evenamide (NW-3509) / Newron - LARVOL DELTA

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

Evenamide, a Glutamate Release modulator, as Add-On to Second-Generation Antipsychotics in Treatment-Resistant schizophrenia: Updates from a Phase 3, Potentially pivotal, international, randomized, double-Blind, Placebo-Controlled Trial (WFSBP 2025) - "The confirmation of evenamide efficacy and safety in patients with TRS would support the necessity to modulate glutamate, on top of dopamine/serotonin modulation, for the optimal treatment of this condition."

Clinical • P3 data • CNS Disorders • Psychiatry • Schizophrenia

Glutamate Modulation as Adjunctive Therapy in Patients with Schizophrenia Not Adequately Responding to Second-Generation antipsychotics: Clinical Benefits of Evenamide in a Phase 2/3, international, randomized, double-Blind, Placebo-Controlled Trial (WFSBP 2025) - "Patients were randomized 1:1 to receive evenamide 30 mg bid or placebo bid added to a stable therapeutic dose of one of the following SGA: aripiprazole, cariprazine, clozapine, quetiapine, olanzapine, paliperidone, or risperidone. Study 008A represents the first randomized, placebo-controlled trial to demonstrate statistically significant and clinically meaningful benefits of adding a glutamate modulator in patients with schizophrenia poorly responding to treatment with SGAs. A phase 3 trial with evenamide will determine the benefits of glutamate modulation in TRS."

Clinical • Late-breaking abstract • P2/3 data • CNS Disorders • Epilepsy • Psychiatry • Schizophrenia

Glutamate Modulation as Adjunctive Therapy in Patients with Schizophrenia Not Adequately Responding to Second-Generation antipsychotics: Clinical Benefits of Evenamide in a Phase 2/3, international, randomized, double-Blind, Placebo-Controlled Trial (WFSBP 2025) - "Patients were randomized 1:1 to receive evenamide 30 mg bid or placebo bid added to a stable therapeutic dose of one of the following SGA: aripiprazole, cariprazine, clozapine, quetiapine, olanzapine, paliperidone, or risperidone. Study 008A represents the first randomized, placebo-controlled trial to demonstrate statistically significant and clinically meaningful benefits of adding a glutamate modulator in patients with schizophrenia poorly responding to treatment with SGAs. A phase 3 trial with evenamide will determine the benefits of glutamate modulation in TRS."

Clinical • P2/3 data • CNS Disorders • Epilepsy • Psychiatry • Schizophrenia

Mechanism of Action of Antipsychotics and Its Impact on Tolerability and Safety (WFSBP 2025) - "KarXT (xanomeline/trospium): xanomeline is an agonist of muscarinic M1, and M4 receptors. Our review indicates that mechanism of action influences the type and pattern of AEs associated of the drug. Lumateperone’s side effects reflect muscarinic, serotoninergic and autonomic adverse effects consistent with its multiple neurotransmitter affinities although muscaninic activity was not reported. Cariprazine’s side effects reflect dopamine antagonism (akathisia, EPs, restlessness), muscarinic (constipation) and serotoninergic activity (headache, insomnia)."

Clinical • CNS Disorders • Insomnia • Sleep Disorder

Evenamide reverses schizophrenia-related dysfunction in a neurodevelopmental animal model. (PubMed, Neuropsychopharmacology) - "These findings suggest that evenamide's efficacy in downregulating the hyperdopaminergic state, social deficits, and recognition memory impairment may result from its ability to attenuate vHipp hyperexcitability. Therefore, evenamide could offer a novel therapeutic strategy that is capable of addressing positive, cognitive, and negative symptoms of schizophrenia."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Design of a phase 3, potentially pivotal, international, randomized, double-blind, placebo-controlled trial with evenamide, a glutamate modulator, add-on to SGA in patients with treatment-resistant schizophrenia (CINP-AsCNP 2025) - "The only drug that demonstrated superiority over other APs in TRS is clozapine, which is vastly underutilized due to its unfavourable safety profile. Positive results from this study would support the need for glutamate modulation for the optimal treatment of patients with schizophrenia not benefitting from SGAs."

Clinical • P3 data • CNS Disorders • Psychiatry • Schizophrenia

Evenamide, a glutamate modulator, provided statistically significant benefits when added to SGA in patients with schizophrenia: phase 2/3, international, randomized, double-blind, placebo-controlled study results (CINP-AsCNP 2025) - "This is the first international, randomized, double-blind, placebo-controlled trial that demonstrated statistically significant and clinically important benefits of adding a glutamate modulator in patients with schizophrenia poorly responding to SGAs. Based on these results, a phase 3 trial will be initiated to determine the benefits of glutamate modulation in patients with treatment-resistant schizophrenia."

