evenamide (NW-3509) / Newron, EA Pharma, Eisai - LARVOL DELTA

ENIGMA-TRS 2: Evenamide, a Glutamate Release Modulator, as Add-On to Standard of Care in Subjects With Documented Treatment-Resistant Schizophrenia (clinicaltrials.gov) - P3 | N=400 | Recruiting | Sponsor: Newron Pharmaceuticals SPA | Trial completion date: Dec 2026 ➔ Mar 2027 | Trial primary completion date: Dec 2026 ➔ Mar 2027

Trial completion date • Trial primary completion date • CNS Disorders • Psychiatry • Schizophrenia

Interim data from ENIGMA – TRS 1 study of evenamide as add on therapy to antipsychotic Standard of Care in patients with treatment resistant schizophrenia (TRS). Difficulties in performing TRS study with TRRIP criteria: the CRO experience (WFSBP 2026) - "One aspect of the ENIGMA – TRS 1 study assesses plasma concentrations of standard of care as selected antipsychotics: Aripiprazole, Brexpiprazole, Cariprazine, Clozapine, Lurasidone, Olanzapine, Paliperidone, Quetiapine, Risperidone and Ziprasidone for subjects treated with those antipsychotics with daily therapeutic doses meeting local product labels requirements and correlated those with minimal duration of 6 weeks treatment with any of those medications. As the study is performed in 20 countries worldwide major issues reside in getting approval by all regulatory approvals, languages use for the rating instruments as well as for the training of the raters. Based on hundreds of patients entering screening, a large proportion failed the screening phase because of lack of adequate concentration of the primary AP. Difficulties have been noticed in ensuring adequate documentation of previous AP failures."

Clinical • CNS Disorders • Psychiatry • Schizophrenia

Glutamate modulation by evenamide: clinically meaningful benefits and the ENIGMA-TRS phase 3 program (WFSBP 2026) - "Sponsored by Newron Pharmaceuticals"

Clinical • P3 data • CNS Disorders • Psychiatry • Schizophrenia

Glutamate modulation by evenamide is associated with clinically meaningful benefits in patients with treatment-resistant schizophrenia and inadequate response to antipsychotics: new clinical findings from post-hoc analyses (WFSBP 2026) - "These findings in addition to the previously demonstrated benefits of evenamide on the PANSS total score, CGI-S/C, and responder rates (Anand et al. 2024 and 2025), strongly support the clinical meaningfulness of benefits achieved through glutamate modulation of hippocampal hyperglutamatergic activity. Uniquely, this mechanism of action can address both positive and negative symptoms, and its effects seem to increase and strengthen over time."

Clinical • Retrospective data • CNS Disorders • Psychiatry • Schizophrenia

ENIGMA-TRS phase 3 program: rationale and study design towards a new therapeutic paradigm in treatment-resistant schizophrenia (TRS) (WFSBP 2026) - "Despite the complex design of ENIGMA-TRS and variability across >90 centers in 20 countries, robust mitigation strategies have been adopted to ensure a reliable program. Results from ENIGMA-TRS trials will confirm the benefits of evenamide - a glutamate modulator added on to AP - demonstrated in prior studies (Study 008A, Anand et al., 2025; Study 014/015, Anand et al., 2024), supporting a novel therapeutic paradigm for people living with TRS."

P3 data • CNS Disorders • Psychiatry • Schizophrenia

Results of Study 008A with evenamide add-on to second-generation antipsychotics in India: influence of cultural, religious, and common background factors on efficacy (WFSBP 2026) - "clozapine) conducted in 11 countries (Asia, Latin America, Europe)...A significant higher proportion of patients was taking risperidone in India... These results point out that the effect of evenamide on the PANSS Total score is statistically significant in India despite the study being performed in 9 languages, and the magnitude of effect observed in India does not differ compared to other countries (-3.0 vs -2.7). More details and considerations will be presented at the Congress."

Clinical • CNS Disorders • Schizophrenia

Do cultural factors and language influence efficacy outcomes? Results from Study 008A in Latin America compared to other countries (WFSBP 2026) - "The results from evenamide addon study 008A (Anand et al 2025), performed in multiple countries in patients who are inadequate responders to SGA, provide an opportunity to assess the results by region...clozapine) conducted in 11 countries (Asia, Latin America, Europe)... These data suggest that the use of a common language (Latam=1, RoW=17), similar cultural background, and clinical practice logistics (higher recruitment density per site (Kantrowitz et al 2025)), contributed to achieving a higher drug-placebo difference compared to the overall Study 008A data. Additional results and explanations will be presented at the Congress."

