NW-3509 · program

Evenamide for Schizophrenia

Phase 3ActiveNewron Pharmaceuticals S.p.A. (NWRN)

Evenamide (NW-3509), a first-in-class oral glutamate release modulator (selective voltage-gated sodium channel blocker), as ADD-ON therapy for schizophrenia — specifically treatment-resistant schizophrenia (TRS), including patients on clozapine, and chronic schizophrenia inadequately controlled by a second-generation antipsychotic. TRS is not a separate curated indication, so the program is filed under schizophrenia; every clinical study is an augmentation design on top of the patient's existing antipsychotic. Evidence base: study 008A (4-week, randomized, double-blind, N=291, 45 centers in Europe/Asia/Latin America) met its PANSS primary endpoint with 30 mg bid vs placebo (10.2- vs 7.6-point reduction at day 29, p<0.05, Cohen's d 0.33; topline 2024-04-30); the open-label, rater-blinded study 014/015 in 161 TRS patients showed benefit increasing from 6 weeks (-9.4 PANSS) to 1 year (-14.7, p<0.001; 75% 1-year completion, final results 2024-01-04). The pivotal Phase 3 ENIGMA-TRS program was cleared by regulators including FDA in May 2025: ENIGMA-TRS 1 (international, 52-week, double-blind, >=600 TRRIP-criteria TRS patients on SGAs incl. clozapine, 15/30 mg bid, primary efficacy at 12 weeks, enrolling in 15 countries across Europe/Asia/Latin America/Canada since 2025-08-12; 12-week results guided for Q4 2026) and ENIGMA-TRS 2 (NCT07184619, 12-week, >=400 documented-TRS patients, 15 mg bid, US + selected countries, first US site UCLA initiated 2025-12-08, first participant 2026-01-23). Since 2026-04-29, FDA has paused enrollment of NEW participants at US sites of ENIGMA-TRS 2 following a sudden unexpected death at a non-US site (investigator-assessed as unrelated; the independent safety monitoring board recommended both studies continue as designed); a Type A meeting was held (update 2026-07-02) and the hold was not yet resolved as of the last public disclosure, while ENIGMA-TRS 1 and ex-US ENIGMA-TRS 2 sites continue. Partnered: EA Pharma/Eisai for Japan and other Asian territories (2024-12-13, up to EUR 117M incl. EUR 44M upfront) and Myung In Pharm for South Korea (2025-01-09); up to EUR 38M tranched equity financing secured 2026-02-16 to fund the program through the pivotal 12-week readouts.

Data current as of

Development timeline

Phase 3Aug 2025 – Dec 2026
  1. UpcomingENIGMA-TRS 1 12-week primary efficacy results (evenamide 15/30 mg bid vs placebo, >=600 TRRIP-criteria TRS patients on SGAs including clozapine), expected Q4 2026.↗
  2. UpcomingENIGMA-TRS 2 topline (evenamide 15 mg bid vs placebo, 12 weeks, >=400 documented-TRS patients; NCT07184619), guided for Q4 2026 — timing at risk from the US enrollment hold in effect since April 2026.↗
  3. FDA regulatory meeting / outcomeNewron updates on Type A meeting with FDA about the ENIGMA-TRS 2 US enrollment hold↗
  4. Clinical holdFDA pauses enrollment of new participants at US sites of the ENIGMA-TRS 2 study↗
  5. FinancingNewron secures up to EUR 38 million in tranched equity to advance the Phase 3 evenamide program↗
  6. Trial startedUS initiation of ENIGMA-TRS 2 Phase 3 study of evenamide (NCT07184619)↗
  7. Newron announced enrollment had begun in the pivotal Phase 3 ENIGMA-TRS program: ENIGMA-TRS 1, an international, 52-week, randomized, double-blind, placebo-controlled study of evenamide 15 and 30 mg bid vs placebo in >=600 TRS patients (TRRIP criteria, on SGAs including clozapine) across Europe, Asia, Latin America and Canada, with the primary efficacy assessment at 12 weeks (results guided for Q4 2026). Regulatory approvals for the two-study program, including FDA clearance of ENIGMA-TRS 2, had been announced 2025-05-12.↗
  8. Trial startedEnrollment begins in pivotal Phase 3 ENIGMA-TRS 1 study of evenamide in treatment-resistant schizophrenia↗
Phase 2/3Apr 2024 – May 2025
  1. IND/CTA clearanceRegulatory approvals received for the pivotal Phase 3 ENIGMA-TRS program, including FDA clearance of ENIGMA-TRS 2↗
  2. Licensing dealNewron licenses evenamide to Myung In Pharm for South Korea↗
  3. Licensing dealNewron licenses evenamide to EA Pharma (Eisai subsidiary) for Japan and other Asian territories↗
  4. metStudy 008A topline (N=291): evenamide 30 mg bid add-on met the PANSS primary endpoint in chronic schizophrenia inadequately responding to a second-generation antipsychotic (PANSS -10.2 vs -7.6 on placebo at day 29, p<0.05, Cohen's d 0.33), with the key secondary CGI-S also positive and good tolerability.↗
Phase 2Dec 2015 – Jan 2024
  1. metStudy 014/015 final 1-year results in TRS: PANSS improvement increased over time (-9.4 at 6 weeks, -12.7 at 6 months, -14.7 at 1 year; p<0.001), responder rate rose to 47.4% at 1 year, 75% completed 1 year of treatment, no psychotic relapses on treatment.↗
  2. metStudy 014 topline (all 161 TRS patients): evenamide add-on to antipsychotics well tolerated with clinically important benefit at 6 weeks; 95% completed the 6-week phase and 89% continued into the 46-week extension.↗
  3. Phase 2a randomized, double-blind study 002 (NCT02624167, NW-3509A/002/II/2015) started December 2015 in 90 chronic schizophrenia patients not responding to their current antipsychotic, 15–25 mg bid titration vs placebo (month precision; day set to the 1st). Later Phase 2 studies: 008 (NCT04461119, 2020, EEG/safety, 138 patients) and the open-label 1-year TRS study 014/015 (161 patients).
Phase 1Jun 2013
  1. First-in-human Phase 1 sequential-cohort maximum-tolerated-dose study in healthy male volunteers (NCT01955564, NW-3509A/001/I/2011) started June 2013 per ClinicalTrials.gov (month precision; day set to the 1st).

