www.nature.com/npjparkd ARTICLE OPEN Safinamide in the treatment pathway of Parkinson’s Disease: a European Delphi Consensus 1✉ Fabrizio Stocchi , Angelo Antonini 2,3, Daniela Berg4,5, Bruno Bergmans6,7, Wolfgang Jost 8 , Regina Katzenschlager9, 10,11,12 Jaime Kulisevsky , Per Odin13, Francesc Valldeoriola 14,15,16,17 and K. Ray Chaudhuri18 Safinamide is a highly selective, reversible MAO B-inhibitor recently marketed in European and North American countries. To better define clinical indications regarding motor and non-motor symptoms, targeted population and safety of this compound, ten movement disorders specialists, experts in their field, convened and developed a panel of statements on: the role of glutamate in Parkinson’s disease, introduction to fluctuations, efficacy of safinamide on motor symptoms, motor complications and non-motor symptoms, quality of life, safety of safinamide and target population for use. Strong consensus was reached for all the statements on the efficacy of safinamide on motor symptoms, motor fluctuations, quality of life and safety. Among non-motor symptoms, a positive consensus was reached for the symptoms sleep/fatigue, mood, and pain while there was a lack of consensus for the statements regarding the efficacy of safinamide in improving cognition, urinary and sexual functions. The statement on orthostatic hypotension obtained a negative consensus. The consistent and large agreement reached in this Delphi panel perfectly reflects the perception of efficacy, safety and tolerability of safinamide as evident from pivotal trials and clinical practice and shows how these findings may guide movement disorders specialists in their clinical therapeutic approach. The impact of non-motor symptoms in PD 1234567890():,; is considerable, and management remains an unmet need. In this context, the ability of safinamide to impact some non-motor symptoms may represent the most promising and distinctive feature of this compound and deserves further investigations. npj Parkinson’s Disease (2022)8:17 ; https://doi.org/10.1038/s41531-022-00277-z INTRODUCTION control dyskinesias in the long term or to address the many non- Monoamine oxidase B inhibitors represent an important treatment motor symptoms that are typical of the advanced stages of the option in the management of Parkinson’s disease (PD), both in the disease. The aim of this study was to obtain a European Consensus early and in the advanced stages of motor complications1,2. The on the use of safinamide, considering the efficacy of this clinical benefit of MAO-B inhibitors arises from the ability of these compound on motor symptoms and motor complications, its medications to enhance the level of dopamine by decreasing its effect on non-motor symptoms (NMS), quality of life in patient catabolism in the brain.3. Among MAO-B inhibitors, safinamide has with PD and how its clinical effect is perceived by clinicians. Moreover, we wished to identify an ideal target population and a dual-mechanism of action since it is able to inhibit (a) MAO-B, delineate the safety in different PD patient sub-populations. potentiating dopaminergic transmission and (b) glutamate release by blocking voltage-dependent sodium channels and modulating calcium channels4,5. Safinamide is a benzylamine derivative which RESULTS acts as potent, highly selective, and reversible MAO-B inhibitor. Hundred and nineteen panelists among movement disorders Due to its reversibility4,6, treatment with safinamide is associated specialists were identified in the following countries: Italy, UK, with reduced risk of hypertensive crises or serotonergic syn- Belgium, Spain, Germany, Sweden, Austria, Netherlands. The drome7,8 as well as drug interaction4,6. response rate was 76% (n = 90) which was considered high, Safinamide is marketed in Europe and in North America under taking into account that the study was performed during the the brand name of Xadago® (Zambon Pharma) and Onstryv® COVID 19 pandemic and related lockdown in most countries. (Valeo Pharma); it was approved in 2015 as adjunctive therapy to Strong consensus was reached for all the statements regarding levodopa in mid- to late-stage fluctuating patients and became the efficacy of safinamide on motor symptoms, motor fluctuations, commercially available in the spring of 2016. While its efficacy in quality of life and safety (29/34 statements, 85,2 % of agreement, controlling motor symptoms and improving motor fluctuations is mean score 91.5), suggesting a shared view of European move- well established9–11, uncertainty remains on its potential ability to ment disorders specialists on these topics. Among NMS, a 1 Department of Neurology, University and IRCCS San Raffaele Pisana, Rome, Italy. 2Parkinson and Movement Disorders Unit, Center for Rare Neurological Diseases (ERN- RND), Tübingen, Germany. 3Department of Neuroscience University of Padua, Padua, Italy. 4Department of Neurology, UKSH, Campus Kiel, Christian-Albrechts-University Kiel, Kiel, Germany. 5Department of Neurodegeneration, Hertie-Institute of Clinical Brain Research Tübingen, Tübingen, Germany. 6Department of Neurology, AZ St-Jan Brugge-Oostende AV, Campus Brugge, Bruges, Belgium. 7Department of Neurology, Ghent University Hospital, Ghent, Belgium. 8Parkinson-Klinik Ortenau, Wolfach, Germany. 