NRX-101 · program

NRX-101 (D-cycloserine/lurasidone) for Bipolar depression

Phase 3ActiveNRx Pharmaceuticals, Inc. (NRXP)
  • FDA Fast Track (Severe Bipolar Depression With Acute Suicidal Ideation And Behavior; August 2017)
  • FDA Breakthrough Therapy (Severe Bipolar Depression With Acute Suicidal Ideation And Behavior; Announced 2018-11-13)

Indications for NRX-101: Bipolar depression · Phase 3 Treatment-resistant depression · Phase 2/3

NRX-101 (oral D-cycloserine/lurasidone) for bipolar depression with suicidal ideation, NRx Pharmaceuticals' original indication. The phase 2 STABIL-B trial (NCT02974010, n=22) gave patients a single ketamine infusion and then randomized them. NRX-101 beat lurasidone alone at maintaining improvement in depression (MADRS difference -7.7, p=0.03) and at reducing suicidal ideation (C-SSRS, p=0.02). On this basis the FDA granted Breakthrough Therapy designation in 2018 and a Special Protocol Agreement for a registrational trial. That Phase 3 maintenance trial (NCT03396068, SBD-ASIB) started in December 2019; its registry status is now unknown and no results are posted. A Phase 2b/3 comparison against lurasidone without prior ketamine (NCT03395392, n=74) reported in April 2024. The two drugs had similar antidepressant effects (each cut depression scores by about 50%). NRX-101 showed a 33% advantage in sustained remission from suicidality, which was not statistically significant, and a roughly 75% reduction in akathisia. In July 2025 NRx submitted the manufacturing (Module 3) portion of an NDA and requested rolling review under its Breakthrough designation. It aims for accelerated approval in bipolar depression with suicidal ideation despite approved medication, with akathisia as a key feature. In June 2026 it agreed to support an open-label trial in treatment-resistant bipolar depression run by the Mass General-led Bipolar Action Network.

Data current as of

Development timeline

Phase 3Aug 2017 – Jun 2026
  1. PartnershipNRx partners with Mass General-led Bipolar Action Network on an NRX-101 trial in treatment-resistant bipolar depression↗
  2. NRx submitted more than 80,000 pages of manufacturing, nonclinical and clinical material (the Module 3 file) to the FDA to begin a rolling NDA for NRX-101 in suicidal bipolar depression, and requested rolling review under its Breakthrough designation. The NDA is not complete, so phase stays phase_3 and not 'filed'. The 10-K gives the month only (July 2025); the date is the month-end anchor.↗
  3. mixedPhase 2b/3 NRX-101 vs lurasidone in bipolar depression with subacute suicidal ideation (no ketamine lead-in): similar antidepressant effect (each about 50% MADRS reduction), a 33% advantage in sustained remission from suicidality that was not statistically significant, and about 70-75% less akathisia (P=0.076).↗
  4. metSTABIL-B (Phase 2) published: after ketamine stabilization, NRX-101 beat lurasidone alone at maintaining improvement in depression (MADRS difference -7.7, p=0.03) and at reducing suicidal ideation (C-SSRS difference -1.5, p=0.02; CGI-SS p=0.03) in 22 patients with severe bipolar depression and acute suicidality.↗
  5. The Phase 3 SBD-ASIB maintenance trial (NCT03396068), run under the FDA Special Protocol Agreement, started (actual start date per ClinicalTrials.gov). Registry status is now UNKNOWN (last updated 2024-01-19, estimated primary completion 2024-12-31, 72 estimated), and no results are posted.
  6. Fast TrackFDA grants Fast Track designation to NRX-101 for severe bipolar depression with acute suicidal ideation and behavior↗
Phase 2Jan 2018 – Nov 2018
  1. Breakthrough TherapyFDA grants Breakthrough Therapy designation to NRX-101 for suicidal bipolar depression↗
  2. STABIL-B (NCT02974010), a two-stage Phase 2 trial in severe bipolar depression with acute suicidal ideation, started (actual start date per ClinicalTrials.gov). Patients received a single ketamine or saline infusion, then NRX-101 or lurasidone. Primary completion 2018-08-31; 22 enrolled.

Readouts

  • 2024-04-30ReportedTopline datamixedNCT03395392

    Phase 2b/3 NRX-101 vs lurasidone in bipolar depression with subacute suicidal ideation (no ketamine lead-in): similar antidepressant effect (each about 50% MADRS reduction), a 33% advantage in sustained remission from suicidality that was not statistically significant, and about 70-75% less akathisia (P=0.076). ↗

  • 2023-08-13ReportedFull resultsmetNCT02974010

    STABIL-B (Phase 2) published: after ketamine stabilization, NRX-101 beat lurasidone alone at maintaining improvement in depression (MADRS difference -7.7, p=0.03) and at reducing suicidal ideation (C-SSRS difference -1.5, p=0.02; CGI-SS p=0.03) in 22 patients with severe bipolar depression and acute suicidality. ↗

Clinical trials in Bipolar depression

NCT03395392NRX101_003Phase 2/3Completedn=74

A Randomized, Double-Blind Controlled Comparison of NRX-101 to Lurasidone for Adults With Bipolar Depression and Subacute Suicidal Ideation or Behavior

Started May 2022· Primary completion Feb 2024· 📍 14 sites across 1 country (United States)

