily treatment, participants randomized to lixisenatide were less disabled, when assessed by the Movement Disorder Society-Unified Parkinson's disease rating scale (MDS-UPDRS). The improved scores on lixisenatide documented in the ON and OFF states favored an improvement in the underlying disease state and not just an amplified pharmacologic impact of drugs already being used, according to the researchers.
LixiPark is multicenter trial performed at 21 centers of the French NS-Park/FCRIN network. A total of 156 patients 40 to 75 years old with early PD (< 3 years since diagnosis) on stable symptomatic medications without motor complications were randomized 1:1 to subcutaneous injections of 20 µg lixisenatide or placebo once daily for 12 months, followed by a 2-month washout period. Patients randomized to lixisenatide received 10 μg/day for 14 days and then 20 μg/day administered by once-daily subcutaneous injections during 12 months. If patients are unable to tolerable the dose of 20 μg/day, it could be reduced to 10 μg/day. Patients were expected to remain on a stable dosage of antiparkinsonian medications for at least the first 6 months of the trial, and optimally for the entire 14 months of follow-up. The primary endpoint was the change from baseline to month 12 in the MDS-UPDRS part III (motor examination) score in the ON condition.
The mean age of patients at baseline was 60 years and their mean time from diagnosis was 1.4 years. The mean MDS-UPDRS III score was 15 and the mean levodopa equivalent daily dosage was 330 mg/day. The study’s drop-out rate was 4.5%, even though it was conducted during the COVID-19 pandemic.
At 12 months, the mean MDS-UPDRS III score increased significantly less for lixisenatide recipients compared with placebo (0.0 vs 3.0; P = 0.0068). At month 14, the mean MDS-UPDRS III score in the OFF phase, a prespecified secondary outcome, was significantly lower for lixisenatide versus placebo (17.7 vs 20.6; P = 0.0445).
There were no between-group differences in other secondary outcomes including the levodopa equivalent daily dose at month 12, mean changes from baseline in MDS-UPDRS I and II scores (motor and nonmotor experiences of daily living) at month 12 in the ON phase, month 6 MDS-UPDRS III scores in the ON phase, and safety and tolerability.
Safety was in line with the known safety profile of lixisenatide in diabetes, with more frequent nausea in patients assigned to lixisenatide (46.2% vs 11.5% in the placebo arm). Some 28 of the 78 (35.9%) patients in the lixisenatide group were unable to tolerate the 20 μg/day dosage and had to decrease their dosage to 10 μg/day at various study visits.
“The study design is innovative, because it examines drug effects in both ON and OFF phases,” commented Christopher Goetz, MD, Rush University, Chicago, IL. “Further, the high retention rates bespeak an impressive, centralized organization across the French centers conducting the research program. Larger international studies will definitively define this drug’s place in our treatment portfolio, but disease-modifying therapies are a goal that would open the prospect of treating the underlying disease as well as ameliorating symptoms.”
References
- Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomized, double-blind, placebo-controlled trial. Lancet 2017; 390(10103):1664-1675. doi: 10.1016/S0140-6736(17)31585-4.
- Malatt C, Wu T, Bresee C, et al. Liraglutide improves non-motor function and activities of daily living in patients with Parkinson’s disease: a randomized, double-blind, placebo-controlled trial (P9-11.005). Neurology 2022; 98(18 Suppl):3068.
- Hogg E, Wu T, Bresee C, et al. A phase II, randomized, double-blinded, placebo-controlled trial of liraglutide in Parkinson's disease. Available at http://dx.doi.org/10.2139/ssrn.4212371.
The study received funding from The Cure Parkinson’s Trust, the French Ministry of Health and Prevention, and Sanofi.