EVENAMIDE, AS AN ADD-ON TO ANTIPSYCHOTICS, PRODUCES LONGLASTING CLINICALLY MEANINGFUL BENEFIT AND CONVERTS TREATMENTRESISTANT SCHIZOPHRENIA (TRS) PATIENTS INTO A RESPONSIVE STATE: 6-MONTH RESULTS FROM AN ONGOING INTERNATIONAL RANDOMIZED STUDY.

Introduction: First-and-second-generation antipsychotics (APs) are widely used in patients with treatment-resistant schizophrenia (TRS), alone or in combination with other 5-HT2/D2-blocking APs, although AP polypharmacy shows no evidence of benefit [1]. In addition, the long-term usage of APs requires frequent dose adjustments due to development of intolerance and relapses [2], representing a major burden for patients, caregivers, and healthcare providers. TRS develops in ~30% of patients within 5 years of treatment, resulting in increased morbidity, suicidality, and mortality. Findings from neurochemistry, neurometabolism, and functional imaging studies in TRS patients indicate abnormalities in glutamatergic rather than dopaminergic neurotransmission [3, 4, 5]. Evenamide, a selective inhibitor of voltage-gated sodium 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. Aim & 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 (except clozapine). Assessment of efficacy was based on changes of PANSSCGI-S/C and functioning (Strauss-Carpenter LOF), while tolerability was assessed based on all safety measures. Methods: Study 014 is a 6-week, randomized, open-label, raterblinded, international study with completers continuing assigned doses for an additional 46 weeks in an ongoing extension study (Study 015). 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 (PANSS positive total score >=20), along with functional deficits (GAF =<50). Efficacy ratings were performed by a trained psychiatrist blinded to the evenamide dose. Data from all 3 doses were combined into a single group and analyzed to assess the responder rate, maintenance of the response up to 6 months and conversion of TRS patients already on an AP into a responsive state, according to the operational severity selection criteria. Results: The high roll-over rate (94.4%) in Study 015 and the low incidence of treatment-emergent adverse events indicate the good tolerability of evenamide. Furthermore, 6-month efficacy results confirmed the increasing and sustained improvement in all efficacy scales as seen in the cohort of the first 100 patients randomized [6,7]. During this period, more than 65% of the patients who achieved a clinically meaningful benefit (>=20% improvement on PANSS total score) at 6-week preserved their response at 6-month. In addition, ~40% of the patients no longer met the operational severity criteria for TRS used to select patients for the study, and no relapses or clinically important worsening over 6-month were observed. Detailed results from further analyses will be presented at the Congress. Discussion: Encouraging long-term results of this study have expedited the design of a phase 3, potentially pivotal, randomized, double-blind, placebo-controlled, 1-year, international study to assess efficacy and safety of two doses (15 and 30 mg bid) of evenamide as add-on treatment in TRS patients not benefiting from their current AP. [ABSTRACT FROM AUTHOR]