2026 ECNP Congress

PS02-2242

Design and updates of the phase-3, potentially pivotal, ENIGMA-TRS program: the global study of evenamide in treatment-resistant schizophrenia

Ravi Anand — A. Turolla, G. Chinellato, F. Sansi, G. Bianchi, R. Hartman · Anand Pharma Consulting, Pharmaceutical R&D, St.Moritz, Switzerland

2026 ECNP Congress

Introduction

Treatment-resistant schizophrenia (TRS) affects 30% of patients with schizophrenia and is associated with substantial clinical and socioeconomic burden, making it a relevant medical unmet need [1]. A safe and effective treatment is still lacking since clozapine, the only approved antipsychotic (AP) for TRS, is associated with safety concerns and a proportion of patients is resistant to it too [2]. Despite being the only evidence-based treatment for TRS, clozapine remains underutilized and alternative strategies like AP polypharmacy are often prescribed, although evidence of superior efficacy is lacking.

Emerging evidence suggests that patients with TRS have absent/poor response to monoamine-based AP since they present excessive glutamatergic rather than dopaminergic abnormalities. Evenamide is a voltage-gated sodium channel blocker able to reduce hippocampal hyperglutamatergic activity and attenuate downstream hyperdopaminergic state [3]. It has shown clinical benefits as an add-on to AP both in a long-term, open-label study in TRS patients [4], and in a 4-week, placebo-controlled trial in poor-responders [5].

Aims

To present the design and innovative aspects of ENIGMA-TRS (EveNamIde’s Glutamate Modulation Ameliorates TRS), the largest phase-3 program ever designed for patients with TRS, and to provide updates on the study progress.

Methods

Study 023 (ENIGMA-TRS 1) is a 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 evaluate the efficacy, tolerability, and safety of 15mg and 30mg BID of evenamide as add-on to standard-of-care in patients with documented TRS according to the Treatment Response and Resistance Psychosis (TRRIP) consensus guidelines. It will involve ~600 patients at sites across Europe, Asia, Latin and North America. The PANSS is the primary efficacy measure; secondary and tertiary measures include the CGI-S, CGI-C, PANSS Positive and Negative subscales, quality of life and functioning scales.

Results

To address the multiple challenges associated with the conduct of such a complex phase-3 trial, various strategies were adopted in its design, such as the identification of patient population following standardized and internationally accepted criteria (TRRIP), with requirement of therapeutic plasma concentrations of the background second-generation antipsychotic (SGA, measured twice during screening), the introduction of a rater training program to standardize rating practices across ~100 centres worldwide, and the confirmation of treatment resistance by an independent committee. To minimize the number of patients exposed to placebo for 1 year while still maintaining statistical power at key endpoints, a placebo switchover design has been implemented, where half of the patients assigned to placebo for the first 12 weeks are later switched to evenamide in a blinded manner at predefined timepoints.

Patient enrolment began in August 2025 and results for the 12-week primary endpoint are expected in the fourth quarter of 2026.

Conclusions

The complexity of an international phase-3 study as ENIGMA-TRS was addressed through the implementation of innovative features aimed at minimizing the variability across centres, ensuring appropriate patient population selection and providing reliable data.

Positive results from the ENIGMA-TRS program will support evenamide as an effective add-on glutamate modulator treatment that addresses the unmet needs of patients living with TRS.

References

  1. Iasevoli, F., Giordano, S., Balletta, R., Latte, G., Formato, M. V., Prinzivalli, E., … & De Bartolomeis, A. (2016). Treatment resistant schizophrenia is associated with the worst community functioning among severely-ill highly-disabling psychiatric conditions and is the most relevant predictor of poorer achievements in functional milestones. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 65, 34-48.
  2. Baig, A. I., Bazargan-Hejazi, S., Ebrahim, G., & Rodriguez-Lara, J. (2021). Clozapine prescribing barriers in the management of treatment-resistant schizophrenia: a systematic review. Medicine, 100(45), e27694.
  3. Uliana, D. L., Walsh, R. A., Fabris, D., & Grace, A. A. (2025). Evenamide reverses schizophrenia-related dysfunction in a neurodevelopmental animal model. Neuropsychopharmacology, 50(11), 1631-1642.
  4. Anand, R., Turolla, A., Chinellato, G., Roy, A., & Hartman, R. D. (2025). Therapeutic effect of evenamide, a glutamate inhibitor, in patients with treatment-resistant schizophrenia (TRS): final, 1-year results from a phase 2, open-label, rater-blinded, randomized, international clinical trial. International Journal of Neuropsychopharmacology, 28(1), pyae061.
  5. Anand, R., Turolla, A., Chinellato, G., Sansi, F., Roy, A., & Hartman, R. (2025). Efficacy and safety of evenamide, a glutamate modulator, added to a second-generation antipsychotic in inadequately/poorly responding patients with chronic schizophrenia: Results from a randomized, double-blind, placebo-controlled, phase 3, international clinical trial. Neuropharmacology, 266, 110275.