9Department of Neurology and Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders Klinik Donaustadt, Vienna, Austria. 10Movement Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 11Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain. 12Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. 13Division of Neurology, Dept of Clinical Sciences Lund, Lund University, Lund, Sweden. 14Universitat de Barcelona Institute of Neurosciences, 537114 Barcelona, Catalunya, Spain. 15Institut d’Investigacions Biomèdiques August Pi i Sunyer, 146245 Barcelona, Catalunya, Spain. 16 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Barcelona, Catalunya, Spain. 17Hospital Clinic de Barcelona, 16493, Movement Disorders Unit, Neurology Service, Barcelona, Catalunya, Spain. 18Parkinson Foundation Centre of Excellence, King’s College Hospital and Kings College, London, UK. ✉email: fabrizio.stocchi@fastwebnet.it Published in partnership with the Parkinson’s Foundation F. Stocchi et al. 2 common, positive consensus was achieved for the symptoms Topic 4: Quality of life sleep/fatigue, mood, and pain while there was a lack of consensus Statement 4.1 (Fig. 4): The positive effect of safinamide on quality for the statements regarding the efficacy of safinamide in of life reached an almost unanimous consensus (98%). improving cognition, urinary and sexual functions. No agreement was reached either on the tolerability of safinamide in patients Topic 5: Safety with hallucinations. The statement on orthostatic hypotension obtained a negative consensus. Statements 5.1–5.8 (Fig. 5): the totality of the Panelists agreed with A second round of questionnaire was deemed unnecessary by the statement that safinamide is safe as add-on therapy for the Board, since all the statements with no or negative agreement symptomatic PD treatment and that its reversible inhibitory effect were considered clearly stated and results obtained reflected of MAO-B represents an advantage in clinical practice. Ninety-six percent of voters believed that safinamide could ameliorate on trends in clinical practice. time without increasing troublesome dyskinesia but only 73% Table 1 summarizes the statements and the percentage of were convinced that the molecule is able to improve dyskinesia in agreement/disagreement reached, based on the responses of the the long-term. Agreement was reached regarding the safety of 90 Panelists. safinamide as an adjunct therapy in patients aged ≥75 years (95%) and in patients with cognitive impairment (89%). No consensus Topic 1: Glutamate role in Parkinson’s disease was reached regarding the tolerability of safinamide in patients Statements 1.1–1.8 (Fig. 1): the glutamatergic circuits within the with hallucinations (39 vs 61%). basal ganglia were confirmed to have a relevant role in the normal control of movement (96% agreement), pain, mood, and cognition Topic 5: Safety - Dyskinesia (93%). A large consensus was reached on the statement that the Statement 5.3 (Fig. 5): The long-term efficacy of safinamide on glutamatergic pathway is involved in the aetiopathogenesis of the dyskinesia reached a relatively weak agreement (73%), reflecting disease (96%) and that the abnormal firing across the glutama- the conflicting results available from the literature to date. tergic cortico-striatal pathway is a key mechanism in the development of dyskinesia (98%). Panelists´ opinions on the 1234567890():,; Topic 6- Target population contributing role of glutamate in the emergence of motor Statements 6.1–6.3 (Fig. 6): safinamide was considered a valid symptoms of PD and in executive dysfunctions were less therapeutic option in patients with advanced PD (100% agree- convergent, even if consensus was obtained for both statements ment), in the early stages of motor fluctuations (97%) and as add- (80 and 86%). Glutamate was considered to be involved in on to LD therapy in PD (100%). neuropathic pain (93%) but to be less crucial in the development of inflammatory pain (80%). These statements reflect the high level of scientific evidence DISCUSSION which has confirmed and defined the role of glutamate in motor The results of this Delphi survey suggest that safinamide is a and non-motor symptoms of PD12,13. useful treatment option for PD patients suffering from motor fluctuations and some specific non-motor fluctuations. The broad Topic 2: Introduction on fluctuations beneficial effect of this compound can most likely be ascribed to its multimodal mechanism of action, which is dopaminergic Statements 2.1–2.3 (Fig. 2): the Panelists agreed that an early (reversible MAO-B inhibition) and non-dopaminergic (modulation fluctuator can be defined as a patient who had motor fluctuations of the abnormal glutamate release). The efficacy of safinamide in for no more than one year and that wearing off phenomena can early and advanced parkinsonian patients has been investigated be present in subjects taking no more than three doses of LD a in double blind, placebo controlled randomized clinical trials. In day (99%). Ninety three percent of the Panelists found the use of early PD patients16, safinamide 100 mg/d induced a significant WOQ19 and WOQ9 to be useful in the diagnosis of wearing off, in improvement in the UPDRS part III score versus placebo (−6.0 agreement with existing