evenamide (NW-3509) / Newron - LARVOL DELTA

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

Evenamide as an add-on to antipsychotics demonstrates significant efficacy in patients with schizophrenia in a pivotal randomized placebo-controlled trial (ECNP 2024) - "During this 1-year period, the benefits on symptoms of psychosis (PANSS), severity of disease (CGI-S) and global evaluation (CGI-C) continued to show increasing improvement with time.New, breakthrough and compelling Results from a phase 3, international, randomized, double-blind, placebo-controlled, 4-week trial, demonstrated the safety and statistically significant efficacy of evenamide 30 mg bid as add-on in patients with chronic schizophrenia poorly responding to their antipsychotic and thus met both primary (PANSS) and key secondary endpoints (CGI-S). Evenamide was well tolerated with a low dropout rate (4%) and adverse dropout rate (1%), and low incidence of TEAEs, comparable rates on evenamide and placebo.This is the first potentially pivotal trial to demonstrate the benefit of adding an antipsychotic to poor-responders: evenamide is the first NCE glutamate modulator that benefits patients with schizophrenia whose symptoms are not adequately controlled by SGAs..."

Clinical • CNS Disorders • Psychiatry • Schizophrenia

Evenamide, as an add-on to antipsychotics, produces long-lasting clinically meaningful benefit and converts treatment-resistant schizophrenia (TRS) patients into a responsive state: 6-month results from an ongoing international randomized study (CINP 2024) - No abstract available

Clinical • CNS Disorders • Psychiatry • Schizophrenia

Evenamide as add-on treatment for treatment-resistant schizophrenia (TRS) patients not benefiting from antipsychotics: design of a phase 3, potentially pivotal, international, randomized, double-blind, placebo-controlled clinical trial (CINP 2024) - No abstract available

Clinical • P3 data • CNS Disorders • Psychiatry • Schizophrenia

Evenamide as add-on treatment for patients with chronic schizophrenia not responding adequately to their current antipsychotic medication: results of a potentially pivotal, phase II/III, international, randomized, double blind, placebo-controlled trial (CINP 2024) - No abstract available

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

Remarkable efficacy of evenamide, a glutamate antagonist, as an add-on to antipsychotics in patients with treatment resistant schizophrenia (TRS): results from a one-year, open-label, dose-comparative, randomized, treatment trial (CINP 2024) - No abstract available

Clinical • CNS Disorders • Psychiatry • Schizophrenia

Addition of Evenamide for 1-Year to Antipsychotics in TRS Patients Results in Increasing Clinically Important Benefit to an Extent That a Substantial Proportion No Longer Meet International Criteria for Treatment Resistance (SIRS 2024) - "The 161 TRS patients randomized to treatment tolerated the study medication very well with a high completion rate at 1 year (~75% at 1-year) and low ADO rate (1.9%). During the 1-year treatment period, ~50% of the patients achieved a clinically meaningful benefit (>=20% improvement on PANSS total score): of the patients who achieved this clinically important reduction, ~40% preserved this benefit for at least 12 weeks according to TRRIP criteria. Remarkably, ~50% of the patients no longer met the operational severity criteria used to diagnose TRS at baseline, therefore converting patients into a responsive state."

Clinical • CNS Disorders • Schizophrenia

Add On Treatment With Evenamide in Schizophrenic Patients Not Responding Adequately to Their Current Antipsychotic: Results of a Potentially Pivotal, Phase 2/3, International, Randomized, Double Blind, Placebo-Controlled Trial (SIRS 2024) - "The most common background APs are risperidone (∼40%), olanzapine (∼20%), and clozapine (∼15%); mean duration of treatment with current AP is >1-year. Approximately 430 patients have been screened and ∼270 patients have been randomized to evenamide or placebo to date. The low attrition rate (<4%) during the randomized treatment period and high compliance to the study medication and procedures suggest that evenamide is well tolerated. Routine interim safety analyses reviewed by an ISMB did not detect any evidence of toxicity."

