315. EVENAMIDE, A GLUTAMATE MODULATOR, PROVIDED STATISTICALLY SIGNIFICANT BENEFITS WHEN ADDED TO SGA IN PATIENTS WITH SCHIZOPHRENIA: PHASE 2/3, INTERNATIONAL, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY RESULTS

Abstract Background The introduction of second-generation-antipsychotics (SGAs), with an improved efficacy and safety profile compared to typical antipsychotics (APs), has certainly improved the lives of patients suffering from schizophrenia, although unmet needs remain (e.g. negative/cognitive symptoms, inadequate/no response). For this reason, the search for novel therapeutic agents with different mechanisms of action not involving the modulation of the dopaminergic system has greatly expanded in the latest years (Citrome et al., 2023). A promising target is the glutamatergic system (Goh et al., 2021), as increasing evidence has showed excessive glutamatergic activity, rather than increased dopamine synthesis, in patients with limited/no response to APs (Mouchlianitis et al., 2023). Evenamide, a VGSC blocker, is a NCE that normalizes excessive glutamate release without affecting its basal levels, and it does not interact with >150 CNS targets. It has been shown to be effective in animal models of psychosis both as monotherapy and add-on to APs, and previous clinical trials have indicated that add-on treatment with evenamide is associated with long-term clinically important benefits in patients with treatment-resistant schizophrenia (Anand et al, 2023). Aims & Objectives Study 008A is a phase 2/3, 4-week, international, randomized, double-blind, placebo-controlled trial conducted to determine the efficacy and safety of evenamide 30 mg bid as add-on in patients poorly responding to an SGA. Method Outpatients with a diagnosis of schizophrenia, still symptomatic (PANSS 70-85; CGI-S 4-6) despite treatment with an atypical AP at a therapeutic dose (compliance confirmed through plasma levels before randomization) for an adequate period, were enrolled. Efficacy was assessed on the PANSS, CGI-S/C, and Strauss-Carpenter LOF (mean changes from baseline to endpoint) using Intent-to-Treat (ITT) population. Moreover, the proportion of patients reaching a clinically important improvement on the PANSS (≥20% reduction from baseline, as described by Rosenheck et al., 1997 and Meltzer et al., 2008) and CGI-C (at least “much improved”) were compared between groups. Safety measures comprised: TEAEs, vital signs, labs, ECG, seizure checklists, EEG, physical/neurological/eye examinations, C-SSRS, ESRS-A, CDSS. Results A total of 291 patients were randomized (11 countries; 45 sites), and 280 completed 4-week of treatment. The low attrition rate (<4%), similar incidence of TEAEs (~25%) in both groups, and absence of patterns of clinically significant abnormalities on any of the safety measures indicate that evenamide was well-tolerated. Evenamide as add-on was associated with statistically significant greater improvement at endpoint on the PANSS total (p-value=0.006; primary endpoint), PANSS positive and negative subscales, and CGI-S (p-value=0.037; key secondary endpoint), and a statistically significant lower score on the CGI-C compared to placebo. All the sensitivity analyses performed confirmed the same pattern of improvement. Furthermore, a significantly higher proportion of evenamide-treated patients, compared to those receiving placebo, achieved a clinically meaningful level of response on PANSS and CGI-C. Discussion & Conclusions This is the first international, randomized, double-blind, placebo-controlled trial that demonstrated statistically significant and clinically important benefits of adding a glutamate modulator in patients with schizophrenia poorly responding to SGAs. Based on these results, a phase 3 trial will be initiated to determine the benefits of glutamate modulation in patients with treatment-resistant schizophrenia.