Xadago

Pharmacotherapeutic group: Anti-Parkinson-Drugs, monoamine oxidase -B inhibitors, ATC code: N04BD03. Mechanism of action Safinamide acts through both dopaminergic and non-dopaminergic mechanisms of action.‍‍‍‍‍‍​​​‍​​​​​​ safinamide is a highly selective and reversible MAO-B inhibitor causing an increase in extracellular levels of dopamine in the striatum. safinamide is associated with state dependent inhibition of voltage-gated sodium (Na+) channels, and modulation of stimulated release of glutamate. To what extent the non-dopaminergic effects contribute to the overall effect has not been established. Pharmacodynamic effects Population PK models developed from studies in patients with Parkinson's disease indicate that the pharmacokinetic and pharmacodynamics effects of safinamide were not dependent on age, gender, weight, renal function and exposure to levodopa, indicating that dose adjustments will not be required based on these variables. Pooled analyses of adverse event data from placebo controlled studies in Parkinson's disease patients indicate that the concomitant administration of safinamide together with a broad category of commonly used medicinal products in this patient population (antihypertensive, beta-blockers cholesterol lowering, non-steroidal anti-inflammatory medicinal products, proton pump inhibitors, antidepressants, etc.) was not associated with an increased risk for adverse events. Studies were not stratified for co-medication, and no randomized interaction studies were performed for these medicinal products. Clinical efficacy Studies in mid- to late-stage PD patients The efficacy of safinamide as add-on treatment in mid-to late-stage PD (LSPD) patients with motor fluctuations, currently receiving L-dopa alone or in combination with other PD medicinal products, was evaluated in two double-blind, placebo-controlled studies: Study SETTLE (Study 27919; 50-100 mg/day; 24 weeks), and Study 016/018 (50 and 100 mg/day; 2-year, double-blind, placebo-controlled study). The primary efficacy parameter was the change from baseline to endpoint in 'ON Time without troublesome dyskinesia'. Secondary efficacy parameters included OFF Time, UPDRS II and III (Unified Parkinson's Disease Rating Scale – sections II and III), and CGI-C (Clinical Global Impression of Change) Both the SETTLE and 016/018 studies indicated significant superiority of safinamide, compared to placebo, at the target doses of 50 and 100 mg/day for the primary, and selected secondary, efficacy variables, as summarized in the table below. The effect on ON Time was maintained at the end of the 24-month double-blind treatment period for both safinamide doses as compared to placebo. Study 016 (24 weeks) 016/018 (2 years) 27919 (SETTLE) (24 weeks) Dose (mg/day) (a) Placebo Safinamide Placebo Safinamide Placebo Safinamide 50 100 50 100 50-100 (d) Randomized 222 223 224 222 223 224 275 274 Age (years) (b) 59.4 (9.5) 60.1 (9.7) 60.1 (9.2) 59.4 (9.5) 60.1 (9.7) 60.1 (9.2) 62.1 (9.0) 61.7 (9.0) PD Duration (years) (b) 8.4 (3.8) 7.9 (3.9) 8.2 (3.8) 8.4 (3.8) 7.9 (3.9) 8.2 (3.8) 9.0 (4.9) 8.9 (4.4) ON time without troublesome dyskinesia (hrs) (c) Baseline (b) 9.3 (2.2) 9.4 (2.2) 9.6 (2.5) 9.3 (2.2) 9.4 (2.2) 9.6 (2.5) 9.1 (2.5) 9.3 (2.4) Change LSM (SE) 0.5 (0.2) 1.0 (0.2) 1.2 (0.2) 0.8 (0.2) 1.4 (0.2) 1.5 (0.2) 0.6 (0.1) 1.4 (0.1) LS Diff vs Placebo 0.5 0.7 0.6 0.7 0.9 95% CI [0.1, 0.9] [0.3, 1.0] [0.1, 1.0] [0.2, 1.1] [0.6, 1.2] p-value 0.0054 0.0002 0.0110 0.0028 <0.0001 OFF time (hrs) (c) Baseline (b) 5.3 (2.1) 5.2 (2.0) 5.2 (2.2) 5.3 (2.1) 5.2 (2.2) 5.2 (2.1) 5.4 (2.0) 5.3 (2.0) Change LSM (SE) -0.8 (0.20) -1.4 (0.20) -1.5 (0.20) -1.0 (0.20) -1.5 (0.19) -1.6 (0.19) -0.5 (0.10) -1.5 (0.10) LS Diff vs Placebo -0.6 -0.7 -0.5 -0.6 -1.0 95% CI [-0.9, -0.3] [-1.0, -0.4] [-0.8, -0.2] [-0.9, -0.3] [-1.3, -0.7] p-value 0.0002 <0.0001 0.0028 0.0003 <0.0001 UPDRS III (c) Baseline (b) 28.6 (12.0) 27.3 (12.8) 28.4 (13.5) 28.6 (12.0) 27.3 (12.8) 28.4 (13.5) 23.0 (12.8) 22.3 (11.8) Change LSM (SE) -4.5 (0.83) -6.1 (0.82) -6.8 (0.82) -4.4 (0.85) -5.6 (0.84) -6.5 (0.84) -2.6 (0.34) -3.5 (0.34) LS Diff vs Placebo -1.6 -2.3 -1.2 -2.1 -0.9 95% CI [-3.0, -0.2] [-3.7, -0.9] [-2.6, 0.2] [-3.5, -0.6] [-1.8, 0.0] p-value 0.0207 0.0010 0.0939 0.0047 0.0514 UPDRS II (c) Baseline (b) 12.2 (5.9) 11.8 (5.7) 12.1 (5.9) 12.2 (5.9) 11.8 (5.7) 12.1 (5.9) 10.4 (6.3) 10.0 (5.6) Change LSM (SE) -1.2 (0.4) -1.9 (0.4) -2.3 (0.4) -1.4 (0.3) -2.0 (0.3) -2.5 (0.3) -0.8 (0.2) -1.2 (0.2) LS Diff vs Placebo -0.7 -1.1 -0.6 -1.1 -0.4 95% CI [-1.3, -0.0] [-1.7, -0.5] [-1.3, 0.0] [-1.8, -0.4] [-0.9, 0.0] p-value 0.0367 0.0007 0.0676 0.0010 0.0564 Responder analyses (post-hoc) (e) n(%) ON time increase ≥60 minutes 93 (43.9) 119 (54.8) 121 (56.0) 100 (47.2) 125 (57.6) 117 (54.2) 116 (42.5) 152 (56.3) p-value 0.0233 0.0122 0.0308 0.1481 0.0013 ≥60 minutes increase ON time and decrease in OFF time and ≥ 30% improvement UPDRS III 32 (15.1) 52 (24.0) 56 (25.9) 28 (13.2) 43 (19.8) 42 (19.4) 24 (8.8) 49 (18.1) p-value 0.0216 0.0061 0.0671 0.0827 0.0017 CGI-C: patients who were much/very much improved 42 (19.8) 72 (33.2) 78 (36.1) 46 (21.7) 62 (28.6) 64 (29.6) 26 (9.5) 66 (24.4) p-value (f) 0.0017 0.0002 0.0962 0.0575 <0.0001 (a) Daily targeted dose, (b) Mean (SD), (c) analysis population (mITT); MMRM model for change from Baseline to Endpoint includes treatment, region, and visit as fixed effects, and baseline value as a covariate; (d) target dose of 100 mg/day; (e) analysis population (mITT); data are presented as the number (percentage) of patients in each group meeting the responder definition (f) chi-square test of the odds ratio of the treatment groups compared to placebo using a logistic regression model, with fixed effects for treatment and country. SE Standard Error, SD Standard deviation, LSM Least Square Mean, LS Diff. Least Square Difference vs Placebo mITT Population: Study 016/018 - Placebo (n=212), safinamide 50 mg/day (n=217) and 100 mg/day (n=216), and SETTLE - Placebo (n=270), safinamide 50-100 mg/day (n=273). Paediatric population The pharmacodynamic effects of safinamide have not been assessed in children and adolescents.