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)
Ad hoc announcement pursuant to Art. 53 LR
ENIGMA-TRS 2 is a global, randomized, double-blind, placebo-controlled 12-week Phase III clinical study designed to enroll at least 400 patients; topline results are expected by Q4 2026
Evenamide is a first-in-class glutamate modulator with a novel mechanism of action for patients who do not respond adequately or are resistant to existing antipsychotic therapies
Newron’s ENIGMA-TRS program (ENIGMA-TRS 1, started in
“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.
ENIGMA-TRS 2: A Global Phase III Study Bringing New Hope to Patients with TRS in the US and other countries
ENIGMA-TRS 2 is a Phase III, 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 to placebo, in patients suffering from TRS. Eligible patients must meet the Treatment Response and Resistance In Psychosis (TRRIP) international consensus criteria for TRS.
The ENIGMA-TRS 2 study design has been approved by the
The primary assessment of efficacy and safety will be performed 12 weeks after randomization to treatment; topline results are expected in Q4 2026.
Earlier clinical trials (Phase II studies 014/015 and Phase III 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 people 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.
The ENIGMA-TRS pivotal Phase III program consists of ENIGMA-TRS 1 and ENIGMA-TRS 2. ENIGMA-TRS 1, initiated in
About treatment-resistant schizophrenia (TRS)
A significant proportion of patients with schizophrenia show virtually little to no beneficial response to currently available antipsychotic (AP) treatments, leading to a diagnosis of treatment-resistant schizophrenia (TRS). TRS is defined as no or inadequate symptom relief despite treatment with therapeutic doses of two APs from two different chemical classes for an adequate period. It is estimated that approximately 15% of patients develop TRS from the onset of illness, and about one-third to 50% of patients with schizophrenia overall. Emerging scientific evidence supports abnormalities in glutamate neurotransmission in TRS, not targeted by current APs, along with normal dopaminergic synthesis, to explain the lack of clinical benefit of most typical and atypical antipsychotics, which act primarily on dopamine receptors. These insights underline the need for novel therapeutic approaches that target the underlying glutamatergic dysfunction in schizophrenia, offering hope for patients who currently have limited or no effective treatment options.
About evenamide
Evenamide is a novel, orally available new chemical entity with a unique mechanism of action distinct from all currently marketed antipsychotics. It acts by selectively blocking voltage-gated sodium channels (VGSCs) and exhibits no biological activity at more than 130 other central nervous system (CNS) targets. It normalizes glutamate release induced by aberrant sodium channel activity (veratridine-stimulated), without affecting basal glutamate levels, due to inhibition of VGSCs. Combinations of subtherapeutic doses of evenamide and other APs, including clozapine, were associated with benefit in animal models of psychosis, suggesting synergies in mechanisms that may provide meaningful benefits for patients who do not adequately respond to current APs, including those on clozapine. Importantly, the benefits seemed to persist for a substantial time after evenamide had been degraded, explaining the long-term effects seen in clinical studies. Through its novel glutamatergic modulation, evenamide represents a first-in-class approach aimed at addressing the unmet needs of patients with schizophrenia who are resistant to existing treatments.
About
Newron (SIX: NWRN, XETRA: NP5) is a biopharmaceutical company focused on the development of innovative therapies for patients with diseases of the central and peripheral nervous system. Headquartered in Bresso near
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