Introduction Treatment resistance schizophrenia (TRS) develops in ~ 30% of patients in about 5 years from starting treatment with 5-HT2/D2 APs, resulting in increased morbidity, suicidality, and mortality. Findings from neurochemistry, neurometabolism, functional imaging in TRS patients indicate abnormalities in glutamatergic neurotransmission (Moghaddam B et al 2012; 37 4-15) rather than excess of dopamine synthesis (Demjaha A et al 2014; 75 11-3; Mouchlianitis E et al 2016; 42 744-52), suggesting the need to add a drug that attenuates glutamate release. Evenamide, a selective inhibitor of voltage-gated Na+ channels, is devoid of biological activity at >130 CNS targets, normalizes glutamate release without affecting basal levels, and demonstrated benefits in animal models of psychosis as monotherapy and as an add on to APs (including clozapine), reversing deficits produced by amphetamine, scopolamine, phencyclidine, or ketamine Objectives Studies 014/015 were designed to evaluate the safety and preliminary efficacy of evenamide given orally at 3 fixed doses (7.5, 15 and 30 mg bid) in patients with TRS not responding to a therapeutic dose of an AP. Assessment of efficacy was based on changes of PANSS and CGI-S/C, while tolerability was assessed based on all safety measures Methods Study 014 is a 6-week, randomized, rater-blinded, international study with completers continuing assigned doses for an additional 46 weeks in an extension study (Study 015). Patients were initially randomized to 7.5 or 15 mg bid; the Independent Safety Monitoring Board (ISMB) allowed randomization to 30 mg bid after reviewing safety data from the first 50 patients. At baseline, patients were moderately to severely ill (CGI-S of 4 to 6), with a PANSS total score of 70-90 and predominant positive symptoms (score of 4 or more on at least 2 core symptoms and a PANSS positive total score ≥ 20), along with functional deficits (GAF ≤50). Efficacy ratings were performed by a psychiatrist blinded to the evenamide dose. Data were analyzed as a single group using descriptive statistics to assess changes from baseline to endpoint (Week 30) Results Interim, group-blinded, 30-week results for safety and efficacy data (PANSS and CGI) for the first 100 patients (including 6 on 30 mg bid) will be presented. Patients randomized to 7.5, 15, and 30 mg bid had all safety and efficacy data pooled in a single group to maintain the blind in the study. All results will be submitted to the ISMB, relevant health authorities and the FDA Conclusions This trial is the first international TRS trial of an NCE AP used as an add-on to a single typical or atypical AP. Results of this study may change the treatment of future TRS patients Disclosure of Interest None Declared

Background: Safinamide (Xadago®, Zambon SpA, Italy) add-on to levodopa in fluctuating patients demonstrated significant superiority over standard-of-care in the 24-week study 016 on ON without troublesome dyskinesia, OFF, UPDRSIII. Objective: To compare pattern of benefit of safinamide at 6 months (Study 016) and 2 years (Study 018), to evaluate its persistence of efficacy. Methods: Data from 016 and 018 were combined and analysed using a modified Intent-to-Treat Population (mITT; groups: placebo; safinamide 50 mg/day, 100 mg/day; All safinamide), for ON (without troublesome dyskinesia), OFF, and the percentage of patients with improvement of ≥60 min in ON and OFF, ≥30% on UPDRSIII, and those meeting all 3 criteria ("responders", chi˗square test). The same analyses were run for the Completer population (who completed 24 months). Results: The mITT Population included 645 patients (safinamide: 50 mg/day = 217; 100 mg/day = 216; placebo = 212). Statistically significant improvement (p < 0.05) at 2 years was observed for ON and OFF (mITT) for the 50, 100 mg/day and the All safinamide vs. placebo. Results for the Completer were similar. The Responder analyses (mITT) showed a statistically significantly (p < 0.05) greater proportion of patients in the 50 mg/day and All safinamide with improvement of ≥60 min in ON vs. placebo. The proportion of patients with improvement ≥30% UPDRSIII was significantly greater for 100 mg/day vs. placebo. The proportion of "responders" was significantly higher for All safinamide vs. placebo. Results for the Completer showed a significantly higher proportion of patients improved in ON, OFF, and UPDRSIII in the 100 mg/day vs. placebo. Conclusions: Safinamide's benefits persisted for 2 years, and were comparable to those observed at 6 months.