Clinical • P2/3 data • CNS Disorders • Schizophrenia

Design of a Potentially Pivotal, Phase 3, International, Randomized, Double-Blind, Placebo-Controlled Clinical Trial Evaluating Evenamide as Add-On Treatment for Treatment-Resistant Schizophrenia (TRS) Patients (SIRS 2024) - "The results of the study will demonstrate if evenamide, a selective modulator of excessive glutamate release, can benefit TRS patients receiving adjunctive APs, thus confirming the benefit seen in the 1-year pilot study. Positive results from this phase 3 study could change the current management of TRS patients, demonstrating the effectiveness of glutamate modulation as a new therapeutic strategy for this condition."

Clinical • P3 data • CNS Disorders • Schizophrenia

Glutamate Modulation by Evenamide as an Add-On to TRS Patients Not Responding to Their Current Antipsychotics is Associated With Clinically Important Improvement Across Outcome Measures: Results From 1-Year, Open-Label Trial (SIRS 2024) - "[Bortolato et al 2018] A pilot, placebo controlled study in patients with schizophrenia inadequately responding to aripiprazole/risperidone provided a statistically significant signal of efficacy on PANSS positive and CGI-C further supporting its benefits in TRS patients. 161 patients with TRS (males= 69%; mean age= 37.7 year; mean duration of illness= 6.8 year; baseline PANSS= 79.4; CGI-S= 4.5) were randomized, of whom 153 completed 6 weeks of treatment, and 144 of these patients continued into 46 week extension with 85% of them completing 1 year of treatment. [Anand et al 2023] At week 6, the PANSS mean change from baseline was -11.9% improving to -20% at 1 year. The proportion of patients with a clinically meaningful improvement in symptoms (PANSS ≥20% [Meltzer et al 2008; Rosenheck et al 1997]) doubled from 6 week (15.4%) to 6 month (34.0%) and increased further at 1 year (41.8%) with the vast majority (~90%) of the patients who met this level of improvement..."

Clinical • CNS Disorders • Schizophrenia

Treatment With Evenamide for 1 Year in TRS Patients Not Benefitting to Current Antipsychotics is Associated With Sustained, Clinically Important Benefit: Results From a Prospective, Pilot, 1 Year, Randomized, Open-Label Trial (SIRS 2024) - "Evenamide was evaluated as monotherapy or add-on to APs in animal models in which pre-pulse inhibition was impaired using amphetamine, scopolamine, phencyclidine, MK-801, ketamine, or sleep deprivation... This is the first international 1-year trial of evenamide add-on to any AP (except clozapine) in patients with TRS. Scheduled review of safety data by an ISMB did not detect any pattern of motor or CNS symptoms, weight gain, sexual dysfunction or laboratory/EKG abnormalities, indicating the good tolerability of evenamide at all doses in addition to low incidence of ADOs (1.9%). Furthermore, the attrition rate was extremely low (~25% at 1-year) in contrast to published TRS studies (Homman et al., 2021). After 1 year of treatment, the overall improvement in symptoms from baseline was -20% (PANSS total), with a clinically important benefit in the positive subscale (-26%)."

Clinical • CNS Disorders • Schizophrenia

Evenamide: a potential pharmacotherapeutic alternative for treatment-resistant schizophrenia. (PubMed, Int J Neuropsychopharmacol) - No abstract available

Journal • CNS Disorders • Psychiatry • Schizophrenia

Newron to Present Three Posters on Its Clinical Program Evaluating Evenamide in the Treatment of Schizophrenia at the 36th European College of Neuropsychopharmacology Congress (Businesswire) - "Newron Pharmaceuticals S.p.A...announced that it will present three posters at the upcoming 36th European College of Neuropsychopharmacology (ECNP) Congress taking place October 7-10, 2023, at the Centre Convencions Internacional de Barcelona (CCIB) in Barcelona, Spain. Full results from all 161 patients who were randomized in study 014 and who completed six months of participation in study 015 will be presented....Newron presented the data from all 161 patients at the six-week time point and data from the first 100 patients randomized in study 014 who completed one-year of participation in these studies at the 34th CINP World Congress of Neuropsychopharmacology and at the 2023 SIRS Annual Congress in May 2023."

