Newron Initiates ENIGMA-TRS 2 Phase III Trial for Treatment-Resistant Schizophrenia in US
核心洞察
Newron Pharmaceuticals (搜索) has initiated its ENIGMA-TRS 2 Phase III clinical study in the US following FDA approval, targeting treatment-resistant schizophrenia patients with evenamide as add-on therapy.
The global study will enroll at least 400 patients across multiple continents and evaluate evenamide 15 mg twice daily compared to placebo over 12 weeks.
Evenamide represents a first-in-class glutamate (搜索) modulator with a novel mechanism targeting voltage-gated sodium channels (搜索), distinct from current dopamine-focused antipsychotics.
Newron Pharmaceuticals (搜索) has launched its ENIGMA-TRS 2 Phase III clinical study in the United States following approvals from the FDA and Institutional Review Board, marking a significant milestone in the development of evenamide as the first potential add-on therapy for treatment-resistant schizophrenia (TRS). The first site to initiate the study is the Semel Translational Research Center for Neuropsychiatry at UCLA, with additional US sites expected to begin enrollment shortly.
Novel Approach to Treatment-Resistant Schizophrenia
ENIGMA-TRS 2 is a global, randomized, double-blind, placebo-controlled 12-week Phase III trial designed to enroll at least 400 patients across the US, Europe, Asia, and Latin America. The study evaluates the efficacy, safety, and tolerability of evenamide 15 mg twice daily as an add-on therapy to current antipsychotics, including clozapine, compared to placebo in patients with 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," said Prof. Stephen Marder, Director of the Section on Psychosis at the UCLA Semel Institute for Neuroscience and Human Behavior and principal investigator for the study. "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."
Rigorous Study Design and Timeline
Eligible patients must meet the Treatment Response and Resistance In Psychosis (TRRIP) international consensus criteria for TRS. Prior to randomization, patients undergo a 42-day screening period during which their TRS diagnosis, plasma levels of background antipsychotic medication, and adherence to protocol-defined eligibility criteria are evaluated by an Independent Eligibility Assessment Committee comprising leading international experts in schizophrenia research.
The primary assessment of efficacy and safety will be performed 12 weeks after randomization to treatment, with topline results expected in Q4 2026. The study represents part of Newron's broader ENIGMA-TRS pivotal Phase III program, which also includes ENIGMA-TRS 1, initiated in August 2025 and currently enrolling at least 600 patients to evaluate both 15mg and 30mg daily doses over one year.
First-in-Class Mechanism of Action
Evenamide represents a novel therapeutic approach as a first-in-class glutamate (搜索) modulator with a unique mechanism of action distinct from all currently marketed antipsychotics. The drug acts by selectively blocking voltage-gated sodium channels (搜索) (VGSCs) and exhibits no biological activity at more than 130 other central nervous system targets. It normalizes glutamate release induced by aberrant sodium channel activity without affecting basal glutamate levels.
Earlier clinical trials, including Phase II studies 014/015 and Phase III study 008A, demonstrated that evenamide was well tolerated and safe when added to standard antipsychotic therapy. Patients in previous trials experienced increasing and sustained symptom improvement, suggesting that evenamide's unique mechanism of modulating excessive glutamatergic activity in the brain could represent a crucial novel approach in schizophrenia treatment.
Addressing Critical Unmet Medical Need
Treatment-resistant schizophrenia affects a substantial portion of patients with the condition. According to the source materials, approximately 15% of patients develop TRS from illness onset, with about one-third to 50% of all schizophrenia patients classified as treatment-resistant. TRS is defined as no or inadequate symptom relief despite treatment with therapeutic doses of two antipsychotics from different chemical classes for an adequate period.
Emerging scientific evidence supports abnormalities in glutamate (搜索) neurotransmission in TRS, which are not targeted by current antipsychotics that act primarily on dopamine receptors (搜索). This glutamatergic dysfunction, combined with normal dopaminergic synthesis, explains the lack of clinical benefit from most typical and atypical antipsychotics in TRS patients.
Global Development Strategy
The ENIGMA-TRS program aims to establish evenamide as the first approved add-on therapy for TRS, providing a new treatment option for a patient population with high morbidity and mortality. Newron has established development and commercialization agreements for evenamide with EA Pharma (搜索) (a subsidiary of Eisai) for Japan and other Asian territories, as well as Myung In Pharm for South Korea.
Clinical trial results to date demonstrate benefits of evenamide in both TRS and poorly responding patient populations, with significant improvements across key efficacy measures increasing over time and a favorable safety profile. Importantly, the benefits appear to persist for a substantial time after evenamide degradation, explaining the long-term effects observed in clinical studies.