Phase 3 Development Plan for Evenamide as Add-On Therapy for Treatment-Resistant Schizophrenia

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Newron Pharmaceuticals announced the approval of the pivotal ENIGMA-TRS phase 3 development program evaluating evenamide as an add-on therapy to current antipsychotics, including clozapine, in patients with treatment-resistant schizophrenia (TRS). This phase 3 development program consists of 2 pivotal studies: ENIGMA-TRS 1 and ENIGMA-TRS 2.¹

“Newron greatly appreciates the regulatory approval of the ENIGMA-TRS trials. The positive results of evenamide observed in clinical studies and demonstrated in disease models have led to high enthusiasm in investigators to participate in this landmark program,” said Ravi Anand, MD, the chief medical officer of Newron.

ENIGMA-TRS 1 is an international, 52-week, randomized, double-blind, placebo-controlled phae 3 study evaluating the efficacy, tolerability, and safety of the 15 mg BID and 30 mg BID therapeutic doses of evenamide compared with placebo. Patients on second-generation anti-psychotics (SGAs), including clozapine, will meet Treatment Response and Resistance Psychosis (TRRIP) international consensus criteria for TRS. ENIGMA-TRS 1 will enroll at least 600 patients at study centers in Europe, Asia, Latin America, and Canada. Participants will undergo a 42-day screening period, during which their TRS diagnosis, antipsychotic plasma levels (background medication), and conformance to protocol selection criteria will be evaluated by an Independent Eligibility Assessment Committee (IEAC) of three leading international schizophrenia experts. The primary assessment of efficacy and safety will be performed 12 weeks after randomization to treatment. The study will continue double-blind and placebo-controlled until the 52-week time point. Enrollment for the study will start imminently. The 12-week results from the study are expected in late 2026.

“The imminent initiation of ENIGMA-TRS 1 study of evenamide is a significant milestone in the search for new medications to treat this devastating condition. Evenamide’s modulation of glutamate, good tolerability, and efficacy in studies performed to date, both in patients who are poor responders or treatment resistant to SGAs, suggests its therapeutic potential in patients with TRS. The field eagerly looks forward for results from this landmark trial,” said Stephen Marder, MD, distinguished professor of Psychiatry at the Semel Institute of Neuroscience & Human Behavior, and director of the Section on Psychosis at the UCLA Neuropsychiatric Institute.

ENIGMA-TRS 2 is a 12-week, randomized, double-blind, placebo-controlled phase 3 study, designed to evaluate the efficacy, tolerability, and safety of the 15 mg BID dose of evenamide in at least 400 participants. As in ENIGMA-TRS 1, participants will meet selection criteria and be reviewed by the IEAC. The analysis for determination of efficacy and safety will be performed after patients complete 12 weeks of participation in the trial. ENIGMAS-TRS 2 will be performed at centers in the US and other additional countries. US investigational centers are expected to initiate the study within the next 3 months.

“Evenamide’s selectivity for sodium channels and consequent modulation of glutamate, the demonstration of its efficacy in multiple animal models of psychosis as well as the MAM model of neurodevelopmental abnormalities, suggests promising results in patients with TRS. Completed studies in inadequate responders to SGAs and the results of a one-year study in patients with TRS predict therapeutic benefit of evenamide in TRS patients,” said Jean-Pierre Lindenmayer, MD, director of Research in Psychopharmacology Research Unit at the Nathan Kline Institute for Psychiatric Research at Manhattan Psychiatric Center. “Evenamide has the potential to fill a wide gap in our treatment for patients with incomplete response to SGAs, including clozapine. I look forward to participating to the ENIGMA-TRS 2 trial as a study center.”

Results from previous phase 2 (study 014/015)² and phase 3 (study 008A)³ studies have demonstrated evenamide’s significant and increasing efficacy as an add-on therapy on multiple measures of psychopathology in patients with TRS and inadequate responders, respectively. Evenamide has also demonstrated a favorable safety and tolerability profile.

References

1. Newron announces approval for pivotal phase III ENIGMA-TRS program with evenamide as add-on therapy in patients with treatment-resistant schizophrenia (TRS). News release. Business Wire. May 12, 2025. https://www.businesswire.com/news/home/20250512167812/en/Newron-Announces-Approval-for-Pivotal-Phase-III-ENIGMA-TRS-Program-With-Evenamide-as-Add-on-Therapy-in-Patients-With-Treatment-resistant-Schizophrenia-TRS

2. Data from Newron’s study 014/015 and an evenamide clinical development outlook presented at the 2024 Annual Congress of the Schizophrenia International Research Society (SIRS). News release. April 8, 2024. Accessed May 12, 2025. https://www.newron.com/news-and-media/regulatory-news/data-newrons-study-014015-and-evenamide-clinical-development-outlook

3. Newron announces positive top-line results from potentially pivotal Phase II/III study 008A with evenamide in schizophrenia patients. News release. April 30, 2024. Accessed May 12, 2025. https://www.newron.com/news-and-media/regulatory-news/newron-announces-positive-top-line-results-potentially-pivotal-phase