P2 data • CNS Disorders • Schizophrenia

Evenamide, as an add-on to antipsychotics, benefits patients with treatment resistant schizophrenia: 6-month results from an ongoing international randomised study (ECNP 2023) - "Evenamide, a selective inhibitor of voltage-gated sodium channels, is devoid of biological activity at >130 CNS targets, normalizes glutamate release without affecting basal levels, and demonstrated benefits in animal models of psychosis as monotherapy and as an add on to APs (including clozapine), reversing deficits produced by amphetamine, scopolamine, phencyclidine, or ketamine. Discussion This is the first international trial of evenamide used as an add-on to a single typical or atypical AP in patients with TRS. Preliminary, encouraging results of this study have expedited the conduct of a randomized, double-blind, placebo-controlled, 1-year, international study to assess efficacy and safety of two doses (15 and 30 mg bid) of evenamide as add-on treatment in TRS patients not benefiting from their current AP"

Clinical • CNS Disorders • Psychiatry • Schizophrenia

Evenamide as add-on treatment for treatment-resistant schizophrenia patients not benefiting from antipsychotics: design of an international potentially pivotal clinical trial (ECNP 2023) - "Combination of ineffective doses of evenamide and 5HT2/D2 blockers APs, was associated with benefit in animal models of psychosis, suggesting synergies in mechanisms that benefit poor responders to current APs, including clozapine. Results The results of the study will demonstrate if addition of evenamide to patients with TRS on APs is associated with efficacy and tolerability. Conclusions Results from this study will determine if glutamate modulation by evenamide may represent a new therapeutic strategy for the treatment of patients with TRS."

Clinical • CNS Disorders • Psychiatry • Schizophrenia

Evenamide, add-on to antipsychotics, benefits patients with treatment-resistant schizophrenia: final dose-wise results from a Pilot, Phase II, multinational, randomized study (ECNP 2023) - "Evenamide, a selective inhibitor of voltage-gated sodium channels, devoid of activity at >130 CNS targets, normalizes glutamate release without affecting basal glutamate levels, and demonstrates benefits in animal models of psychosis as monotherapy and add on to APs, reversing deficits produced by amphetamine, scopolamine, phencyclidine, or ketamine. Combination of ineffective doses of evenamide and other APs, including clozapine, is associated with similar benefits, suggesting synergies in mechanisms that may benefit poor responders to current APs...Discussion This is the first international trial of a drug acting on the glutamate system as an add-on to a single typical or atypical AP in patients with TRS. Positive results from this study have expedited the design of an international, Phase 3, double-blind, placebo-controlled study of evenamide as add-on to APs in patients with TRS."

Clinical • P2 data • CNS Disorders • Psychiatry • Schizophrenia

Significant And Clinically Important Efficacy Of Evenamide Add - on To An Antipsychotic In Trs Patients Treated For 1 - year In A Phase 2 Study (CINP 2023) - "Evenamide, a selective inhibitor of voltage-gated sodium channels, is devoid of biological activity at >130 CNS targets, normalizes glutamate release without affecting basal levels, and demonstrated benefits in animal models of psychosis as monotherapy and as an add on to APs, reversing deficits produced by amphetamine, scopolamine, phencyclidine, or ketamine. Study 014, with its long-term extension, is the first international trial of a drug acting on the glutamate system as an add-on to APs in patients with TRS. Confirmation of these results in a phase III, double-blind, placebo-controlled study would support the safety and efficacy of evenamide in patients with TRS."

Clinical • P2 data • CNS Disorders • Psychiatry • Schizophrenia