Clinical • CNS Disorders • Schizophrenia

Evenamide, added on to second-generation antipsychotics, is associated with statistically significant results in in poorly responding patients with schizophrenia enrolled in India: by-country analysis from Study 008A (WFSBP 2026) - No abstract available

Clinical • CNS Disorders • Psychiatry • Schizophrenia

Unique preclinical effects of evenamide predict benefits in patients with inadequate response and treatment-resistant schizophrenia (TRS) (CINP 2026) - "Sponsored By Newron Pharmaceuticals. will present evidence demonstrating how the preclinical effects of evenamide translate into clinical benefits for patients with inadequate treatment response and those with treatment-resistant schizophrenia."

Preclinical • CNS Disorders • Psychiatry • Schizophrenia

Targeting negative and cognitive symptoms in schizophrenia: discussion of novel preclinical and clinical findings with evenamide (CINP 2026) - "Moreover, apart from clozapine, available AP have not demonstrated efficacy in benefiting patients with treatment-resistant schizophrenia (TRS), characterized by glutamatergic rather than dopaminergic abnormalities (Demjaha et al., 2014).Evenamide is a voltage-gated sodium channel blocker with higher affinity for the inactivated state of the channels, which reduces neuronal hyperexcitability. Through the modulation of hippocampal hyperglutamatergic activity, evenamide acts directly at the site of dysfunction and offers broader effects across the various symptom domains, which are durable in time likely due to neuroplasticity. Therefore, evenamide represents an innovative therapeutic approach, which is expected to make an impact on the quality of life of patients with TRS."

Preclinical • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Translating glutamate modulation into clinical advances for patients with treatment-resistant schizophrenia: challenges and updates from the ENIGMA-TRS phase 3 program (CINP 2026) - "Clozapine is the only approved treatment for TRS, yet it's underused due to safety concerns and mandatory blood monitoring, leading to widespread use of antipsychotic polypharmacy - usually ineffective since all available antipsychotics (APs) share a similar DA/5HT receptor blockade mechanism of action.Growing evidence suggests that excessive glutamatergic, rather than dopaminergic, activity underlies poor/absent response to AP, highlighting the need for novel therapeutic approaches targeting glutamate signaling. In the design of the ENIGMA-TRS studies special attention was given to minimizing variability across sites in both patient ratings and selection. This is crucial for minimizing the placebo response, which may confound the efficacy of the drug, particularly in add-on studies where patients are kept on their Standard-of-Care. The goal is to generate reliable data supporting evenamide as an effective alternative for treating TRS."

Clinical • P3 data • CNS Disorders • Psychiatry • Schizophrenia

Antipsychotic drug action, novel treatment targets, and the failure of current clinical trial designs in evaluating new target molecules. (PubMed, Biol Psychiatry) - "The discovery of antipsychotic drugs over 65 years ago revolutionized the treatment of schizophrenia that was initially based on serendipitous findings with chlorpromazine...Preclinical models have also identified potential novel treatments targeting the hippocampal hyperexcitability, including GABA α5-positive allosteric modulators and evenamide...This evidence underscores the importance of patient treatment history and the design of trials that account for prior antipsychotic exposure when evaluating new compounds. Targeting upstream pathology in the hippocampus offers a promising approach for developing more effective, side-effect-sparing treatments for schizophrenia."

Journal • Review • CNS Disorders • Psychiatry • Schizophrenia

ENIGMA-TRS 2: Evenamide, a Glutamate Release Modulator, as Add-On to Standard of Care in Subjects With Documented Treatment-Resistant Schizophrenia (clinicaltrials.gov) - P3 | N=400 | Recruiting | Sponsor: Newron Pharmaceuticals SPA | Trial completion date: Sep 2026 ➔ Dec 2026 | Trial primary completion date: Sep 2026 ➔ Dec 2026

Trial completion date • Trial primary completion date • CNS Disorders • Psychiatry • Schizophrenia

NW-3509/023/III/2024: Evenamide in patients with treatment-resistant schizophrenia not responding to antipsychotics (clinicaltrialsregister.eu) - P2/3 | N=135 | Recruiting | Sponsor: Newron Pharmaceuticals S.p.A.

