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

Abstract 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, rater-blinded, 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. References 1.Galling, B., Roldá n, A., Hagi, K., Rietschel, L., Walyzada, F., Zheng, W., Cao, X. L., Xiang, Y. T., Zink, M., Kane, J. M., Nielsen, J., Leucht, S., & Correll, C. U. (2017). 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Phase 2 results indicate evenamide, a selective modulator of glutamate release, is associated with clinically important long-term efficacy when added to an antipsychotic in patients with treatment-resistant schizophrenia. Int J Neuropsychopharmacology, 26(8), 523–528.