526. Translating glutamate modulation into clinical advances for patients with treatment-resistant schizophrenia: challenges and updates from the ENIGMA-TRS phase 3 program

Abstract

Abstract Background Treatment-resistant schizophrenia (TRS) affects one-third of patients with schizophrenia and is associated with high risk for morbidity, mortality, and hospitalization, impacting on patients’ wellbeing and healthcare costs (Kennedy et al., 2014). Clozapine is the only approved treatment for TRS, yet it’s underused due to safety concerns and mandatory blood monitoring, leading to widespread use of antipsychotic polypharmacy - usually ineffective since all available antipsychotics (APs) share a similar DA/5HT receptor blockade mechanism of action. Growing evidence suggests that excessive glutamatergic, rather than dopaminergic, activity underlies poor/absent response to AP, highlighting the need for novel therapeutic approaches targeting glutamate signaling. Evenamide is a new drug under development, a voltage-gated sodium channel blocker which restores hippocampal glutamatergic activity and attenuates downstream hyperdopaminergic state (Uliana et al., 2025). Clinical benefits of evenamide as an add-on to Standard-of-Care were observed in a long-term open-label study in TRS patients (Anand et al., 2024) and confirmed in a short-term placebo-controlled study in inadequate responders (Anand et al., 2025). Aims & Objectives To present challenges in the design and implementation of ENIGMA-TRS, the largest phase 3 clinical program ever designed for patients with TRS. Method ENIGMA-TRS (EveNamIde’s Glutamate Modulation Ameliorates TRS) includes two international clinical trials (Study 023 and 022) and will determine the efficacy and safety of evenamide as add-on to therapeutic plasma concentrations of second-generation AP (SGA), including clozapine, in patients with documented TRS according to the Treatment Response and Resistance Psychosis (TRRIP) consensus guidelines (Howes et al., 2017). Study 023 (ENIGMA-TRS 1) is 1-year, randomized, double-blind, placebo-controlled trial, with the primary efficacy endpoint at 12 weeks and long-term efficacy endpoints at 26 and 52 weeks. It will enroll ~600 patients at sites in Europe, Asia, Latin and North America. Study 022 (ENIGMA-TRS 2) is a 12-week, randomized, double-blind, placebo-controlled trial, that will include ~400 patients in Asia, Latin and North America. Results Patient enrolment in Study 023 began in August 2025, with 12-week study results expected in the fourth quarter of 2026. Initiation of ENIGMA-TRS 2 in the US has been announced, following approvals from the US FDA. The design and execution of the ENIGMA-TRS program posed multiple challenges related to the complexity of study design such as the identification of patient population (i.e. TRS based on TRRIP criteria with requirement of therapeutic plasma concentrations of background SGA) and the involvement of > 90 centers worldwide. Many strategies have been put in place to address these challenges, including a rater training program designed to standardize rating practices across centers and the confirmation of treatment resistance status by an Independent Eligibility Assessment Committee. Key characteristics of the patient population will be presented. Discussion & Conclusions In the design of the ENIGMA-TRS studies special attention was given to minimizing variability across sites in both patient ratings and selection. This is crucial for minimizing the placebo response, which may confound the efficacy of the drug, particularly in add-on studies where patients are kept on their Standard-of-Care. The goal is to generate reliable data supporting evenamide as an effective alternative for treating TRS.