Readouts

  • Q4 2026AnticipatedTopline data

    ENIGMA-TRS 1 12-week primary efficacy results (evenamide 15/30 mg bid vs placebo, >=600 TRRIP-criteria TRS patients on SGAs including clozapine), expected Q4 2026. ↗

  • Q4 2026AnticipatedTopline dataNCT07184619

    ENIGMA-TRS 2 topline (evenamide 15 mg bid vs placebo, 12 weeks, >=400 documented-TRS patients; NCT07184619), guided for Q4 2026 — timing at risk from the US enrollment hold in effect since April 2026. ↗

  • 2024-04-30ReportedTopline datamet

    Study 008A topline (N=291): evenamide 30 mg bid add-on met the PANSS primary endpoint in chronic schizophrenia inadequately responding to a second-generation antipsychotic (PANSS -10.2 vs -7.6 on placebo at day 29, p<0.05, Cohen's d 0.33), with the key secondary CGI-S also positive and good tolerability. ↗

  • 2024-01-04ReportedFull resultsmet

    Study 014/015 final 1-year results in TRS: PANSS improvement increased over time (-9.4 at 6 weeks, -12.7 at 6 months, -14.7 at 1 year; p<0.001), responder rate rose to 47.4% at 1 year, 75% completed 1 year of treatment, no psychotic relapses on treatment. ↗

  • 2023-03-20ReportedTopline datamet

    Study 014 topline (all 161 TRS patients): evenamide add-on to antipsychotics well tolerated with clinically important benefit at 6 weeks; 95% completed the 6-week phase and 89% continued into the 46-week extension. ↗

Clinical trials in Schizophrenia

NCT07184619NW-3509/022/III/2024Phase 3Recruitingn=400

ENIGMA-TRS 2: A Phase III, 12-week, Prospective, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multi-center Study to Determine the Efficacy, Safety, and Tolerability of a Dose of 15 mg Bid of Evenamide as Add-on in Patients With Documented Treatment-resistant Schizophrenia

Started Jan 2026· Primary completion Dec 2026· 📍 10 sites across 2 countries (United States, India)

ENIGMA-TRS 1Phase 3Recruitingn=600

ENIGMA-TRS 1: international, 52-week, randomized, double-blind, placebo-controlled Phase 3 study of evenamide 15 and 30 mg bid as add-on to second-generation antipsychotics (including clozapine) in at least 600 patients with treatment-resistant schizophrenia meeting TRRIP criteria; primary efficacy assessment at 12 weeks

