REMARKABLE EFFICACY OF EVENAMIDE, A GLUTAMATE ANTAGONIST, AS AN ADD-ON TO ANTIPSYCHOTICS IN PATIENTS WITH TREATMENT RESISTANT SCHIZOPHRENIA (TRS): RESULTS FROM A ONE-YEAR, OPEN- LABEL, DOSE-COMPARATIVE, RANDOMIZED, TREATMENT TRIAL
Authors: Anand *Ravi , Turolla Alessio , Chinellato Giovanni , Hartman Richard 
Published: February 2025

Abstract

Background
Numerous findings indicate reduced life-expectancy in patients with TRS, along with multiple morbidities, frequent hospitalizations, indigent status, and increasing costs of care for families and society [1]; no new treatment has emerged since clozapine approval in 1989 [2]. Despite its therapeutic promise, current experience indicates that less than 5% and 15% of TRS patients in the US, and in the EU respectively, receive clozapine [Global Data; 2017]. The vast majority of TRS patients are managed by off-label use of first and second-generation antipsychotics (APs) in conjunction with other psychopharmaceuticals, without showing efficacy [3]. Evenamide, a selective inhibitor of voltage-gated sodium channels, devoid of biological activity at &gt;130 CNS targets, normalizes glutamate release [4,5,6,7] without affecting its basal levels. Preclinical experiments have indicated that it is likely to benefit patients responding inadequately or resistant to APs. Evenamide was evaluated as monotherapy or add-on to APs in animal models in which PPI was impaired using amphetamine, scopolamine, phencyclidine, MK-801, ketamine, or sleep deprivation. It demonstrated efficacy across a broad spectrum of experiments, including models of mania, depression, impulse control loss, and obsessive-compulsive behavior.

Aims & Objectives
To present final, 1-year results of evenamide treatment in TRS patients unstable on their current AP. This data will demonstrate the unique benefits of glutamate modulation, when added to 5HT2/D2 modulators. It is likely that profound long-lasting efficacy of the combination, observed in shorter trials, will be demonstrated on efficacy variables used to assess patients with schizophrenia, as well as on key characteristics of TRS patients.

Methods
The selection criteria for the study require patients to meet standardized criteria for TRS: non-response to two APs, baseline PANSS total score 70-90 with predominant positive symptoms, at least two moderate core symptoms and functional deficits. Efficacy data (PANSS, CGI-S/C, and LOF) were analyzed using paired t-test to assess changes from baseline to endpoint (1-year) for each dose group and provide descriptive statistics for the responder analyses.

Results
The high retention rate [82.5% after 6-month] and the low incidence of adverse dropouts [1.9%] indicate the good tolerability of evenamide. Interim analyses at 6-month (mITT=156) and 1-year for the first cohort of 100 patients, indicated that a large proportion of patients improve to an extent that they no longer meet the operational severity criteria for TRS; and a significant proportion can be considered ‘responders’ based on TRRIP definition (&gt;=20% improvement on PANSS maintained for &gt;=12 weeks [8]). Comparison of results available after 6-week, 6-month, and 1-year are likely to indicate a pattern of unique efficacy over time. Furthermore, increasing and long-lasting improvement was observed in all efficacy scales [9,10], with the largest improvement in the 15 and 30 mg bid dose groups. Full, 1-year results, available by the time of the Congress, will be presented demonstrating remarkable efficacy of evenamide at 1-year in TRS patients.

Discussion
This is the first international trial of evenamide add-on to any AP (except clozapine) in patients with TRS. Encouraging results of this study have expedited the conduct of a potentially pivotal, randomized, double-blind, placebo-controlled, 1-year, international study.

References
1.Kennedy J, Altar CA, Taylor DL Degtiar I, Hornberger JC. The social and economic burden of treatment-resistant schizophrenia: a systematic literature review. International Clinical Psychopharmacology 29(2):p 63-76, March 2014.
2.Kane, J, Honigfeld, G, Singer, J, Meltzer, H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789–96.
3.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). Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis. World Psychiatry : Official Journal of the World Psychiatric Association (WPA), 16(1), 77–89.
4.Moghaddam B, Javitt D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology. 2012 Jan;37(1):4-15.
5.Demjaha A, Egerton A, Murray RM, Kapur S, Howes OD, Stone JM, McGuire PK. Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function. Biol Psychiatry. 2014 Mar 1;75(5):e11-3.
6.Mouchlianitis E, Bloomfield MA, Law V, Beck K, Selvaraj S, Rasquinha N, Waldman A, Turkheimer FE, Egerton A, Stone J, Howes OD. Treatment-resistant schizophrenia patients show elevated anterior cingulate cortex glutamate compared to treatment-responsive. Schiz. Bull. 2016 May;42(3):744-52.
7.Howes, O. D., McCutcheon, R., Agid, O., de Bartolomeis, A., van Beveren, N. J., Birnbaum, M. L., Bloomfield, M. A., Bressan, R. A., Buchanan, R. W., Carpenter, W. T., Castle, D. J., Citrome, L., Daskalakis, Z. J., Davidson, M., Drake, R. J., Dursun, S., Ebdrup, B. H., Elkis, H., Falkai, P., Fleischacker, W. W., … Correll, C. U. (2017). Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology. The American journal of psychiatry, 174(3), 216–229.
8.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.
9.Anand R., Giuliani R., Turolla A., Chinellato G., Hartman R. Addition of evenamide, a glutamate release inhibitor, to patients with treatment resistant schizophrenia (TRS) on an antipsychotic is effective and associated with long-term efficacy. SIRS 2023-poster.
10.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.