Evenamide for Treatment-Resistant Schizophrenia: Initiation of ENIGMA-TRS 2 Phase 3 Clinical Study

Newron Pharmaceuticals today announced the initiation of its ENIGMA-TRS 2 phase 3 clinical study in the US, following approvals from the US Food and Drug Administration (FDA) and the Institutional Review Board. The first site to initiate the study will be the Semel Translational Research Center for Neuropsychiatry, University of California, Los Angeles (UCLA).¹

ENIGMA-TRS 2 is a phase 3, global, 12-week, randomized, double-blind, placebo-controlled trial evaluating the efficacy, safety, and tolerability of evenamide 15 mg twice daily as an add-on therapy to current antipsychotics, including clozapine, compared with placebo, in patients with treatment-resistant schizophrenia (TRS). Eligible patients must meet the Treatment Response and Resistance In Psychosis international consensus criteria for TRS.

“This study addresses a significant unmet medical need in patients with treatment-resistant schizophrenia who are not responding to their current second-generation antipsychotic medication. Previous studies in patients who are inadequate responders and with treatment-resistant schizophrenia have demonstrated clinically meaningful benefits of evenamide with no evidence of intolerance,” said Prof. Stephen Marder, the director of the Section on Psychosis at the UCLA Semel Institute for Neuroscience and Human Behavior, and principal investigator for the study.

The ENIGMA-TRS 2 study design was approved by the FDA. Investigators will enroll at least 400 participants across the US, Europe, Asia, and Latin America. Before being randomly assigned to treatment or placebo, participants undergo a 42-day screening period, during which their TRS diagnosis, plasma levels of their background antipsychotic medication, and adherence to protocol-defined eligibility criteria will be evaluated by an Independent Eligibility Assessment Committee. This committee will be comprised of leading international experts in the field of schizophrenia research.

Previous studies (phase 2 studies 014/015 and phase 3 study 008A) demonstrated that evenamide, when added to standard antipsychotic therapy, was well tolerated and safe. Importantly, evenamide may lead to clinically meaningful improvements for individuals who fail to respond or become resistant to other antipsychotic treatments. Patients in previous trials experienced increasing and sustained symptom improvement, suggesting that evenamide’s unique mechanism of action of modulating excessive glutamatergic activity in the brain could represent a crucial novel approach in the treatment of schizophrenia.

In a Q&A with Psychiatric Times, evenamide researcher Anthony A. Grace, PhD, shared more on the importance of this study: “It is a trial that we hope will immediately cement evenamide as a treatment of choice when it comes to treatment resistant schizophrenia. Right now, the criteria we use to define treatment resistance is for patients who have been on 2 drugs that have failed to work, particularly a failure of clozapine to work, since clozapine is usually prescribed to treatment-resistant patients. This trial should be able to show us that evenamide is going to be long-term effective.”²

The ENIGMA-TRS pivotal phase 3 program consists of ENIGMA-TRS 1 and ENIGMA-TRS 2. ENIGMA-TRS 1, initiated in August 2025 and currently enrolling patients on all 3 target continents, is an international, 1-year, double-blind, placebo-controlled study in at least 600 participants to evaluate the efficacy, tolerability, and safety of 2 daily doses: 15 mg and 30 mg. The primary assessment of efficacy and safety will be performed 12 weeks after randomization to treatment. Topline results are expected in late 2026.The remaining US sites participating in ENIGMA-TRS 2 are expected to initiate the study shortly. Regulatory submissions are currently being made in the other countries that are expected to participate in this trial in the coming months.

References

1. Newron announces the US initiation of its ENIGMA-TRS 2 phase III global clinical study with evenamide as an add-on therapy for patients with treatment-resistant schizophrenia (TRS). News release. December 8, 2025. Accessed December 8, 2025. https://www.businesswire.com/news/home/20251208306491/en/Newron-Announces-the-US-Initiation-of-Its-ENIGMA-TRS-2-Phase-III-Global-Clinical-Study-With-Evenamide-as-an-Add-On-Therapy-for-Patients-With-Treatment-Resistant-Schizophrenia-TRS

2. Grace AA, Walters J. Innovation in schizophrenia treatment: evenamide research with Anthony Grace, PhD. Psychiatric Times. November 11, 2025. https://www.psychiatrictimes.com/view/innovation-in-schizophrenia-treatment-evenamide-research-with-anthony-grace-phd