New P2/3 trial • CNS Disorders • Psychiatry • Schizophrenia

Emerging neurobiological targets in psychiatric treatment. (PubMed, Eur Neuropsychopharmacol) - "Recent evidence suggests that sodium channel modulators, such as evenamide, may offer therapeutic benefits for treatment-resistant schizophrenia by stabilizing glutamatergic neurotransmission...Additionally, Sigma-1 receptor agonists, including Blarcamesine and Pridopidine, have shown neuroprotective and cognitive-enhancing properties, making them attractive candidates for psychiatric and neurodegenerative disorders. Orexin receptor antagonists, such as suvorexant and seltorexant, have potential in mood disorders and substance dependence, highlighting the broader therapeutic applications of targeting the orexinergic system...The identification of biomarkers for patient stratification will be critical in the hitherto elusive goal of developing precision medicine approaches. Targeted pharmacological interventions offer a path toward more effective, well-tolerated, and potentially individualized treatment options for patients with severe mental illness."

Journal • Review • Bipolar Disorder • CNS Disorders • Depression • Inflammation • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry • Schizophrenia

Adjunctive treatment with evenamide, a glutamate modulator, is associated with clinically meaningful benefits in patients with treatment-resistant schizophrenia and inadequate response to antipsychotics: recent clinical findings from randomized trials. (PubMed, Ther Adv Psychopharmacol) - "In Study 008A as well, evenamide resulted in a greater effect, compared to placebo, on the same subdomains. Add-on treatment with evenamide to APs (including clozapine) was associated with clinically meaningful and progressive long-term benefits across numerous post-hoc analyses including improvements on patient's daily life and functioning."

Clinical • Journal • CNS Disorders • Psychiatry • Schizophrenia

ENIGMA-TRS 2: Evenamide, a Glutamate Release Modulator, as Add-On to Standard of Care in Subjects With Documented Treatment-Resistant Schizophrenia (clinicaltrials.gov) - P3 | N=400 | Recruiting | Sponsor: Newron Pharmaceuticals SPA | Initiation date: Oct 2025 ➔ Jan 2026 | Not yet recruiting ➔ Recruiting

Enrollment open • Trial initiation date • CNS Disorders • Psychiatry • Schizophrenia

EA Pharma, a subsidiary of Eisai, Announces the Initiation of its Phase III Clinical Trial with Evenamide, a Novel Treatment for Schizophrenia, in Japan (Newron Press Release) - "EA Pharma initiates the Trial after review by the institutional review board of the clinical site and other related procedures. This Trial is a multicenter randomized double-blind placebo-controlled clinical trial in patients with treatment-resistant schizophrenia who show poor or inadequate response to at least two different types of antipsychotics, evaluating the efficacy, safety and tolerability of EA8001 as an add-on treatment."

New P3 trial • Schizophrenia

Newron Further Expands Intellectual Property Portfolio for Evenamide with New EU Composition of Matter Patent (Newron Press Release) - "EP4615820 – 'Crystalline Forms of Evenamide' is expected to extend asset exclusivity in EU into 2044; Evenamide is currently being investigated in Newron’s global ENIGMA-TRS Phase III development program, enrolling at least 1,000 schizophrenia patients with topline results expected in Q4-2026"

P3 data: top line • Patent • Schizophrenia

Glutamate modulation by evenamide produces statistically significant and clinically relevant improvement in patients with treatment-resistant schizophrenia (ECNP 2025) - "Recent examples include pimavanserin, which did not provide evidence of significant benefit as adjunctive therapy in inadequate responders [1] and Lu-AF35700 which failed to produce significant improvement as monotherapy in TRS [2]. Glycine re-uptake inhibition with bitopertin did not produce significant benefits in patients with inadequately controlled positive symptoms [3]. New results with KarXT indicate no significant benefit compared to placebo when used as add-on to second-generation antipsychotics (SGA) in inadequate responders despite having demonstrated improvement in acutely psychotic patients as monotherapy [4]...Results from the more recent, phase 3, double-blind, placebo-controlled, 4-week, add-on study demonstrated statistically significant and clinically important improvements in 291 patients with inadequate response to SGA including clozapine. Positive findings from these two studies, which will need to be confirmed in a larger phase 3 trial in patients..."

