297. DESIGN OF A PHASE 3, POTENTIALLY PIVOTAL, INTERNATIONAL, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL WITH EVENAMIDE, A GLUTAMATE MODULATOR, ADD-ON TO SGA IN PATIENTS WITH TREATMENT-RESISTANT SCHIZOPHRENIA

Abstract Background Almost one third of patients with schizophrenia develop resistance to treatment (TRS), either in their first-episode or at later stages of illness after an initial response to antipsychotics (APs) (Siskind et al., 2022). Opportunities of treatment for patients with TRS are limited. The only drug that demonstrated superiority over other APs in TRS is clozapine, which is vastly underutilized due to its unfavourable safety profile. The superior efficacy of clozapine in TRS is believed to be owed to its unique mechanism of action: rather than being restricted to DA/5HT modulation, clozapine seems to act on multiple receptor systems (De Bartolomeis et al., 2022). The necessity of modulating non-monoaminergic targets is highlighted by findings of excessive glutamatergic activity, rather than increased dopamine synthesis, in TRS (Mouchlianitis et al., 2023). Evenamide, a new chemical entity, is a voltage-gated sodium channel blocker devoid of biological activity at >150 CNS targets, that normalizes excessive glutamate release without affecting its basal levels. Preclinical experiments in various animal models of psychosis have demonstrated benefits associated with evenamide, both when used as monotherapy and when combined with APs. Clinical benefits of evenamide as add-on to an AP in TRS patients were demonstrated in a pilot, phase 2, open-label, rater-blinded, 1-year trial (Anand et al., 2023); in addition, a phase 2/3, international, randomized, double-blind, placebo-controlled trial in patients with schizophrenia not adequately benefitting from a SGA showed statistically significant and clinically meaningful improvements associated with evenamide add-on treatment for 4 weeks. Aims & Objectives This study will evaluate the efficacy, safety, and tolerability of fixed doses of 15 mg bid and 30 mg bid of evenamide as add-on treatment in patients with documented TRS receiving AP treatment but not adequately benefitting from a stable therapeutic dose of an SGA. Method This is a prospective, potentially pivotal, phase 3, international, 1-year, randomized, double-blind, placebo-controlled, study, with a primary efficacy endpoint at 12 weeks and long-term efficacy endpoints at 26 and 52 weeks. Eligible patients must have a diagnosis of TRS according to the TRRIP consensus guidelines (Howes et al, 2017). During the 6-week screening period and throughout the study, adherence to background AP(s) and evenamide will be confirmed through measurements of plasma levels. Psychiatric selection criteria include CGI-S of mildly to severely ill (3-6); BPRS total score ≥45, with a score ≥18 on core symptoms of psychosis, and PANSS total score ≥70. An Independent Eligibility Committee will determine patients’ eligibility. Patients improving ≥20% on the BPRS or ≥1 category on the CGI-S during the screening period will be excluded. Efficacy (PANSS, CGI-S/C, Q-LES-Q-SF, GAF, PSP scales) and safety (vital signs, ECG, lab tests, physical/neurological/eye exams, ESRS-A, CDSS, C-SSRS) will be evaluated at regular intervals. Results The study will be initiated by the time of the congress. Results will determine whether treatment with evenamide as add-on to SGAs is associated with statistically significant and clinically important improvement in patients with TRS. Discussion & Conclusions Positive results from this study would support the need for glutamate modulation for the optimal treatment of patients with schizophrenia not benefitting from SGAs.