Mechanism of Action
Safinamide has a selective and reversible MAO-B inhibitory effect and increases brain concentrations of intrinsic dopamine and dopamine of levodopa origin. This MAO-B inhibition is considered as the main mechanism of action of safinamide. Safinamide also has a nondopaminergic effect (glutamate release suppressive effect via a voltage-gated sodium channel inhibitory effect).
MAO-B inhibition
For inhibitory effect of safinamide on MAO-B, IC50 was 79 nM in the human brain and 98 nM in the rat brain, showing that MAO-B inhibition was approximately 1000-fold more potent in the human brain and approximately 6000-fold more potent in the rat brain than MAO-A inhibition (in vitro). MAO-B inhibition of safinamide was reversible (in vitro, in vivo ).
Voltage-gated sodium channel inhibition
Safinamide inhibited a voltage-gated sodium channel in an activity-dependent manner. In human Nav subtypes (Nav 1.1 – 1.8), IC50 was 13 – 82 μM under rest conditions and 1.6 – 4.9 μM in the inactivated state (in vitro). In a microdialysis study in the rat hippocampus, safinamide significantly suppressed glutamate release induced by sodium channel agonists (in vivo ).
Effect in Parkinson’s disease model
Although coadministration of levodopa and benserazide to rats with 6-hydroxydopamine (6-OHDA) is associated with rotary motion, multiple dosing of levodopa and benserazide reduces rotary motion (wearing-off phenomenon). Safinamide significantly reversed this reduction in rotary motion.
In a cynomolgus monkey model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), treatment with safinamide prolonged the duration of the therapeutic effect of levodopa on Parkinson’s disease.
Clinical Studies
Clinical Studies for Efficacy and Safety
Japanese phase 2/3 study
In a randomized, double-blind study in Japanese patients with Parkinson’s disease with wearing-off phenomenon under treatment with levodopa-containing products, there was a statistically significant increase in the change in mean daily “on” time from the baseline to the last evaluation point in the safinamide 50 mg and 100 mg groups compared with the placebo group (P=0.0002 and P<0.0001, respectively).
Table 1 Changes in Mean Daily “On” Time from the Baseline to the Last Evaluation Point
| Treatment Group (Number of Subjects Evaluated) |
Last Evaluation Point – Baselinea (hours) | Comparison With the Placebo Groupb | |
| Difference in Change Between Groups [95%CI, Lower, Upper] |
P-value | ||
| Placebo (n=136) |
–0.17 ± 0.26 | – | – |
| Safinamide 50 mg (n=131) |
1.22 ± 0.26 | 1.39 [0.67, 2.11] |
0.0002 |
| Safinamide 100 mg (n=128) |
1.49 ± 0.26 | 1.66 [0.93, 2.39] |
< 0.0001 |
a: LS Mean ± SE b: Mixed model for repeated measure (MMRM) with changes from the baseline as a response variable, the treatment group, evaluation time point, and an interaction between the treatment group and evaluation point as fixed effects, and the baseline value as a covariate
The incidence of adverse reactions was 31.6% (42/133 subjects) in the 50 mg group and 30.3% (40 /132 subjects) in the 100 mg group. Major adverse reactions were dyskinesia 8.3% (11/133 subjects), visual hallucinations 3.0% (4/133 subjects), headache 2.3% (3/133 subjects), somnolence 2.3% (3/133 subjects), and nausea 2.3% (3/133 subjects) in the 50 mg group, and dyskinesia 10.6% (14/132 subjects), visual hallucinations 4.5% (6/132 subjects), somnolence 2.3% (3/132 subjects), nausea 2.3% (3/132 subjects), decreased weight 2.3% (3/132 subjects), and decreased appetite 2.3% (3/132 subjects) in the 100 mg group.
Japanese phase 3 study
In an open-label, long-term study in Japanese patients with Parkinson’s disease with wearing-off phenomenon under treatment with levodopa-containing products, the change in mean daily “on” time from the baseline with safinamide 50 to 100 mg/day (mean ± SD) was 1.05±1.74 hours (n=193) at Week 4 and 1.42±2.72 hours (n=142) at Week 52, showing a persistent effect after long-term treatment. The incidence of adverse reactions was 38.9% (79/203 subjects). Major adverse reactions were dyskinesia 16.3% (33/203 subjects), fall 3.4% (7/203 subjects), constipation 3.0% (6/203 subjects), visual hallucinations 2.5% (5/203 subjects), insomnia 2.5% (5/203 subjects), and nausea 2.5% (5/203 subjects).
Others
Effect on QT interval
When safinamide 100 and 350 mg was administered to healthy adult subjects once daily for 6 days, the QTc interval reached a minimum 1 hour after administration, with a difference from the placebo group of -5.4 and -15.5 msec, respectively. This effect was correlated with plasma concentrations of safinamide (non-Japanese data).
Note) The approved daily dose of this drug is generally 50 mg and the maximum is 100 mg.