Started Aug 2025

NCT04461119NW-3509/008/II/2019Phase 2Completedn=138

A Phase II, Randomized, 4-Week, Double-Blind, Placebo-Controlled, Multiple-Dose Study, Designed to Determine the Safety, Tolerability, EEG Effects and Preliminary Efficacy of Fixed Oral Doses of 7.5 and 15 mg BID of Evenamide in Patients With Chronic Schizophrenia Who Are Symptomatic on Their Current Second-Generation Antipsychotic Medication

Started Jun 2020· Primary completion Feb 2021· 📍 14 sites across 2 countries (India, United States)

NCT03446274NW3509-007Phase 1Unknownn=6

An Open Label, Single-Dose Study of 14C-NW-3509 in Healthy Male Subjects

Started Apr 2018· Primary completion Apr 2018

NCT02624167NW-3509A/002/II/2015Phase 2Completedn=90

A Phase IIA, Prospective, Randomized, Double-blind, Multiple-dose Study of NW-3509A in Chronic Schizophrenia Patients Not Responding to Their Current Anti-psychotic Medication

Started Dec 2015· Primary completion Dec 2016· 📍 5 sites across 2 countries (India, United States)

NCT01955564NW-3509A/001/I/2011Phase 1Completedn=54

A Phase I - Sequential Cohort Dosing to Determine Maximum Tolerated Dose in Healthy Male Volunteers

Started Jun 2013· Primary completion Sept 2014· 📍 1 site across 1 country (United States)

014/015Phase 2Completedn=161

Study 014/015: 6-week, randomized, open-label, rater-blinded study of evenamide (7.5, 15, 30 mg bid) as add-on to antipsychotics in treatment-resistant schizophrenia, with 46-week extension (1 year total)

mixedPANSS total score change from baseline (pooled doses, LOCF)

008APhase 2/3Completedn=291

Study 008A: 4-week, prospective, randomized, double-blind, placebo-controlled study of evenamide 30 mg bid as add-on in chronic schizophrenia inadequately responding to a second-generation antipsychotic (45 centers in Europe, Asia and Latin America)

mixedPANSS total score change from baseline to day 29 (primary)

Formulations

FormulationRouteRegimenPharmacokinetics
Evenamide oral capsule (7.5–30 mg twice daily)
Oral capsules dosed twice daily. Phase 3: 15 mg bid in ENIGMA-TRS 2 (NCT07184619); 15 mg and 30 mg bid in ENIGMA-TRS 1. Earlier studies: 30 mg bid in study 008A; 7.5, 15, and 30 mg bid in study 014/015; 7.5 and 15 mg bid in study 008 (NCT04461119); 15–25 mg bid titration in study 002 (NCT02624167).
OralTwice daily—

Mechanism of action (compound-wide)

Selective blocker of voltage-gated sodium (Nav) channels that reduces neuronal hyperexcitability and normalizes aberrant, excessive glutamate release without affecting basal glutamatergic transmission, and without direct activity at dopamine or other monoamine receptors — which is why it is developed strictly as add-on therapy to antipsychotics rather than as monotherapy. Newron describes evenamide as the first compound acting exclusively through glutamatergic modulation to demonstrate efficacy in placebo-controlled schizophrenia trials. In the methylazoxymethanol acetate (MAM) neurodevelopmental rat model of schizophrenia, acute evenamide normalized ventral tegmental area dopamine neuron population activity (the hyperdopaminergic state), reduced ventral hippocampal pyramidal-neuron hyperactivity, and reversed recognition-memory and social deficits, consistent with the hypothesis that damping hippocampal hyperexcitability upstream of the dopamine system addresses positive, negative, and cognitive symptom domains. No subtype-resolved human Nav pharmacology (e.g. Nav1.2 vs Nav1.6 potency) or binding constants are publicly citable from open sources.

TargetActionAffinity
Presynaptic glutamate release (voltage-gated Na+ channels)primaryInhibitor—ⓘ

← Full NW-3509 compound page (identity, identifiers, all indications)