Clinical • CNS Disorders • Epilepsy • Psychiatry • Schizophrenia

Success in the mechanism-based development of evenamide for patients with inadequate response or treatment-resistant schizophrenia (ECNP 2025) - "Study 008A determined the efficacy and safety of evenamide 30 mg bid as add-on in patients poorly responding to a second-generation antipsychotic (including clozapine); study 014/015 evaluated the long-term efficacy and safety of three fixed doses of evenamide (7.5/15/30 mg bid) as add-on in patients with TRS. These results are consistent with the hypothesis that glutamate modulation can provide additional benefits and address unmet needs in patients with poor/no AP response. Based on these findings, a phase 3, international, randomized, double-blind, placebo-controlled trial has been initiated to confirm the benefits of glutamate modulation in patients with documented TRS."

Clinical • CNS Disorders • Epilepsy • Psychiatry • Schizophrenia

Evenamide Phase 3 Program: Study 023 (ENIGMA-TRS) evaluates the efficacy of add-on glutamate modulation in patients with documented treatment-resistant schizophrenia (ECNP 2025) - "Positive results from the global phase 3 program would support add-on glutamate modulation by evenamide as an alternative efficacious strategy for managing unmet needs in TRS."

Clinical • P3 data • Bipolar Disorder • CNS Disorders • Mood Disorders • Psychiatry • Schizophrenia

ENIGMA-TRS 2: Evenamide, a Glutamate Release Modulator, as Add-On to Standard of Care in Subjects With Documented Treatment-Resistant Schizophrenia (clinicaltrials.gov) - P3 | N=400 | Not yet recruiting | Sponsor: Newron Pharmaceuticals SPA

New P3 trial • CNS Disorders • Psychiatry • Schizophrenia

New Developments in the Treatments of Psychosis (WFSBP 2025) - "Objective: Despite the discovery of chlorpromazine over 70 years ago and substantial pharmacologic advances, postsynaptic dopamine blockade has remained the sole mechanism of action of approved drugs for schizophrenia... Newly/recently approved agents include vesicular monoamine transporter-2 inhibitors valbenazine and deutetrabenazine for tardive dyskinesia and, possibly, residual positive symptoms; olanzapine/samidorphan combination, lumateperone, new formulations, including subcutaneous injections, and ultra-long-acting injectable antipsychotics. Agents in development that have at least one positive phase 1B, 2 or 3 trial include the trace amine-associated receptor-1 (TAAR1) ulotaront, M1/M4 muscarinic agonist xanomeline plus peripherally restricted anticholinergic trospium, the M4 muscarinic positive allosteric modulator emraclidine, as well as multiple other muscarinic receptor modulators for total psychopathology, methylated amisulpride (LB-102), and evenamide, a..."

CNS Disorders • Movement Disorders • Psychiatry • Schizophrenia

Augmentation of glutamatergic modulators for schizophrenia: A network meta-analysis. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "Among add-on glutamatergic modulators with moderate to high certainty of benefit over placebo, piracetam 2400-4800 mg/day showed the greatest improvement in total psychopathology (standardized mean differences [SMD] -0.94, 95 % confidence interval [CI] -1.47 to -0.41), benzoate 1000-2000 mg/day was most effective for positive symptoms (SMD -0.43, 95 % CI -0.71 to -0.16), memantine 5-20 mg/day ranked highest for negative symptom reduction (SMD -0.64, 95 % CI -0.85 to -0.43), and the combination of sarcosine 2000 mg/day and benzoate 1000 mg/day showed the greatest enhancement in global cognitive function (SMD 1.08, 95 % CI 0.45 to 1.71). Other agents, including d-serine 2000-4000 mg/day, evenamide 30-60 mg/day, iclepertine 10-25 mg/day, lamotrigine, luvadaxistat 50 mg/day, minocycline 100-300 mg/day, N-acetylcysteine 2000 mg/day, sarcosine 2000 mg/day, and topiramate demonstrated benefits with moderate to high certainty in one or more domains. Notably, memantine,..."

Journal • Retrospective data • Review • CNS Disorders • Psychiatry • Schizophrenia