EVENAMIDE AS ADD-ON TREATMENT FOR TREATMENT-RESISTANT SCHIZOPHRENIA (TRS) PATIENTS NOT BENEFITING FROM ANTIPSYCHOTICS: DESIGN OF A PHASE 3, POTENTIALLY PIVOTAL, INTERNATIONAL, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL

Abstract Background TRS affects 30% of patients with schizophrenia, resulting in higher rates of hospitalization, morbidity, suicidality, and mortality [1,2]. Clozapine, the only drug approved for TRS, is vastly under-utilized, due to its severe side-effects and blood monitoring requirement, and >30% of patients do not respond to clozapine. Other strategies to treat TRS such as high doses of antipsychotics (APs), or AP polypharmacy, are not shown to be effective [3,4,5]. Findings from neurochemistry, neuroimaging and neurometabolism studies of TRS patients indicate abnormalities in the glutamatergic neurotransmission, rather than excess of dopamine synthesis, that lead to failure to respond to current 5HT/D2 antipsychotics.[6] Evenamide, an orally available new chemical entity, is a voltage-gated sodium channel blocker, with no biological activity at >130 CNS targets and normalizes glutamate release induced by aberrant sodium channel activity, without affecting basal glutamate levels. The combination of ineffective doses of evenamide and 5HT2/D2 blocking APs was associated with benefit in animal models of psychosis, suggesting synergies in mechanisms that may benefit poor responders to current APs, including clozapine.[7] Preliminary evidence of efficacy of evenamide in TRS patients has been shown in a pilot, phase 2, open-label, rater-blinded, 1-year study, where increasing benefits were noted across all efficacy measures over time. Clinically important increases in responder rates were noted for the key efficacy measures (PANSS, CGI-S, and CGI-C).[8] Aims & Objectives A prospective, potentially pivotal, phase 3, randomized, double-blind, placebo-controlled, 1-year, international study will be performed to demonstrate the efficacy and tolerability of two doses (15 and 30 mg bid) of evenamide as add-on therapy in TRS patients not benefiting from their ’ standard of care’ treatment with APs (including clozapine). Methods This study will enrol >450 adult schizophrenia patients meeting the TRRIP criteria [9], requiring a history of failure on at least 2 APs (2 different chemical classes; at least one second-generation AP) for an adequate period, including a 6-week prospective failure. Selection criteria include schizophrenia diagnosis (DSM V), CGI-S score 3-6; BPRS total score >45, with a score >=18 on positive symptoms of psychosis. Patients will be enrolled based on acceptability of their screening data by an Independent Eligibility Committee. Patients improving >=20% on the BPRS or >=1 category on the CGI-S during the 6-week screening period will be excluded. Adherence to the background AP and study medication will be confirmed by measurement of plasma levels. Efficacy and safety will be evaluated regularly, with Weeks 12 and 26 as efficacy endpoints; the study will continue under blinded conditions up to Week-52. Efficacy Measures Include PANSS total (primary), CGI-S (key secondary), CGI-C, Q-LES-Q-SF and PSP scales, assessment of cognition and pharmacoeconomic outcomes. Safety measurements include vital signs, ECG, laboratory tests, physical/neurological/eye examinations, ASEX, ESRS-A, CDSS, and C-SSRS. Results The results of the study will demonstrate if addition of evenamide to patients with TRS on APs is associated with efficacy and tolerability. Discussion & Conclusions Results from this study will determine if glutamate modulation by evenamide may represent a new therapeutic strategy for the treatment of patients with TRS. References 1.Solanki RK, Singh P, Munshi D. Current perspectives in the treatment of resistant schizophrenia. Indian J Psychiatry 2009; 51:254-260. 2.Pompili M, Giordano G, Luciano M, et al. Unmet Needs in Schizophrenia. CNS Neurol Disord Drug Targets. 2017;16(8):870-884. 3.Elkis H, Buckley PF (2016) Treatment-resistant schizophrenia. Psychiatr Clin North Am 39:239–265. 4.Nucifora FC, Woznica E, Lee BJ, Cascella N, Sawa A (2019) Treatment resistant schizophrenia: clinical, biological and therapeutic perspectives. Neurobiol Dis 131:104257. 5.Pandarakalam JP (2019) Combination therapy for treatment resistant schizophrenia. Br J Med Practitioners 12:a015. 6.Demjaha A, Egerton A, Murray RM et al. Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function. Biol Psychiatry 2014;75:e11-3 7.Anand R, Forrest EC, Hartman RD, Graham SM, Faravelli L (2018) T48. Antipsychotic efficacy of evenamide (NW-3509) is due to modulation of glutamatergic dysregulation. Schizophr Bull 44(Suppl1):S132. 8.Anand, R., Turolla, A., Chinellato, G., Roy, A., & Hartman, R. D. (2023). 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. 9.Howes OD, McCutcheon R, Agid O, et al. Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology. Am J Psychiatry. 2017; 174(3):216-229.