Objective: To evaluate the efficacy of mesdopetam for the treatment of levodopa-induced dyskinesia in Parkinson’s disease (PD-LID), based on two Phase 2 trials.

Background: Mesdopetam is a dopamine D3 receptor antagonist in clinical development for treatment of PD-LID. It has demonstrated antidyskinetic effects in preclinical models, including reduction of abnormal involuntary movements as well as abnormal high frequency oscillations in the 6-OH-DA hemi-lesion rodent model. In a Phase 2a trial, a reduction in ON time with troublesome dyskinesia (Bad ON) and a concomitant increase in ON time without troublesome dyskinesia (Good ON) was seen. In a Phase 2b trial, treatment with mesdopetam was associated with a significant reduction of dyskinesia assessed by UDysRS.

Method: Data from a phase 2a study (4 weeks) and a phase 2b study (12 weeks) comparing mesdopetam with placebo were included. The dose range investigated in these trials was 5, 7.5 and 10 mg (Phase 2a) and 2.5, 5 and 7.5 mg (Phase 2b), b.i.d. This analysis focusses on the evaluation of mesdopetam doses up to 7.5 mg b.i.d vs. placebo. The analysis assessed baseline characteristics and 4-week outcomes on dyskinesia that were evaluable from both trials: UDysRS part 1, UPDRS 4.2 (functional impact of dyskinesia), and patient diaries (Good ON). Furthermore, MDS-UPDRS part II was evaluated as a measure of overall motor function. Analyses were performed with MMRM with fixed effects for study and study x treatment interaction. 8 and 12-week data from the phase 2a study were imputed using multiple imputation (MI) (which represent a random sample of the missing values) or LOCF, using the 4-week data within the phase 2a study, as a sensitivity analysis.

Results: Baseline characteristics were similar across treatment groups and studies. The meta-analysis showed significant and clinically relevant improvements in LID as assessed by UDysRS (part 1a, part 1b and total score for part 1), UPDRS 4.2 and Good ON time. Further, it was confirmed that there was no worsening of motor function assessed by UPDRS part II. MI and LOCF gave similar results.

Conclusion: Based on meta-analysis using MMRM with multiple imputation of missing data, mesdopetam demonstrated significant reduction of dyskinesia as measured by UDysRS, UPDRS 4.2, and motor diaries, without compromising motor function.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/meta-analysis-of-two-randomized-controlled-trials-assessing-the-efficacy-of-mesdopetam-irl790-in-levodopa-induced-dyskinesia-in-parkinsons-disease/