Mesdopetam showed significant effects on the secondary end point of Unified Dyskinesia Rating Scale, an assessment of involuntary movements associated with long-term treatment with dopaminergic medication.
Recently announced findings from a phase 2b trial (NCT04435431) showed that mesdopetam (IRLAB Therapeutics), an oral dopamine D3-receptor antagonist, did not meet its primary end point of change in ON time in patients with Parkinson disease (PD); however, the agent did demonstrate anti-dyskinetic effects without impairing motor function. Further analysis of the full data will be presented at future scientific congresses and publications in scientific journals.
The double-blind, placebo-controlled study randomly assigned 156 patients with PD experiencing troublesome dyskinesia to either 3 doses of mesdopetam (2.5, 5.0, and 7.5 mg BID) or placebo. Of them, 125 patients completed the 12-week treatment period. At the conclusion of the study, treatment with mesdopetam did not reach statistically significant change in daily ON time without troublesome dyskinesia. Additionally, the agent showed an acceptable safety profile and an adverse event (AE) profile that was similar to placebo.
"Although the study did not meet its primary efficacy endpoint, a well-established scale used to assess dyskinesia, the UDysRS, demonstrated anti-dyskinetic effects by mesdopetam," Nicholas Waters, executive vice president and head of Research & Development, IRLAB, said in a statement.1 “Notably, these anti-dyskinetic properties were obtained without impairing normal motor function and are further strengthened by an apparent reduction in OFF-time. The effect is observed at doses with a side effect profile on par with placebo. This was also a dose-finding study and we now have a clear understanding that 7.5 mg bid is the preferred dose for further clinical studies."
Although the therapy did not meet its primary end point, it showed significant anti-dyskinetic effects at 4 weeks (P = .045) and 8 weeks (P = .004) that persisted through the end of the 12-week treatment period (P = .026) in doses of 7.5 mg BID. Calculated using the Unified Dyskinesia Rating Scale (UDysRS), this effect was corroborated by the numerical improvement in scales measuring disability associated with dyskinesia. A secondary end point, the daily time spent in OFF showed a dose-dependent pattern and numerical decrease favoring the 7.5 mg BID dose relative to placebo.
At the conclusion of the treatment period, investigators observed no change in Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part II, indicating that mesdopetam does not impair normal motor function in patients with PD. In terms of safety, AEs were reported by 56.9% and 46.2% of mesdopetam- and placebo-treated patients, respectively. Both groups had similar rates of withdrawal, indicating good tolerability.
The most common AEs reported by system organ class were nervous system disorders, which were found in 19.8% of mesdopetam-treated individuals and 23.0% of those on placebo. Parkinsonism was reported by 4.3% of those on mesdopetam vs 10.3% of those on placebo. During the first month of treatment, 6.9% of mesdopetam-treated individuals and no individuals on placebo experienced decreased mobility; however, this was not seen during the second and third months of treatment.
"Unfortunately, the primary endpoint to increase “good ON”-time compared to placebo was not met. I am, however, encouraged that the UDysRS results suggest that mesdopetam has potential to become an effective treatment of Parkinson’s disease,” Richard Godfrey, chief executive officer, IRLAB, said in a statement.1 "Clearly, further detailed analysis is required to fully understand the potential of this first-in-class compound. I am grateful to the clinical development team, PIs and CRO for their diligent and hard work with the Phase IIb trial, and I would like to thank the patients and their caregivers for their trust and participation in this study."
In 2019, IRLAB announced an in-depth analysis on data from a concluded phase 2a study of mesdopetam, formerly known as IRL790, in patients with PD-induced dyskinesia. Findings showed clinically meaningful effects on dyskinesias assessed by the Hauser standardized patient reported diaries and by MDS-UPDRS. Patient reported diaries showed that treatment with IRL790, compared with placebo, significant reduced patient’s time with troublesome dyskinesias by 1.6 hours daily. In patients without concomitant amantadine treatment, the reduction in time increased to 2.7 hours daily, compared with placebo.2
In that study, investigators found no difference between active drug and placebo on UDysRS, despite the significant effects reported in diaries and on MDS-UPDRS assessments. An in-depth analysis of the UDysRS data generated showed that the assessments had technical shortcomes during the sampling of the UDysRS since many of the patients were not in ON state during those assessments. The study investigators concluded that the frequency of patients not in ON state indicated that UDysRS data was not relevant for the assessment of ON state dyskinesias in the study.