Safinamide for Parkinson’s: Dyskinesia up short term, motor symptoms down long term

A post-hoc analysis of a phase III trial of long-term safinamide for Parkinson’s disease (PD) finds a significant early increase in pre-existing dyskinesia as well as improved motor symptoms in patients with or without pre-existing dyskinesia at 1 year.

Safinamide is a selective and reversible monoamine oxidase (MAO)-B inhibitor, which can be used as add-on therapy in patients with PD experiencing motor fluctuations with levodopa. [Expert Opin Drug Saf 2022;21:137-147] Several clinical studies have examined the effects of safinamide on dyskinesias, but findings have been controversial, ranging from lack of efficacy, to benefits in some patients and onset of dyskinesias in others. [Mov Disord 2014;29:1273-1280; J Parkinsons Dis 2015;5:475-481; J Parkinsons Dis 2021;11:187-198]

“In this post-hoc study, we aimed to investigate the long-term effect of safinamide on dyskinesia, using results of a phase III 52-week open-label study of safinamide 50 mg/day or 100 mg/day in Japanese patients with PD who had [levodopa] wearing-off,” wrote the researchers. “We also explored the safety and efficacy of safinamide in patients with pre-existing dyskinesia [pre-D group], as well as the incidence rate of new-onset dyskinesia.” [J Neural Transm (Vienna) 2022;129:1277-1287]

A total of 194 patients were included in the full analysis set. There were 81 patients in the pre-D group (mean age, 66.3 years; male, 24.7 percent; PD duration, 12.3 years) and 113 patients in the group without pre-D (mean age, 67.8 years; male, 52.2 percent; PD duration, 8.0 years). Compared with the group without pre-D, the pre-D group had a significantly longer mean duration of levodopa treatment (9.58 years vs 5.44 years; p<0.0001), significantly higher levodopa doses (508.64 mg vs 403.54 mg; p<0.0001), and significantly lower activities of daily living (ADL) according to Unified Parkinson’s Disease Rating Scale (UPDRS) Part II (OFF-phase) assessment (16.07 vs 12.90; p=0.0029) at baseline.

In the pre-D group, average daily ON time with troublesome dyskinesia (ON-TD) increased significantly from baseline to week 4, but gradually decreased up to week 52, with a mean change from baseline of −0.08 hours (p=0.6224). While ON-TD did not change significantly vs baseline throughout the observation period in patients without pre-D, their duration of dyskinesia (item 32 in UPDRS Part IV) increased significantly (p=0.0014). At the same time, their UPDRS Part II score (ON-phase) significantly improved from baseline (p<0.01), suggesting that increased dyskinesia time did not affect ADL.

“The results of this study should be interpreted with caution because UPDRS Part IV and adverse drug reactions were clinician-reported, while ON-TD and ON time without TD [ON-WOTD] were patient-reported using 24-hour symptom diaries, and recent research points to a gap between physician assessment and patient self-awareness concerning presence of dyskinesia,” commented the researchers. [Parkinsons Dis 2021;doi:10.1155/2021/1599477]

ON-WOTD significantly increased at each time point from week 4 to week 52 vs baseline in patients with or without pre-D (p<0.05 for each time point). Both UPDRS Part II (OFF-phase) and Part III showed significant improvement (p<0.01 for each time point for both parts) from week 4 to week 52 vs baseline, regardless of the presence of dyskinesia at baseline.

“The addition of safinamide could be a treatment option for patients with levodopa wearing-off. However, further prospective clinical trials are warranted to investigate the potential benefits and clinical relevance of safinamide on dyskinesia, such as the difference in effects between safinamide 50 mg/day and 100 mg/day,” concluded the researchers.