The Specialist in CNS Drug Development

Evenamide – a potential new treatment paradigm in schizophrenia:

Evenamide is a new oral chemical entity being developed by Newron as an add-on therapy to existing antipsychotics for two difficult-to-treat patient populations:

=> Treatment-resistant schizophrenia (TRS)
=> Chronic schizophrenia with poor response to standard treatment

Evenamide is a novel antipsychotic drug with a unique mechanism of action, distinct from existing treatments. It selectively inhibits voltage-gated sodium channels in hyper-active neurons, leading to normalization of the glutamatergic dysfunction—a key factor in patients who do not respond well to traditional antipsychotic medications. By reducing hippocampal and cortical hyper-excitability, evenamide directly addresses the root cause of the dysfunction. This action restores neurophysiological balance without interfering with over 150 receptors, enzymes, or transporters involved in CNS activity.

Clinical results have demonstrated that adding evenamide to a course of treatment in patients who are inadequately responding to their current therapies provides additional efficacy benefit turns out into with no relevant additional side effects.

Robust clinical data support evenamide’s potential:

• In the one-year Phase II clinical study 014/15, evenamide as add-on therapy to antipsychotics in TRS demonstrated sustained, progressive, and clinically significant improvements across key efficacy measures. These included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression of Severity (CGI-S), and Level of Functioning (LOF). Over 70% of patients were showing reduced disease severity and 25% achieving remission – unprecedented in TRS. Remarkably, no patient relapsed during the study, and nearly 50% of patients were no longer considered to have TRS after one year of treatment.

• In the potentially pivotal four-week Phase II/III study 008A, evenamide, added to second-generation antipsychotics, significantly improved symptoms in patients with chronic schizophrenia inadequately responding to current treatments. The study met both its primary (PANSS total score) and key secondary (CGI-S) endpoints. It showed statistically significant benefits, confirming evenamide’s favorable safety and tolerability profile. 008A was also the first randomized, placebo-controlled, and adequately designed study to demonstrate the benefits of a glutamate modulator as an adjunct to atypical antipsychotics.

Phase III development program with Evenamide: ongoing “EveNamIde’s Glutamate Modulation Ameliorates TRS” – ENIGMA-TRS

The ENIGMA-TRS Phase III development program consists of two pivotal studies, ENIGMA-TRS 1 and ENIGMA-TRS 2. The two studies are expected to meet the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) specified regulatory requirements by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) for submission of the registration dossier for evenamide in major territories, including the US and Europe.

ENIGMA-TRS 1 is a 52-week, randomized, double-blind, placebo-controlled, international Phase III study evaluating the efficacy, tolerability, and safety of the 15mg BID and 30mg BID therapeutic doses of evenamide compared to 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. Patients 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 (i.e. one year) time point.

ENIGMA-TRS 2, approved by the US Food and Drug Administration (FDA), will be performed at centers in the US and selected additional countries and will include at least 400 patients in a 12-week, randomized, double-blind, placebo-controlled international Phase III study, designed to evaluate the efficacy, tolerability, and safety of the 15mg BID dose of evenamide. Patients will meet selection criteria and be reviewed by the above mentioned IEAC. The analysis for determination of efficacy and safety will be performed after patients complete 12 weeks of participation in the trial.

New Preclinical Study Highlights Evenamide’s Potential to Address Core Schizophrenia Symptoms

New research published in Neuropsychopharmacology demonstrates that evenamide, Newron’s first-in-class glutamate modulator in Phase III development for treatment-resistant schizophrenia, improved positive, negative, and cognitive symptoms in the validated neurodevelopmental MAM model of schizophrenia.

Study results from the University of Pittsburgh show how evenamide, a selective voltage-gated sodium channel blocker, selectively inhibited hyperactive neurons and reduced pyramidal neuron hyperactivitiy in the hippocampus. Additionally, time-course analysis indicated effects of a single dose of evenamide lasted long after its elimination, suggesting evenamide may impact on neuronal plasticity.

These findings suggest for the first time that evenamide’s efficacy in downregulating the hyperdopaminergic state, social deficits, and recognition memory impairment may result from its ability to attenuate hippocampal hyperexcitability and, thus, support the therapeutic relevance of evenamide’s glutamate-modulating mechanism.

The results help explain the robust and sustained symptom improvements observed in Newron’s Phase II and Phase III trials in patients with chronic schizophrenia, reinforcing evenamide’s potential as a transformative therapy in treatment-resistant and poorly responding patients, offering a promising alternative to traditional dopamine D2-based antipsychotics.

https://www.nature.com/articles/s41386-025-02188-y

Schizophrenia

Schizophrenia is a long-term mental health condition that causes a range of different psychological symptoms. It is one of the most common serious mental health conditions. About 1 in 100 people will experience schizophrenia in their lifetime, with many continuing to lead normal lives. Schizophrenia is most often diagnosed between the ages of 15 and 35. Men and women are affected equally. There is no single test for schizophrenia. It is most often diagnosed after an assessment by a mental health care professional, such as a psychiatrist. It is important to diagnose schizophrenia as early as possible, as the chances of recovery improve the earlier it is treated. Schizophrenia is often described in terms of positive and negative (or deficit) symptoms. Positive symptoms are those that most individuals do not normally experience but are present in people with schizophrenia. They can include delusions, disordered thoughts and speech, and tactile, auditory, visual, olfactory and gustatory hallucinations, typically regarded as manifestations of psychosis. Hallucinations are also typically related to the content of the delusional theme. Positive symptoms generally respond well to medication. Negative symptoms are deficits of normal emotional responses or of other thought processes and are less responsive to medication.

Schizophrenia: high medical need for 20 million patients worldwide 

Useful Links
Schizophrenia International Research Society (SIRS)
The Johns Hopkins Schizophrenia Center
The European Psychiatric Association