literature14,15. points versus −3.6 (p = 0.0419). This positive trend was confirmed in the following double-blind, placebo-controlled extension Topic 3: Efficacy - Motor symptoms study17. In contrast, when added to DAs at 200 mg a day, Statement 3.2 (Fig. 3): there was almost unanimous consensus on safinamide failed to provide a significant improvement in motor the ability of safinamide to improve motor symptoms, both in the functions in early PD patients. short and long term (98%). In advanced patients, safinamide was associated to a significant improvement of motor symptoms, evaluated through the UPDRS- III (motor score) administered during the ON period, in the three Topic 3: Efficacy - Motor fluctuations pivotal trials performed. In the 016 Study18, the UPDRS-III Statements 3.1 and 3.3–3.4 (Fig. 3): There was full agreement on significantly improved, both in the safinamide 50 mg and the efficacy of safinamide in reducing off time (100%). The efficacy 100 mg groups compared to placebo (LS mean changes for the of safinamide was believed to be related not only to MAO-B 50 mg/day: −1.8 [95% CI, −3.3 to −0.4; p = 0.0138]; for the inhibition (98%) and that the glutamate-modulating component 100 mg/day: −2.6 in hours [95% CI, −4.1 to −1.1; p = 0.00060]). of this compound contributes to its clinical efficacy in increasing These results were confirmed and maintained throughout the good on time (without troublesome dyskinesia, 94%). double-blind, placebo-controlled, parallel group, extension study19. In the SETTLE trial20, when evaluated in the on phase, the mean UPDRS-III score was found to improve significantly in Topic 3: Efficacy - NMS the safinamide 100 mg group compared to placebo: –3.43 (7.72) Statements 3.5–3.11 (Fig. 3): a positive consensus was achieved for vs –1.83 (8.23), (LS mean difference, –1.82; 95% CI, –3.01 to –0.62; the symptoms sleep/fatigue, mood, and pain (respectively 80, 83 p = 0.003). and 81%) while no agreement was observed in relation to The improvement reported in the UPDRS was clearer in early cognition, urinary and sexual function. Seventy-two percent of the patients but was less evident in fluctuators when UPDRS was Panelists disagreed with the statement: safinamide improves administered during ON and was not the primary endpoint. In orthostatic hypotension. early PD patients, the improvement observed with safinamide at npj Parkinson’s Disease (2022) 17 Published in partnership with the Parkinson’s Foundation F. Stocchi et al. 3 Table 1. Consensus score. Disagreement Agreement (score 1-2) (score 3-4-5) TOPIC 1 - Glutamate pathway role in Parkinson’s Disease 1.1 Glutamate is involved in the pathophysiology and 4% 96% pathogenesis of PD. 1.2 Glutamate overactivity observed in PD basal ganglia contributes to 20% 80% the occurrence of motor symptoms such as hypokinesia, bradykinesia and rigidity 1.3 Glutamatergic neurotransmission in the basal ganglia is relevant for 4% 96% the normal control of movement 1.4 Glutamatergic neurotransmission in the basal ganglia is relevant for 7% 93% the normal control of pain, cognition and mood 1.5 Abnormal firing across the glutamatergic corticostriatal pathway has 2% 98% gained support as a key mechanism contributing to dyskinesia 1.6 Abnormalities in cortical glutamate levels may play a role in decline of 14% 86% executive functions in early PD and in the development of dementia in advanced PD. 1.7 An increase in glutamate signaling can play a role in 20% 80% inflammatory pain 1.8 An increase in glutamate signaling can play a role in neuropathic pain. 7% 93% TOPIC 2 - Introduction to fluctuations 2.1 Wearing OFF can be present in patients taking three doses of 1% 99% levodopa daily 2.2 An early fluctuator is a patient who has had motor fluctuation for no 23% 77% more than one year 2.3 The use of a questionnaire (such as WOQ19, WOQ9) is useful in the 7% 93% diagnosis of WO TOPIC 3 - Efficacy of Safinamide: Motor Symptom 3.1 Safinamide is not just an MAOB inhibitor 2% 98% 3.2 Safinamide improves motor symptoms (UPDRSIII) in the short and in 2% 98% the long term 3.3 Safinamide reduces OFF time in patients with fluctuation (motor 0% 100% complication) TOPIC 3 - Efficacy of Safinamide: Motor Complications 3.4 The Glutamate-modulating component of safinamide may contribute 6% 94% to its clinical effects of increasing “on” time without troublesome dyskinesia. TOPIC 3 - Efficacy of Safinamide: Non Motor Symptom 3.5 Safinamide improves orthostatic hypotension 72% 28% 3.6 Safinamide improves sleep/fatigue 20% 80% 3.7 Safinamide improves mood 17% 83% 3.8 Safinamide improves cognition 40% 60% 3.9 Safinamide improves urinary function 46% 54% 3.10 Safinamide improves sexual function 60% 40% 3.11 Safinamide is effective for the management of pain in PD 19% 81% TOPIC 4 - Quality of life 4.1 Safinamide improves QOL in PD patients 2% 98% TOPIC 5 - Safety of Safinamide 5.1 Safinamide is a safe add-on therapy for symptomatic PD treatment. 0% 100% 5.2 Safinamide increases “on” time without increasing troublesome 4% 96% dyskinesia. 