2026 ECNP Congress

PS04-4200

Evenamide in patients with poor response to antipsychotics or treatment-resistance: unique benefits extending to social functioning and life engagement domains

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

It is well-established that currently available antipsychotics (AP) have limitations in addressing negative symptoms and cognitive impairments whose improvement is the main determinant to achieve better functioning. These symptoms are largely driven by brain regions such as the hippocampus, amygdala, and prefrontal cortex [1]. Evenamide, a novel sodium channel blocker, normalizes excessive hippocampal glutamatergic activity, a core pathological feature of schizophrenia, and consequently reduces hyperdopaminergic activity in the ventral tegmental area [2]. Through the connections from the hippocampus to the amygdala and prefrontal cortex, evenamide was effective in reversing schizophrenia-associated cognitive and social dysfunctions in the MAM neurodevelopmental animal model [2]. Evenamide as add-on treatment has demonstrated long-term benefits in patients with treatment-resistant schizophrenia (TRS) [3] and was associated with statistically significant and meaningful improvements in inadequate responders to second-generation antipsychotics (SGA) [4].

Aims

Based on preclinical findings in the MAM model, post-hoc analyses on data from previously conducted clinical trials with evenamide were performed to assess its effect on patients’ negative symptoms, including their social functioning and life engagement.

Methods

Study 014/015, a phase 2, 1-year, randomized, open-label, rater-blinded, international study, assessed the long-term efficacy and safety of three fixed doses of evenamide (7.5/15/30 mg bid) as add-on to an AP (excluding clozapine) in patients with TRS (PANSS 70-90; CGI-S 4-6).

Study 008A, a phase 2/3, 4-week, international, randomized, double-blind, placebo-controlled trial, evaluated the efficacy and safety of evenamide 30 mg bid as add-on in patients with inadequately controlled schizophrenia (PANSS 70-85; CGI-S 4-6) despite stable treatment with an SGA (including clozapine) at a therapeutic dose for an adequate period (compliance confirmed through plasma levels before randomization).

Post-hoc analyses were conducted for both studies to evaluate the effect of evenamide on the PANSS-derived subdomains that are suggestive of benefit on social functioning and life engagement:

PANSS items linked to social functioning (Purnine et al., 2000): P3, P6, N2, N4, N7, G16

PANSS items linked to life engagement (Ismail et al., 2024): N1, N2, N3, N4, N5, N6, G6, G7, G13, G15, G16

Results

Add-on treatment with evenamide was associated with an increasing improvement over time in social functioning (SF) and life engagement (LE), with benefits arising at Week 6 (SF -2.6; LE -2.4) and further developing up to 1-year (SF -4.4; LE -4.1) in Study 014/015 in patients with TRS. In the placebo-controlled Study 008A, the improvement in these subdomains for patients receiving evenamide in addition to their AP medication was greater after 4 weeks of treatment compared to that of patients receiving only their background treatment (SF drug-placebo difference -0.7, p=0.012; LE drug-placebo difference -0.7, p=0.055) [5].

Conclusions

These results add-up to the previously demonstrated benefits of evenamide on the PANSS Total, Positive and Negative subscales, CGI-S/C, and responder rates, suggesting that modulation of hippocampal hyperglutamatergic activity is an effective therapeutic mechanism that can produce clinically significant benefits across both positive and negative symptoms, with effects that appear to increase and strengthen over time. Moreover, these advocate for evenamide as an innovative therapeutic opportunity for patients with TRS.

References

  1. Ghoshal A, Conn PJ. The hippocampo-prefrontal pathway: a possible therapeutic target for negative and cognitive symptoms of schizophrenia. Future Neurol. 2015;10:115–28
  2. Uliana DL, Walsh RA, Fabris D, et al. Evenamide reverses schizophrenia-related dysfunction in a neurodevelopmental animal model. Neuropsychopharmacology 2025; 50: 1631–1642
  3. Anand R, Turolla A, Chinellato G, Roy A, Hartman RD. 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. Int J Neuropsychopharmacol 2024. 28(1):pyae061. doi: 10.1093/ijnp/pyae061
  4. Anand R, Turolla A, Chinellato G, Sansi F, Roy A, Hartman R. 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 2025. 266:110275. doi: 10.1016/j.neuropharm.2024.110275
  5. Anand R, Turolla A, Chinellato G, Sansi F, Roy A, Hartman R. Adjunctive treatment with evenamide, a glutamate modulator, is associated with clinically meaningful benefits in patients with treatment-resistant schizophrenia and inadequate response to antipsychotics: recent clinical findings from randomized trials. Ther Adv Psychopharmacol. 2026 Jan 26;16:20451253251414529. doi: 10.1177/20451253251414529