EVENAMIDE AS ADD-ON TREATMENT FOR PATIENTS WITH CHRONIC SCHIZOPHRENIA NOT RESPONDING ADEQUATELY TO THEIR CURRENT ANTIPSYCHOTIC MEDICATION: RESULTS OF A POTENTIALLY PIVOTAL, PHASE II/III, INTERNATIONAL, RANDOMIZED, DOUBLE BLIND, PLACEBO- CONTROLLED TRIAL

Abstract Background Despite over 5 decades of availability of antipsychotics (APs), 30-60% of patients with schizophrenia show no, and another 10 30% show inadequate, benefit from APs [1,2], resulting in increased risk for hospitalization, morbidity, suicidality, and reduced lifespan [3,4]. Increasing evidence supports an important role of the glutamatergic neurotransmitter system, which is not targeted by 5HT2/D2- blocking APs [5,6,7]. Evenamide is a selective inhibitor of voltage-gated sodium channels, devoid of effects at more than130 CNS targets [8]. It reduces aberrant neuronal firing, normalizing excessive glutamate release without any effect on basal glutamate. Data from animal models of psychosis indicate the combination of ineffective doses of APs and evenamide was associated with significant benefit, suggesting synergistic mechanisms that would benefit patients with inadequate response to current APs. Preliminary evidence of efficacy of evenamide added on to an AP was demonstrated in two phase II trials, one placebo-controlled in non-TRS [9], the other open-label, long-term in TRS patients [10]. Aims & Objectives This phase 2/3, potentially pivotal, international, randomized, double-blind, placebo- controlled, 4-week study was designed to assess the efficacy and safety of evenamide 30 mg bid added on to an atypical AP (including clozapine) in patients with schizophrenia not responding adequately to their current AP. Method Eligible patients must have a diagnosis of schizophrenia (DSM-5) and be symptomatic despite treatment with an atypical AP for an adequate period at a therapeutic dose. Adherence to the current AP was assessed through determination of blood levels. At baseline, patients were moderately to severely ill (CGI-S 4-6), with a PANSS total score of 70-85 and predominant positive symptoms (PANSS positive total score equal or more than 20). Changes from baseline to endpoint (Day 29) for the key efficacy outcome measures (PANSS, CGI-S, LOF, MSQ) will be compared between evenamide and placebo groups using a Mixed Model Repeated Measures (MMRM) analysis. Proportions of patients improving on the CGI- C, as well as meeting other responder criteria, will be compared between groups using a logistic regression model (chi-square test). Results To date ~235 patients have been randomized, with a very low dropout rate (~2.5%) and high compliance to the study medication, suggesting that evenamide is well tolerated. Routine interim safety analyses reviewed by the ISMB did not detect any evidence of toxicity. Patients’ mean age is ~40 years, ~75% are males, with a mean PANSS total score of 78, and mean duration of illness of ~11 years. The most common background APs are risperidone (~40%), olanzapine (~20%), and clozapine (~15%); mean duration of treatment with current AP is >1-year. Although the protocol excluded patients with TRS, many patients (55%) had already failed at least 2 trials with different APs. Final efficacy and safety results will be available by the time of the Congress. Discussion & Conclusions Study 008A represents the first placebo-controlled, double-blind trial of evenamide 30 mg bid as add-on to an AP in patients with schizophrenia. If positive, these results may change the treatment paradigm of patients with chronic schizophrenia, confirming the benefit of evenamide in patients with schizophrenia on an AP. References 1.Solanki RK, Singh P, Munshi D. Current perspectives in the treatment of resistant schizophrenia. Indian J Psychiatry 2009; 51:254-260. 2.Lieberman JA, Stroup TS, McEvoy JP, et al, For the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209-1223. 3.Laursen TM, Nordentoft M, Mortensen BO. Excess early mortality in schizophrenia. Ann Rev Clin Psychol 2013; 10:425–48. 4. Pompili M, Giordano G, Luciano M, et al. Unmet Needs in Schizophrenia. CNS Neurol Disord Drug Targets. 2017;16(8):870-884. 5.Moghaddam B and Javitt D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology Reviews 2012; 37:4-15. 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.Mouchlianitis E, Bloomfield MAP, Law V, et al. Treatment-resistant schizophrenia patients show elevated anterior cingulate cortex glutamate compared to treatment-responsive. Schizophr Bull 2016;42:744-52. 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(Suppl 1):S132. doi: 10.1093/schbul/sby016.324. 9.Anand R, Forrest EC, Hartman RD, Graham SM, Faravelli L (2017) Evenamide, a voltage-gated sodium channel blocker in the treatment of schizophrenia: results from the placebo-controlled Study 002. European Neuropsychopharmacology 27:S947-S948. doi:10.1016/S0924-977X(17)31676-0 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 remarkable clinically important long-term efficacy when added to an antipsychotic in patients with treatment-resistant schizophrenia (TRS). Int J Neuropsychopharmacology, 26(8), 523–528.