5.3 Safinamide 100 mg improves dyskinesia in the long term 27% 73% 5.4 Safinamide is well tolerated in patients with cognitive impairment 11% 89% 5.5 Safinamide is well tolerated in patients with hallucinations 39% 61% 5.6 Safinamide should be dosed as 100 mg daily within 2–4 weeks if 14% 86% 50 mg daily is tolerated well Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2022) 17 F. Stocchi et al. 4 Table 1 continued Disagreement Agreement (score 1-2) (score 3-4-5) 5.7 Safinamide as an adjunct therapy in patients aged ≥75 years with 5% 95% advanced PD is safe and tolerated 5.8 The reversible effect of MAOB inhibition like safinamide can be an 1% 99% advantage in clinical practice TOPIC 6 - Target Population 6.1 Safinamide is an effective and safe add-on to levodopa therapy in PD 0% 100% 6.2 Safinamide is a valid therapeutic option in early stages of fluctuations 3% 97% 6.3 Safinamide is a valid therapeutic option in patients with advanced PD 2% 98% Fig. 1 Delphi questionnaire results: topic 1 “Glutamate pathway role in Parkinson’s Disease”. Numbers in the colored bars are the total number of votes received for each level of disagreement/agreement (1, extremely disagree; 2, disagree; 3, agree; 4, mostly agree; and 5, extremely agree). The “negative consensus score” and the “positive consensus score3 are percentage. Fig. 2 Delphi questionnaire results: topic 2 “Introduction to fluctuations”. Numbers in the colored bars are the total number of votes received for each level of disagreement/agreement (1, extremely disagree; 2, disagree; 3, agree; 4, mostly agree; and 5, extremely agree). The “negative consensus score” and the “positive consensus score3 are percentage. 200 mg daily failed to reach statistical significance, probably in from baseline (median 60 min vs 30, p = 0.0001), and in on time relation to the higher discontinuations rate registered in the group with dyskinesia; a significant improvement from baseline was also treated at this dosage, which may have masked the clinical found in UPDRS part III and UDysRS item 921. The recently benefit. published results of the SYNAPSES trial are in line with the Regarding the efficacy on motor fluctuations, a high level of literature, showing a progressive improvement of wearing off and evidence supports the consensus obtained in this Delphi panel on early morning off over the 12 months study, a reduction in the motor fluctuations. Safinamide has been demonstrated to percentage of fluctuating patients from 73.5% to 67.4%22 Two significantly increase on time without dyskinesia and with non- retrospective observational studies also highlighted the beneficial troublesome dyskinesia compared with placebo, in both the 016 effect of this drug on fluctuations measured by the WOQ 1923 and Study (least squares mean change versus placebo for safinamide CGI24. 50 mg/day 0.51 h; 95% CI, 0.07–0.94; p = 0.0223 and for 100 mg/ The conflicting results obtained in this Delphi panel on day 0.55 h; 95% CI, 0.12–0.99; p = 0.0130) and the 018 Study (LS dyskinesia reflect the uncertainty that emerged from clinical increase from baseline: 1.01 h for the safinamide 50 mg/d group, studies, where dyskinesia was the most frequently reported 95% CI, 0.23, 1.11; p = 0.0031 and 1.18 h for the 100 mg/d group, AE18,20. Indeed, in the 018 Study19 the primary endpoint, i.e., mean 95% CI; 0.39, 1.27; p = 0.0002)18,19. A parallel, significant decrease change from baseline (at Study 016 start18) to endpoint of the in off time was also noted (−0.6, p = 0.0043 and −0.6, p = 0.0034) total score of the Dyskinesia Rating Scale (DRS) during on time, in the 016 trial. Moreover, a significant increase in on time without was not met. Nevertheless, a subsequent ad hoc analysis troublesome dyskinesia (+1.42, least-squares mean difference, performed on moderately-to-severely dyskinetic patients who 0.96 h; 95% CI, 0.56−1.37 h; p < 0.001) was reported in the SETTLE entered Study 016 (n = 242, 36%) showed a statistically significant Study20. The efficacy of safinamide on motor fluctuations and reduction in the mean DRS total scores (p = 0.0317) and the same motor symptoms was shown in an uncontrolled study on 91 trend was observed in a post hoc analysis of the 018 study25, patients, which reported a significant reduction in daily off time where safinamide, only when administered at 100 mg day, was npj Parkinson’s Disease (2022) 17 Published in partnership with the Parkinson’s Foundation F. Stocchi et al. 5 Fig. 3 Delphi questionnaire results: topic 3 “Efficacy of Safinamide”. Numbers in the colored bars are the total number of votes received for each level of disagreement/agreement (1, extremely disagree; 2, disagree; 3, agree; 4, mostly agree; and 5, extremely agree). The “negative consensus score” and the “positive consensus score3 are percentage. Fig. 4 Delphi questionnaire results: topic 4 “Quality of life”. Numbers in the colored bars are the total number of votes received for each level of disagreement/agreement (1, extremely disagree; 2, disagree; 3, agree; 4, mostly agree; and 5, extremely agree). The “negative consensus score” and the “positive consensus score3 are percentage. Fig. 5 Delphi questionnaire results: topic 5 “Safety of Safinamide”. Numbers in the colored bars are the total number of votes received for each level of disagreement/agreement (1, extremely disagree; 2, disagree; 3, agree; 4, mostly agree; and 5, extremely agree). The “negative consensus score” and the “positive consensus score3 are percentage. Fig. 6 Delphi questionnaire results: topic 6 “Target Population”. Numbers in the