Clinical • P2/3 data • CNS Disorders • Epilepsy • Psychiatry • Schizophrenia

Newron Announces Approval for Pivotal Phase III ENIGMA-TRS Program With Evenamide as Add-on Therapy in Patients With Treatment-resistant Schizophrenia (TRS) (Businesswire) - "ENIGMA-TRS 1 is an international, one-year, double-blind, placebo-controlled Phase III study in at least 600 patients; enrollment to start imminently; 12-week study results expected in Q4 2026; ENIGMA-TRS 2, approved by the US Food and Drug Administration (FDA), is a US-based and international, 12-week, double-blind, placebo-controlled Phase III study in at least 400 patients; study expected to start within the next three months...Newron Pharmaceuticals S.p.A...announced the approval for its pivotal ENIGMA-TRS Phase III development program evaluating evenamide as an add-on therapy to current antipsychotics, including clozapine, in patients with treatment-resistant schizophrenia (TRS)....The ENIGMA-TRS Phase III development program consists of two pivotal studies, ENIGMA-TRS 1 and ENIGMA-TRS 2."

New P3 trial • P3 data • Schizophrenia

Newron and Myung In Pharm Announce License Agreement for evenamide in South Korea (Businesswire) - "Newron Pharmaceuticals S.p.A...and Myung In Pharm Co. Ltd...today announced that they have entered into a license agreement to develop, manufacture and commercialize Newron’s innovative modulator of the excessive release of glutamate, evenamide, an add-on therapy for treatment-resistant schizophrenia (TRS) and poorly responding patients with schizophrenia, in South Korea. Under the terms of the license agreement, Myung In Pharm will contribute 10% of the total patient population to be enrolled into Newron’s upcoming pivotal Phase III trial and cover the costs related to this population...The Phase III randomized, double-blind, one-year trial is expected to begin in H1 2025 and will compare evenamide to placebo as an add-on treatment in at least 600 patients with TRS."

Licensing / partnership • New P3 trial • CNS Disorders • Schizophrenia

Efficacy and safety of evenamide, a glutamate modulator, added to a second-generation antipsychotic in inadequately/poorly responding patients with chronic schizophrenia: results from a randomized, double-blind, placebo-controlled, phase 3, international clinical trial. (PubMed, Neuropharmacology) - "The demonstration of statistically significant and clinically meaningful benefit of evenamide, a glutamate modulator, as add-on treatment in patients with chronic schizophrenia inadequately responding to their second-generation antipsychotic may represent a new treatment paradigm for this population."

Clinical • Journal • P3 data • CNS Disorders • Psychiatry • Schizophrenia

Therapeutic, effect of evenamide, a glutamate inhibitor, in patients with treatment-resistant schizophrenia (TRS): final, 1-year results from a phase 2, open-label, rater-blinded, randomized, international clinical trial. (PubMed, Int J Neuropsychopharmacol) - No abstract available

Journal • P2 data • CNS Disorders • Psychiatry • Schizophrenia

Evenamide as an add-on to antipsychotics demonstrates significant efficacy in patients with schizophrenia in a potentially pivotal randomized placebo-controlled trial (ECNP 2024) - "This is the first randomized, placebo-controlled trial to demonstrate that glutamate modulation is effective in managing inadequate response to antipsychotics in patients with schizophrenia and that evenamide should become the first-choice treatment for such patients."

Clinical • CNS Disorders • Epilepsy • Psychiatry • Schizophrenia

Evenamide as add-on to antipsychotics in treatment-resistant schizophrenia: design of a potentially pivotal, phase 3, international, randomized, double-blind, placebo-controlled trial (ECNP 2024) - "The usage of clozapine, the only drug approved for TRS, remains remarkably low due to its severe side effects. Positive Results would confirm the benefit seen in the pilot study, paving the way for a new treatment paradigm for patients with TRS."

Clinical • P3 data • CNS Disorders • Psychiatry • Schizophrenia

Achievement of clinically meaningful response and remission in treatment-resistant schizophrenia patients: Results from a long-term international study with evenamide add-on (ECNP 2024) - "Study 014/015 was a 1-year, randomized, open-label, rater-blinded, international study in patients with TRS not responding to a therapeutic dose of an AP (except clozapine). The addition of evenamide to APs in TRS patients resulted in clinically important improvement of symptoms of psychosis to such an extent that a meaningful proportion of patients no longer met the criteria for TRS, and a subgroup eventually achieved remission. These Results are unique for a NCE that acts solely through modulation of glutamate. If confirmed in a phase III, double-blind, placebo-controlled trial, these Results would indicate the necessity of glutamate modulation for the optimal treatment of TRS patients."

Clinical • CNS Disorders • Psychiatry • Schizophrenia