ABSTRACTLevodopa is effective for the motor symptoms of Parkinson's disease (PD), but is associated with motor fluctuations and dyskinesia. Many patients require add‐on therapy to improve motor fluctuations without exacerbating dyskinesia. The objective of this Phase III, multicenter, double‐blind, placebo‐controlled, parallel‐group study was to evaluate the efficacy and safety of safinamide, an α‐aminoamide with dopaminergic and nondopaminergic mechanisms, as add‐on to l‐dopa in the treatment of patients with PD and motor fluctuations. Patients were randomized to oral safinamide 100 mg/day (n = 224), 50 mg/day (n = 223), or placebo (n = 222) for 24 weeks. The primary endpoint was total on time with no or nontroublesome dyskinesia (assessed using the Hauser patient diaries). Secondary endpoints included off time, Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor) scores, and Clinical Global Impression‐Change (CGI‐C). At week 24, mean ± SD increases in total on time with no or nontroublesome dyskinesia were 1.36 ± 2.625 hours for safinamide 100 mg/day, 1.37 ± 2.745 hours for safinamide 50 mg/day, and 0.97 ± 2.375 hours for placebo. Least squares means differences in both safinamide groups were significantly higher versus placebo. Improvements in off time, UPDRS Part III, and CGI‐C were significantly greater in both safinamide groups versus placebo. There were no significant between‐group differences for incidences of treatment‐emergent adverse events (TEAEs) or TEAEs leading to discontinuation. The addition of safinamide 50 mg/day or 100 mg/day to l‐dopa in patients with PD and motor fluctuations significantly increased total on time with no or nontroublesome dyskinesia, decreased off time, and improved parkinsonism, indicating that safinamide improves motor symptoms and parkinsonism without worsening dyskinesia. © 2013 International Parkinson and Movement Disorder Society

Background: The mechanism of action of safinamide, a new chemical entity, combines both dopaminergic and non-dopaminergic activity in producing benefit in patients with Parkinson's disease (PD).

Background and purposeSafinamide is an α‐aminoamide with both dopaminergic and non‐dopaminergic mechanisms of action in Phase III clinical development as a once‐daily add‐on to dopamine agonist (DA) therapy for early Parkinson's disease (PD).MethodsStudy 017 was a 12‐month, randomized, double‐blind, placebo‐controlled pre‐planned extension study to the previously reported Study 015. Patients received safinamide 100 or 200 mg/day or placebo added to a single DA in early PD. The primary efficacy endpoint was the time from baseline (Study 015 randomization) to ‘intervention’, defined as increase in DA dose; addition of another DA, levodopa or other PD treatment; or discontinuation due to lack of efficacy. Safinamide groups were pooled for the primary efficacy endpoint analysis; post hoc analyses were performed on each separate dose group.ResultsOf the 269 patients randomized in Study 015, 227 (84%) enrolled in Study 017 and 187/227 (82%) patients completed the extension study. Median time to intervention was 559 and 466 days in the pooled safinamide and placebo groups, respectively (log‐rank test; P = 0.3342). In post hoc analyses, patients receiving safinamide 100 mg/day experienced a significantly lower rate of intervention compared with placebo (25% vs. 51%, respectively) and a delay in median time to intervention of 9 days (P < 0.05; 240‐ to 540‐day analysis).ConclusionsThe pooled data from the safinamide groups failed to reach statistical significance for the primary endpoint of median time from baseline to additional drug intervention. Post hoc analyses indicate that safinamide 100 mg/day may be effective as add‐on treatment to DA in PD.