colored bars are the total number of votes received for each level of disagreement/agreement (1, extremely disagree; 2, disagree; 3, agree; 4, mostly agree; and 5, extremely agree). The “negative consensus score” and the “positive consensus score3 are percentage. found to improved DRS scores, regardless of LD changes. distinguishes safinamide from amantadine, which is an anti- Moreover, in a retrospective study published recently, the dyskinetic drug that directly inhibits glutamatergic receptors, but introduction of safinamide was not associated with an improve- it is characterized by a somewhat unfavorable safety profile. ment in the severity of dyskinesia, which remained unchanged in Furthermore, a study to solely explore the effect of safinamide on 85.4% of the enrolled population24. A potential anti-dyskinetic dyskinesia has not been conducted yet and therefore it is difficult effect of safinamide may be related to a reduction in the to infer a definite conclusion. The conflicting results on this topic excitatory overdrive of the direct pathway26. This characteristic may be also interpreted as an indication of the different Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2022) 17 F. Stocchi et al. 6 therapeutic strategies adopted by neurologists when introducing confusion was higher among patients with more severe cognitive safinamide in a therapeutic schedule, where the simultaneous impairment24. The lack of agreement on hallucinations reflects adjustment of the concomitant dopaminergic drugs may have an what emerged from post-marketing studies and in clinical practice important role in the severity of dyskinesia observed. where the use of safinamide was found to potentially increase the With respect to the glutamatergic system, all the panelists risk of hallucinations, most likely related to the higher dopami- acknowledged that this plays an important role in PD aetiopatho- nergic load induced by the drug23,24. genesis as well as in the emergence of its complications and that The consensus on a likely lack of positive effects of safinamide the anti-glutamatergic properties of safinamide may potentially on orthostatic hypotension was expected: even though the use of explain an observed beneficial effect on dyskinesia and NMS. A safinamide has been associated to a slight, non-significant raise in dysfunction of both dopaminergic and non-dopaminergic path- blood pressure values in pivotal trials18,19, the enhancements of ways is known to contribute to development of NMS, thus drugs the vasodilating action of dopaminergic drugs may explain the that interact with several neurotransmission systems may be lack of tolerability observed in patients with OH. It has to be noted helpful in alleviating these dysfunctions. though that in a post-marketing study performed to evaluate the It has been suggested that the anti-glutamatergic properties of safety of the immediate switch from rasagiline to safinamide, safinamide may be particularly beneficial in addressing motor blood pressure variability in systolic and diastolic values was complications and some specific NMS. This is a speculative comment unchanged between baseline and end of study 24-hour ambula- but can be supported by animal models; there are data indicating the tory blood pressure monitoring recordings41. role of glutamatergic neurotransmission in modulating pain in normal The beneficial effect of safinamide on QoL is supported by a and neuropathic rats27,28. Preclinical data suggest that the brain high level of evidence. All studies that included QoL as an glutamate system may be involved in depression related behavior like outcome parameter have demonstrated the efficacy of safina- anhedonia29. In humans with depression, neuroimaging studies found mide, when use at 100 mg, in benefiting both short-term and increased levels of glutamate in the putamen, highlighting a potential long-term quality-of-life outcomes in advanced PD patients role of the basal ganglia in the neurophysiology of depression30. measured by the PDQ-39 and the EQ5D questionnaires18–20,42,43. Glutamate was also hypothesized to influence the sleep-wake rhythm The safety of safinamide was acknowledged by all panelists, in through the release of glutamate from the supra-mammillary region, agreement with what had emerged from clinical trials in early16,17 which was associated to a sustained behavioral and EEG arousal and advanced PD patients18–20, where the majority of TEAE were response31. mild to moderate in intensity and the most serious adverse events A general consensus was reached on the efficacy of safinamide reported were judged as not related to the investigational drug. A on pain, mood and sleep, based on literature findings. The large multinational, multicenter, retrospective, prospective 12- possible effect of safinamide on NMS needs to be further explored month observational cohort study evaluated the safety of in dedicated trials, since evidence currently available is limited32. safinamide in a real-life population of PD patients22 and showed Treatment with Safinamide was related to a long-lasting, a 30% lower rate of AEs compared to pivotal trials performed18–20. significant reduction of pain-related sub-items of quality of life Subgroup analyses were performed for the following categories: questionnaire (PDQ-39). Moreover, a reduction of concomitant age>75 years old, presence of relevant comorbidities and pain killer treatment in fluctuating PD patients in a post-hoc psychiatric conditions. Among these categories, SAEs were more analysis of the 018 study33 and in a pooled analysis of the 016 and frequent in patients aged >75 and AEs/SAEs were more frequent SETTLE studies was observed34. A beneficial effect on pain was in those with relevant comorbidities. There were no cases of also shown in a small prospective study where safinamide was serotoninergic syndrome in participants treated with SSRI/SNRI or used to address pain related to motor fluctuations35. In a small tricyclics, nor cases of impulse control disorders or sleep retrospective analysis performed in fluctuating PD patients with deterioration in patients taking concomitant dopamine-agonists. sleep disruption, a significantly greater improvement of both, Dyskinesia was confirmed to be the most frequently reported AE, nocturnal sleep and diurnal sleepiness, was highlighted in the although observed at lower rates compared to the published RCTs group of subjects treated with safinamide compared to those on (13.7% vs 18.3% for the 016 Study and 14.6% for the SETTLE)18,20. rasagiline36. The SYNAPSES study22, conducted in a real word setting in six Safinamide was found to significantly improve emotional well- European countries, confirmed the safety and tolerability of being and depression for up to two years in a post hoc, pooled safinamide, as adjunct therapy, in fluctuating patients and in analysis of the 016 and 018 Studies37, even though in the original special groups of subjects such as those suffering from studies the improvement in the GRID Hamilton Rating Scale for neuropsychiatric symptoms (depression, bipolar disorders, psy- Depression failed to reach statistical significance compared to chosis and apathy). placebo. In another retrospective study, safinamide was shown to The reversibility of the MAO-B inhibition of safinamide significantly improve depressive symptoms in PD patient after just represents a clear advantage compared to the other MAO-B one month of treatment and to be well tolerated when co- inhibitors when treating advanced PD patients with concomitant administered with antidepressants38. morbidities and high concomitant medications load, due to the A beneficial effect on pain was shown in a retrospective survey reduced risk of drug interactions. Studies in healthy volunteers7,8 and in a small prospective study35. In another retrospective study and patients44 have also confirmed that safinamide is not safinamide was shown to be useful for treating depressive associated with any change of tyramine potentiation, with no risk symptoms in PD patients and safe when administered with of serotonin syndrome or hypertensive crisis. concomitant antidepressant38. The positive effect on chronic pain Safinamide is a well-tolerated and easy to use drug thanks to its and mood may be also related to the ability of safinamide to once-a-day administration. In fluctuating PD patients, this inhibit sodium channel39,40. compound reduces OFF time without increasing troublesome No agreement was obtained regarding domains like cognition, dyskinesia. Its indirect anti-glutamatergic properties represent a bladder, and sexual dysfunctions, highlighting the paucity of novelty among the drugs for PD; its ability to reduce the supporting evidence in these areas. Regarding cognition, in hyperactivity of the direct pathway may potentially have long- studies performed to explore the tolerability of safinamide in term positive effect on the natural course of motor complications. elderly and in general population, patients enrolled had no Possibly due to its dual mechanism of action, it can be particularly cognitive impairment (MMSE ≤ 23) or previous history of halluci- useful in addressing NMS, whose treatment represents one of the nations;24 when patients with cognitive impairment were current unmet needs of PD. Indeed, the ability to ameliorate NMS included, the number of withdrawals due to the occurrence of may be the most promising and distinctive feature of this npj Parkinson’s Disease (2022) 17 Published in partnership with the Parkinson’s Foundation F. Stocchi et al. 7 compound: its potential efficacy in controlling pain, mood and Members of the validation panel sleep abnormalities may open the door to new therapeutics Valentina Leta (UK), Jasmin Rahimi (Austria), Katarina Rukavina (UK), perspective if confirmed in randomized clinical trials. Daniele Urso (UK) The Delphi method requires participants to respond considering their personal experience/judgment on the proposed statements: the Panelists conclusions provided in this report are based therefore on the Araceli Alonso (Spain), Lucia Batzu (UK), Anna Rita Bentivoglio (Italy), Filip opinions of a panel of European movement disorder specialists, Bergquist (Sweden), Marta Blázquez Estrada (Spain), Alexandra Boogers opinions maturated through a vast experience with the use of (Belgium), Christof Brücke Brücke (Austria), Nuria Caballol Pons (Spain), Paolo safinamide. The considerations highlighted in the paper may serve as Calabresi (Italy), Camille Carroll (Uk), Buhmann Carsten (Germany), Roberto a general reference