Dopamine D3 Receptor Mesdopetam Maintains Anti-Dyskinesia Effects Despite Failure to Improve Parkinson Disease ON Time

A phase 2b study (NCT04435431) published in early 2025 revealed that treatment with mesdopetam (IRLAB Therapeutics), an investigational dopamine D3 receptor agonist, failed to have a dose-dependent effect in ON time for patients with Parkinson disease (PD) over a 12-week period. Despite this, secondary outcomes highlighted the agent’s positive impacts on reducing LID severity and functional impact, while also reducing OFF time with no worsening of parkinsonism.¹

Published in Movement Disorders, the dose-finding study tested the efficacy and safety of mesdopetam at doses of 2.5 mg, 5 mg, and 7.5 mg twice daily (BID) in patients with PD with at least 2 hours of troublesome dyskinesia. Led by Joakim Tedroff, MD, PhD, chief medical officer at IRLAB, the study’s primary end point was change in 12-week ON time without troublesome dyskinesia, while secondary outcomes included ON phase dyskinesia through the modified Unified Dyskinesia Rating Scale (UDysRS) and Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 4.2.

On the primary analysis, investigators recorded no significant effect of mesdopetam relative to placebo after 12 weeks of treatment. For the key secondary end point of LID disability (UDysRS part 1b+4), treated patients had a 3.5 point improvement vs placebo (P = .06), based on randomized doses, which reached statistical significance in a prespecified analysis based on adjusted dose (7.5 mg vs placebo: –3.9; 95% CI, –7.7 to –0.1; P = .045). Notably, LID severity (UDysRS sum of parts 1, 3, and 4) showed significant improvements vs placebo with the largest contrast at the top dose (7.5 mg BID week 12: 6.2 points; P <.05).

Post hoc responder analysis of the modified UDysRS in the FAS showed that 71.4% of patients randomized to 7.5 mg achieved an improvement of at least 8 points at week 12, compared with 51.5% in the placebo group. Subjective functional impact of LID (MDS-UPDRS item 4.2) demonstrated a numerical, dose-dependent trend toward improvement versus placebo. Neither MDS-UPDRS Part II nor OFF-time worsened relative to placebo; instead, OFF-time showed a numerical dose-dependent improvement, reaching a 0.7-hour reduction versus placebo with 7.5 mg BID.

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Because bad ON time showed no separation from placebo at week 12 while UDysRS measures consistently improved across subscales, investigators evaluated the internal consistency of the dyskinesia assessments. At baseline, bad ON time did not correlate with any other dyskinesia measures. Notably, UDysRS Part 1b, which captures patient-reported disability from dyskinesia over the prior week, showed no correlation with bad ON time recorded via 3-day home diaries during that same week. By week 12, these correlations improved, particularly in the placebo group, where bad ON time and UDysRS Part 1b demonstrated a significant linear relationship (r = 0.548) for the week preceding the week 12 visit.

In contrast, change from baseline in the modified UDysRS was positively correlated with change from baseline in MDS-UPDRS item 4.2 across all subjects in the FAS (r = 0.5138). No treatment-related differences were observed in Clinical Global Impression, Mini-Mental State Exam, MDS-UPDRS Part I, or MDS-UPDRS Part III.

In terms of safety, adverse events (AEs) were recorded in 56.9% of patients on mesdopetam, with serious AEs found in 3.4% of treated individuals. Of note, there was 1 serious AE of increased parkinsonism and increased falls in a participant randomized to 5 mg mesdopetam that was deemed possibly related to the study drug. In addition, among the common TEAEs, parkinsonism was reported in a larger percentage of patients randomized to placebo (10.3%) than those randomized to mesdopetam (4.3%). However, mobility decreased which also may represent increased parkinsonism was reported in 6.9% of the subjects in the mesdopetam arm, but not in the placebo arm.

Prior to the phase 2b study, mesdopetam was evaluated in a smaller phase 2a trial lasting 4 weeks total. In that study, investigators continued to see antidyskinetic effects of the therapy, with treated patients demonstrating a 1.6-hour reduction in good ON time with troublesome dyskinesia, captured by 24-hr home diaries. The results on these diary items were not evident in the present trial, with only a marginal numerical improvement of Good ON vs. placebo at the 7.5 mg bid dose in the FAS.

“One important difference between these two trials is the inclusion criterion requiring at least 2 hr of bad ON time applied in the present study and where the previous study had no minimal requirement of bad ON time,” the study authors wrote. “The finding that bad ON time at baseline could not be anchored to any other assessment of dyskinesia in this study supports this statement and questions the validity of this instrument to describe severity and disability of dyskinesia at baseline in the present trial. The requirement of at least 2 hr of bad ON, which was recommended by regulatory agency advice, may thus have resulted in an unevenly distributed overestimation of bad ON at baseline, causing a drift in the perception of troublesome dyskinesia during the treatment period, hampering the analysis of change to baseline for bad ON.”

REFERENCES
1. Antonini A, O’Suilleabhain P, Stocchi F, et al. Mesdopetam for the Treatment of Levodopa Induced Dyskinesia in Parkinson's Disease: A Randomized Phase 2b Trial. Mov Disord. 2025;12(6):796-806. doi:10.1002/mdc3.70004
2. Carroll C, Odin P, Sonesson C, et al. A Phase 2a study evaluating mesdopetam for the treatment of levodopa-induced dyskinesia in Parkinson's disease. NCT03368170 (manuscript in preparation).