NCT03396068NRX101_002Phase 3Unknownn=72

NRX-101 for Maintenance of Remission From Severe Bipolar Depression in Patients With Acute Suicidal Ideation and Behavior: The SBD-ASIB Study

Started Dec 2019· Primary completion Dec 2024· 📍 4 sites across 1 country (United States)

NCT03402152NRX101_004Phase 2/3Completedn=8

NRX101 Glx Biomarker Validation Study

Started Nov 2018· Primary completion Jan 2021· 📍 1 site across 1 country (United States)

NCT02974010NRX 101-001Phase 2Completedn=22

Sequential Therapy for the Treatment of Severe Bipolar Depression (STABIL-B)

Started Jan 2018· Primary completion Aug 2018· 📍 4 sites across 1 country (United States)

Formulations

FormulationRouteRegimenPharmacokinetics
NRX-101 oral capsule (high-dose D-cycloserine/lurasidone, twice daily)
Fixed-dose combination of D-cycloserine and lurasidone taken twice daily by mouth in the bipolar depression trials (NCT03395392, NCT03396068). The Glx biomarker pilot used D-cycloserine 950 mg + lurasidone 66 mg. A non-CNS urinary tract infection study (NCT06128213) used 487.5 mg DCS + 16.5 mg lurasidone HCl twice daily. Exact per-capsule strengths for the bipolar Phase 2b/3 trial are not stated in the sources opened.
OralTwice daily—

Mechanism of action (compound-wide)

Two-component NMDA-directed strategy. D-cycloserine binds the NMDA receptor and is dose-dependent: at low doses (50-100 mg) it functions as a partial agonist that can enhance synaptic plasticity, and at higher doses (>500 mg) as a functional antagonist. Lurasidone, an approved second-generation antipsychotic, offsets the psychotomimetic effects of D-cycloserine. NRx describes lurasidone as a 5-HT2A antagonist and states that it increases NMDA receptor expression through 5-HT7 antagonism. The bipolar depression program uses high-dose D-cycloserine, aiming to maintain ketamine-like NMDA antagonism. The TMS augmentation program uses a lower D-cycloserine dose, aiming to enhance the NMDA-dependent synaptic plasticity thought to drive TMS response.

TargetActionAffinity
NMDA receptorprimaryGRIN1Partial agonist—ⓘ
5-HT2AHTR2AAntagonist—ⓘ
5-HT7HTR7Antagonist—ⓘ

← Full NRX-101 compound page (identity, identifiers, all indications)

Sources

  1. Franzen AD, et al. Mechanism-Based Polypharmacy as a Repurposing Strategy: The Case of D-Cycloserine and Lurasidone. Clin Transl Sci. 2026;19(6):e70624 — Clinical and Translational Science / PubMed
  2. NCT02974010 (NRX 101-001, STABIL-B) — Sequential Therapy for the Treatment of Severe Bipolar Depression — ClinicalTrials.gov (U.S. National Library of Medicine)
  3. NCT03395392 (NRX101_003) — A Randomized, Double-Blind Controlled Comparison of NRX-101 to Lurasidone for Adults With Bipolar Depression and Subacute Suicidal Ideation or Behavior — ClinicalTrials.gov (U.S. National Library of Medicine)
  4. NCT03396068 (NRX101_002, SBD-ASIB) — NRX-101 for Maintenance of Remission From Severe Bipolar Depression in Patients With Acute Suicidal Ideation and Behavior — ClinicalTrials.gov (U.S. National Library of Medicine)
  5. NCT03402152 (NRX101_004) — NRX101 Glx Biomarker Validation Study — ClinicalTrials.gov (U.S. National Library of Medicine)
  6. NeuroRx Receives FDA Breakthrough Therapy Designation for NRX-101, First Oral Drug Targeting Suicidal Bipolar Depression (2018-11-13) — NeuroRx, Inc. (via Business Wire / BioSpace)
  7. Nierenberg A, et al. NRX-101 (D-cycloserine plus lurasidone) vs. lurasidone for the maintenance of initial stabilization after ketamine in patients with severe bipolar depression with acute suicidal ideation and behavior: a randomized prospective phase 2 trial. Int J Bipolar Disord. 2023;11(1):28 — International Journal of Bipolar Disorders / PubMed
  8. NRx Defense Systems Awarded $11 Million DARPA Prime Contract to Evaluate Robotic Magnetic Stimulation in conjunction with NRX-101 for Treatment Resistant Depression (press release 2026-09-30; Form 8-K Ex. 99.1 filed 2026-10-05) — NRx Pharmaceuticals, Inc. / SEC EDGAR
  9. NRx Pharmaceuticals Announces Promising Findings in Phase 2b/3 Clinical Trial of NRX-101 vs. Lurasidone for Treatment of Suicidal Bipolar Depression (2024-04-30; Form 8-K Ex. 99.2) — NRx Pharmaceuticals, Inc. / SEC EDGAR
  10. NRx Pharmaceuticals Form 10-K for fiscal year 2025 (filed 2026-03-23) — NRx Pharmaceuticals, Inc. / SEC EDGAR
  11. NRx Pharmaceuticals Form 10-Q for the quarter ended June 30, 2026 (filed 2026-08-14) — NRx Pharmaceuticals, Inc. / SEC EDGAR