for a more rational approach when prescribing Ceravolo (Italy), Roberto Cilia (Italy), Carlo Colosimo (Italy), Radu Constantinescu (Sweden), Pietro Cortelli (Italy), David Crosiers (Belgium), Beatriz De La Casa safinamide, allowing movement disorders neurologists to further Fages (Spain), Gino De la Meilleure (Belgium), Mieke De Weweire (Belgium), deepen, and not limit, their personal experience with this compound. Woitalla Dirk (Germany), Atbin Djamshidian (Austria), Laurens Dobbels The consensus reached in this Delphi study provides an overview (Belgium), Christian Dresel (Germany), Georg Ebersbach (Germany), Karla of how European movement disorders specialists view the role of Eggert (Germany), Reinhard Ehret (Germany), Roberto Eleopra (Italy), Roberto safinamide in their clinical practice. The large agreement obtained Erro (Italy), Francisco Escamilla Sevilla (Spain), Giovanni Fabbrini (Italy), Thomas reflects how specialists are mindful of the results of RCTs published Foki (Austria), Pieret Françoise (Belgium), Rocío García-Ramos (Spain), Ransmayr and how these results guide their therapeutic perspective. The Gerhard (Austria), Juan Carlos Gomez Esteban (Spain), Ayoze Nauzet González Hernández (Spain), Victoria Haunton (UK), Jorrit Hoff (Netherlands), Jagdish outcome almost perfectly reflects findings that have emerged in the Sharma Jagdish (UK), Kassubek Jan (Germany), Maes Jen (Belgium), Leenders literature and provides an interesting snapshot of the issues not yet Jo (Belgium), Anders Johansson (Sweden), Winkler Juergen (Germany), Vinod addressed by the existing studies. Indeed, data on dyskinesia and Metta (UK), Ines Legarda (Spain), Johan Lökk (Sweden), Leonardo Lopiano NMS such as pain and mood are still limited, and more studies are (Italy), Michael Lorrain (Germany), Rosario Luquin (Spain), Martina Müngersdorf needed to draw definite conclusion. However, clinical experience to (Germany), Juan Carlos Martínez Castrillo (Spain), Pablo Mir (Spain), Thomas date and the results of this Delphi process emphasizes that the data Müller (Germany), Nina De Klippel (Belgium), Bruggemann Norbert (Germany), from controlled studies translate into a valuable clinical role of Dag Nyholm (Sweden), Sven Pålhagen (Sweden), Santens Patrick (Belgium), Manuela Pilleri (Italy), Andrea Pilotto (Italy), Monika Pötter-Nerger (Germany), safinamide, which may be due to its dual mechanism of action, and Rocco Quatrale (Italy), Silvia Ramat (Italy), Jason Raw (UK), Heinz Reichmann this is true even at an early stage of motor fluctuations. (Germany), Mario Giorgio Rizzone (Italy), Pilar Sanchez (Spain), Diego Santos García (Spain), Klaus Seppi (Austria), Ángel Sesar (Spain), Nishantha Silva (UK), Monty Silverdale (UK), Örjan Skogar (Sweden), Antonio Suppa (Italy), Per METHODS Svenningsson (Sweden), JP ter Bruggen (Netherlands), Alessandro Tessitore Study design and methods (Italy), Warnrecke Tobias (Germany), Lars Toenges (Germany), Volker The Delphi method is a survey technique that uses responses to a standardized Tomantschger (Austria), Thomas Vaterrodt (Germany), Pieter Viaene (Belgium), questionnaire developed by a panel of experts to facilitate the convergence of Dieter Volc (Austria), Hofmann W. E. (Germany), Karoline Wenzel (Austria), opinions or the achievement of a common opinion in areas where scientific Christian Winkler (Germany), Mario Zappia (Italy), Anna Lena Zecchinelli (Italy). evidence is scarce or needed45–47. The Delphi method involves the repeated administration of questionnaires, where each statement can be evaluated Reporting summary through a five-point Likert scale, with a score from 1 to 5 (1, extremely Further information on research design is available in the Nature Research disagree; 2, disagree; 3, agree; 4, mostly agree; and 5, extremely agree). Results Reporting Summary linked to this article. are expressed as a percentage of respondents who scored each item as 1 or 2 (disagreement) or as 3, 4, or 5 (agreement). A positive consensus is reached if the percentage of agreement is greater than 66%. No consensus is reached, DATA AVAILABILITY when the sum of the responses for a negative consensus (1 and 2) or a positive The data that support the findings of this study are available from the corresponding consensus (3, 4, and 5) is <66%. author upon reasonable request. 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Real life evaluation of safinamide effectiveness in Parkinson’s AUTHOR CONTRIBUTIONS disease. Neurol. Sci. 39(Apr), 733–739 (2018). F.S., A.A., D.B., B.B., W.J., R.K., J.K., P.O., F.V. and K.R.C. drafted the manuscript. F.S., A.A., 22. Abbruzzese, G. et al. SYNAPSES Study Investigators Group. A European obser- vational study to evaluate the safety and the effectiveness of safinamide in D.B., B.B., W.J., R.K., J.K., P.O., F.V. and K.R.C. contributed to formulating the routine clinical practice: the SYNAPSES Trial. J Parkinsons Dis 11, 187–198 (2021). questionnaire, analyzing the responses, and made critical revisions of the manuscript. 