Sources

  1. Anand R, et al. Therapeutic effect of evenamide, a glutamate inhibitor, in patients with treatment-resistant schizophrenia: final, 1-year results from a phase 2, open-label, rater-blinded, randomized, international clinical trial (study 014/015). Int J Neuropsychopharmacol. 2024;28(1):pyae061 — International Journal of Neuropsychopharmacology (Oxford/CINP) / PubMed
  2. Anand R, Turolla A, Chinellato G, Sansi F, Roy A, Hartman R. Efficacy and safety of evenamide, a glutamate modulator, added to a second-generation antipsychotic in inadequately/poorly responding patients with chronic schizophrenia (study 008A). Neuropharmacology. 2025;266:110275 — Neuropharmacology (Elsevier) / PubMed
  3. NCT01955564 (NW-3509A/001/I/2011) — Phase 1 sequential-cohort maximum-tolerated-dose study in healthy male volunteers (N=54, completed 2014) — ClinicalTrials.gov (U.S. National Library of Medicine)
  4. NCT02624167 (NW-3509A/002/II/2015) — Phase 2a randomized double-blind study of NW-3509A 15–25 mg bid in chronic schizophrenia patients not responding to their current antipsychotic (N=90, completed 2017) — ClinicalTrials.gov (U.S. National Library of Medicine)
  5. NCT03446274 (NW3509-007) — Open-label, single-dose 14C-NW-3509 human ADME study in healthy males (N=6, 2018; no results posted) — ClinicalTrials.gov (U.S. National Library of Medicine)
  6. NCT04461119 (NW-3509/008/II/2019) — Phase 2, 4-week, double-blind, placebo-controlled study of evenamide 7.5/15 mg bid in chronic schizophrenia symptomatic on a second-generation antipsychotic (N=138, completed 2021) — ClinicalTrials.gov (U.S. National Library of Medicine)
  7. NCT07184619 (NW-3509/022/III/2024, ENIGMA-TRS 2) — Evenamide as Add-On to Standard of Care in Subjects With Documented Treatment-Resistant Schizophrenia (Phase 3, 15 mg bid, N=400, recruiting; actual start 2026-01-23) — ClinicalTrials.gov (U.S. National Library of Medicine)
  8. Newron and EA Pharma (a subsidiary of Eisai Co., Ltd.) announce license agreement for evenamide in Japan and other Asian territories (2024-12-13; up to EUR 117M incl. EUR 44M upfront, milestones and tiered royalties) — Newron Pharmaceuticals S.p.A.
  9. Newron and Myung In Pharm announce license agreement for evenamide in South Korea (2025-01-09; upfront, milestones, royalties; Myung In contributes 10% of Phase 3 patients and shares global development costs) — Newron Pharmaceuticals S.p.A.
  10. Newron announces approval for pivotal Phase III ENIGMA-TRS program with evenamide as add-on therapy in patients with treatment-resistant schizophrenia (2025-05-12; ENIGMA-TRS 1 and 2 designs, FDA approval of ENIGMA-TRS 2, Q4 2026 guidance) — Newron Pharmaceuticals S.p.A.
  11. Newron announces positive top-line results from potentially pivotal Phase II/III study 008A with evenamide in schizophrenia patients (2024-04-30; PANSS primary endpoint met, N=291, 30 mg bid, 45 centers in Europe/Asia/Latin America) — Newron Pharmaceuticals S.p.A.
  12. 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 (2025-12-08; first site UCLA; topline expected Q4 2026) — Newron Pharmaceuticals S.p.A.
  13. Newron begins enrollment in pivotal Phase III ENIGMA-TRS program with evenamide as add-on therapy in patients with treatment-resistant schizophrenia (2025-08-12) — Newron Pharmaceuticals S.p.A.
  14. Newron provides update following Type A meeting with FDA — Newron Pharmaceuticals
  15. Newron reports a pause in enrollment of new study participants in US centers of ENIGMA-TRS 2 study (2026-04-29; FDA hold after sudden unexpected death at a non-US site assessed as unrelated; safety board recommended studies continue) — Newron Pharmaceuticals S.p.A.
  16. Newron reports compelling topline results from all patients in study 014, its Phase II clinical trial evaluating evenamide as add-on therapy for treatment-resistant schizophrenia (2023-03-20) — Newron Pharmaceuticals S.p.A. (via Business Wire)
  17. Newron reports exceptional one-year results of study 014/15 with evenamide in treatment-resistant schizophrenia (2024-01-04; 161 patients, 75% one-year completion, PANSS/CGI-S/LOF improvement p<0.001) — Newron Pharmaceuticals S.p.A.
  18. Newron secures up to EUR 38 million to advance Phase III evenamide program (2026-02-16; three-tranche equity investment from existing and new shareholders) — Newron Pharmaceuticals S.p.A.
  19. Uliana DL, Walsh RA, Fabris D, Grace AA. Evenamide reverses schizophrenia-related dysfunction in a neurodevelopmental animal model. Neuropsychopharmacology. 2025;50(11):1631-1642 ('a selective voltage-gated sodium channel blocker that reduces neuronal hyperexcitability') — Neuropsychopharmacology (Nature/ACNP) / PubMed