HONOLULU—Safinamide, a new investigational drug for the treatment of Parkinson’s disease, reduces motor fluctuations associated with the use of levodopa and may therefore be an effective add-on therapy, according to research that was presented at the 63rd Annual Meeting of the American Academy of Neurology.
“Levodopa is probably the most effective treatment for motor symptoms, but long-term use is associated with potential neurotoxicity, more specifically the development of dyskinesia,” said Ravi Anand, MD, Chief Medical Officer at Newron Pharmaceuticals in Bresso, Italy. “To date, there is no treatment that has been approved for the treatment of dyskinesia.”
Dr. Anand presented the results of a two-year controlled clinical trial. The study was designed to evaluate the efficacy of safinamide in improving “on” time, dyskinetic symptoms, and quality of life when used as add-on therapy to levodopa.
A Two-Part Trial
The study consisted of an initial six-month treatment period, followed by an 18-month extension trial, during which investigators administered a daily dose of safinamide (50 mg or 100 mg) or placebo pill to 669 patients.
Participants were men and women (age range, 30 to 80 years) with a three-year history of idiopathic Parkinson’s disease and motor fluctuations who were already taking levodopa or other dopaminergic treatments.
Of the initial 669 patients, 222 received placebo, 223 received 50 mg safinamide, and 224 received 100 mg safinamide. Four hundred and forty patients completed a full two years of treatment. Improvement was measured according to the Unified Parkinson’s Disease Rating Scale, which measured movement ability and performance on daily activities, and a dyskinesia rating scale.
No Increase in Adverse Events Compared With Placebo
“At the end of two years, approximately 75% to 80% of the patients were still in the trial, which tells us that the drug is very well-tolerated,” Dr. Anand reported. In addition, the drop-out rate at the end of six months was exactly the same as that in the placebo group. The incidence of adverse events was also similar among all participant groups.
“In the assessment of dyskinesia in the overall population, what happened was exactly what had been hypothesized to a certain extent,” Dr. Anand stated. “The placebo patients worsened; the drug-treated patients at the two doses of 50 mg and 100 mg both showed an improvement, but the difference was not statistically significant.”
Participants taking safinamide did, however, experience a significant increase in “on” time, a reduction in “off” time, and improvements in performing daily activities, without experiencing an increase in dyskinetic symptoms. “Many drugs improve ‘on’ time,” Dr. Anand reported, “but they also do it at the expense of increasing troublesome dyskinesia.”
Improvement in Motor Fluctuations Was Insignificant in Initial Analysis
To investigate the lack of significant difference in dyskinesia scores, the researchers also performed a post hoc analysis of patients who had dyskinesia at baseline. “We realized that actually only one-third of the patients had dyskinesia at baseline,” Dr. Anand explained. “Obviously, it’s very difficult to improve something that doesn’t exist.”
When the analysis was restricted to 242 dyskinetic patients at baseline, the researchers observed decreases in dyskinesia severity scores for both doses of safinamide and placebo, but only the 100-mg dose reached statistical significance. The 76 patients receiving placebo had a mean deacrease of 0.8 points in dyskinesia severity score, 86 patients receiving 50 mg safinamide decreased 1.4 points, and 80 patients receiving 100 mg safinamide decreased 2 points.
“In the safinamide 100-mg/day group, [improvements in ‘on’ time] were accompanied by long-term improvements in motor function, nonmotor symptoms (activities of daily living, depressive symptoms), and patients’ clinical status,” Dr. Anand reported.
Safety and Efficacy Outcomes Are Promising for Future Studies
“This is the first two-year, prospective, placebo-controlled study in patients with mid- to late Parkinson’s disease and motor fluctuations despite optimized antiparkinsonian treatment,” Dr. Anand stated. “[Safinamide] reduced ‘off’ time, and, in doing so, also showed a pattern that was unique—there was no increase in troublesome dyskinesia.
“Currently, there are studies with safinamide that are ongoing worldwide,” he concluded, noting the importance of these findings for developing future add-on treatments for the negative effects of long-term levodopa use. “These data allow us now to design additional studies looking at patients with severe dyskinesia where this effect would, if translated, mean that you have a treatment that could really reduce dyskinesia in patients with Parkinson’s disease who are taking levodopa.”
—Ariel Jones