23. Rinaldi, D. et al. The tolerability, safety and efficacy of safinamide in elderly Parkinson’s disease patients: a retrospective study. Aging Clin Exp Res. 33, 1689–1692 (2021). COMPETING INTERESTS 24. Martí-Andrés, G. et al. Safinamide in clinical practice: a Spanish multicenter cohort Fabrizio Stocchi has received compensation for consultancy and speaker related activities study. Brain Sci. 9(Oct), 272 (2019). from Zambon, UCB, Chiesi Pharma, Lundbeck, Sunovion, Bial, SynAgile, Biogen, Kiowa and 25. Cattaneo, C. et al. Long-term effects of safinamide on dyskinesia in mid-to late- stage Parkinson’s disease: a post-hoc analysis. J. Parkinsons Dis. 5, 475–481 (2015). Impax. Angelo Antonini has received compensation for consultancy and speaker related 26. Blandini, F., Porter, R. H. & Greenamyre, J. T. Glutamate and Parkinson’s disease. activities from UCB, Boehringer Ingelheim, General Electric, Britannia, AbbVie, Kyowa Kirin, Mol. Neurobiol. 12, 73–94 (1996). Zambon, Bial, Neuroderm, Theravance Biopharma, Roche, Medscape; he receives research 27. Chen, S. R. & Pan, H. L. Distinct roles of group III metabotropic glutamate support from Bial, Lundbeck, Roche, Angelini Pharmaceuticals, Horizon 2020 - Grant receptors in control of nociception and dorsal horn neurons in normal and nerve- 825785, Horizon2020 Grant 101016902, Ministry of Education University and Research injured rats. J. Pharm. Exp. Ther. 312, 120–126 (2005). (MIUR) Grant ARS01_01081, Cariparo Foundation. He serves as consultant for 28. Marabese, I. et al. Metabotropic glutamate receptor subtype 7 in the dorsal Boehringer–Ingelheim for legal cases on pathological gambling. Daniela Berg reports striatum oppositely modulates pain in sham and neuropathic rats. Neuro- grants from Janssen Pharmaceutica, grants from the Damp foundation, grants from the pharmacology 135, 86–99 (2018). German Parkinson’s Disease Association (dPV), grants from BMWi, grants from BMBF, 29. Mao, L. M. & Wang, J. Q. Alterations in mGlu5 receptor expression and function in grants from the ParkinsonFonds Deutschland GmbH, grants and speaker’s honoraria from the striatum in a rat depression model. J. Neurochem. 145, 287–298 (2018). and consultancy honoraria of UCB Pharma GmbH, grants from and consultancies for 30. Godlewska, B. R. et al. Brain glutamate in medication-free depressed patients: a Novartis Pharma GmbH, grants and speaker’s honoraria from and consultancy honoraria proton MRS study at 7Tesla. Psychol. Med. 48, 1731–1737 (2018). of Lundbeck, speaker’s honoraria from and consultancy honoraria of BIAL, speaker’s 31. Pedersen, N. P. et al. Supramammillary glutamate neurons are a key node of the honoraria from and consultancy honoraria of Biogen, honoraria from Bayer and Zambon arousal system. Nat. Commun. 8, 1405 (2017). outside the submitted work. Bruno Bergmans has received grants and compensation for 32. Seppi, K. et al. The movement disorder society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson’s disease. Mov. lectures and advisory functions from Abbvie, Zambon, Merz Pharma, Orion, Allergan and Disord. 26(Oct), S42–S80 (2011). Suppl 3(0 3). St Jude. Wolfgang Jost is advisor and speaker for Abbvie. Bial, Desitin, Stada, UCB, 33. Cattaneo, C., Kulisevsky, J., Tubazio, V. & Castellani, P. Long-term efficacy of Zambon. Regina Katzenschlager has received honoraria for speaking and consulting from safinamide on parkinson’s disease chronic pain. Adv. Ther. 35, 515–522 (2018). AbbVie, AOP Orphan, Bial, Britannia, Ever Pharma, Stada, UCB, and Zambon, and research 34. Cattaneo, C., Barone, P., Bonizzoni, E. & Sardina, M. Effects of safinamide on pain grants from Britannia, Stada and Zambon within the past 3 years. Pier Odin has received in fluctuating parkinson’s disease patients: a post-hoc analysis. J. Parkinsons Dis. compensation for lectures and advisory functions from AbbVie, Bial, Britannia, Ever 7, 95–101 (2017). Pharma, Lobsor, Nordic Infucare, Stada and Zambon. Jaime Kulisevsky: No conflicts 35. Geroin, C. et al. Effects of safinamide on pain in Parkinson’s disease with motor regarding this manuscript. K. Ray Chaudhuri: Advisory board: AbbVie, UCB, GKC, Bial, fluctuations: an exploratory study. J. Neural Transm. (Vienna). 127, 1143–1152 (2020). Cynapsus, Lobsor, Stada, Medtronic, Zambon, Profile, Sunovion, Roche, Therevance, Scion, 36. Liguori, C., Stefani, A., Runi, R., Mercuri, N. B. & Pierantozzi, M. Safinamide effect on Britannia, Acadia, 4D. Honoraria for lectures: AbbVie, Britannia, UCB, Zambon, Novartis, sleep disturbances and daytime sleepiness in motor fluctuating Parkinson’s dis- Boeringer Ingelheim, Bial; Grants (Investigator Initiated): Britania Pharmaceuticals, AbbVie, ease patients: A validated questionnaires-controlled study. Park. Relat. Disord. 57, UCB, GKC, Bial, Academic grants: EU, IMI EU, Horizon 2020, Parkinson' UK, NIHR, PDNMG, 80–81 (2018). EU (Horizon 2020), Kirby Laing Foundation, NPF, MRC, Wellcome Trust. npj Parkinson’s Disease (2022) 17 Published in partnership with the Parkinson’s Foundation F. Stocchi et al. 9 ADDITIONAL INFORMATION Open Access This article is licensed under a Creative Commons Supplementary information The online version contains supplementary material Attribution 4.0 International License, which permits use, sharing, available at https://doi.org/10.1038/s41531-022-00277-z. adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Correspondence and requests for materials should be addressed to Fabrizio Stocchi. Commons license, and indicate if changes were made. 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