NBI-1065844 · program
Luvadaxistat (TAK-831) for Schizophrenia
Phase 2 program in schizophrenia, evolving from negative symptoms to cognitive impairment associated with schizophrenia (CIAS). The Phase 2 INTERACT study (NCT03382639) in persistent negative symptoms missed its primary PANSS Negative Symptom Factor Score endpoint at Week 12 but showed nominally significant improvements on cognitive secondaries (BACS composite and SCoRS) at the 50 mg dose, prompting a CIAS-focused follow-up. The Phase 2 ERUDITE study (NCT05182476), with the BACS composite cognition score as the primary endpoint, failed to meet that endpoint (reported 2024-09-12). Neurocrine announced it would halt further development of luvadaxistat and redirect resources to other schizophrenia (NBI-1117568) and MDD (NBI-1065845) programs.
Development timeline
- missedERUDITE Phase 2 missed its primary BACS cognition endpoint; Neurocrine discontinued luvadaxistat.↗
- mixedINTERACT missed its primary negative-symptom endpoint (PANSS NSFS) but hit cognitive secondaries (BACS, SCoRS) at 50 mg.↗
- Neurocrine in-licensed luvadaxistat (TAK-831 -> NBI-1065844) from Takeda among seven psychiatry pipeline programs; collaboration effective July 2020 (per Neurocrine 8-K). At in-license, the Phase 2 INTERACT study in schizophrenia negative symptoms was ongoing.↗
Readouts
- 2024-09-12ReportedTopline datamissedNCT05182476
ERUDITE Phase 2 missed its primary BACS cognition endpoint; Neurocrine discontinued luvadaxistat. ↗
- 2021-03-02ReportedTopline datamixedNCT03382639
INTERACT missed its primary negative-symptom endpoint (PANSS NSFS) but hit cognitive secondaries (BACS, SCoRS) at 50 mg. ↗
Clinical trials in Schizophrenia
NCT05182476NBI-1065844 (ERUDITE)Phase 2Completedn=216
ERUDITE: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy, Safety, and Tolerability of Luvadaxistat in Subjects With Cognitive Impairment Associated With Schizophrenia
missedprimaryChange from baseline on the BACS (Brief Assessment of Cognition in Schizophrenia) composite score at Day 98
ERUDITE failed to meet its primary BACS composite cognition endpoint; the cognitive benefit seen at 50 mg in INTERACT did not replicate, attributed in part to large variability in cognitive measures and possible baseline imbalance across arms. Neurocrine halted further development of luvadaxistat.
NCT03382639TAK-831-2002 (INTERACT)Phase 2Completedn=256
INTERACT: A Phase 2, 12-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate 3 Dose Levels of Luvadaxistat (TAK-831) in Adults With Negative Symptoms of Schizophrenia
metsecondaryChange from baseline in SCoRS interviewer total score (cognition/function), luvadaxistat 50 mg vs placebo (0.011 (nominal, one-sided))
Nominally significant improvement on the Schizophrenia Cognition Rating Scale interviewer total at 50 mg; luvadaxistat was well tolerated with no new safety signals.
metsecondaryChange from baseline in BACS composite score (cognition), luvadaxistat 50 mg vs placebo (0.031 (nominal, one-sided))
Nominally significant improvement on the BACS cognitive composite at the 50 mg dose; cognitive signal motivated the CIAS-focused ERUDITE follow-up.
missedprimaryChange from baseline in PANSS Negative Symptom Factor Score (NSFS) at Week 12
No significant improvement in PANSS NSFS at any dose (50/125/500 mg) versus placebo at Week 12 in adults with persistent negative symptoms. N=256 randomized (placebo n=87, 50 mg n=58, 125 mg n=56, 500 mg n=55).
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Luvadaxistat oral tablet 20 mg or 50 mg once daily (ERUDITE Phase 2, CIAS); doses of 50/125/500 mg once daily tested in the INTERACT Phase 2 negative-symptoms study | Oral | Once daily | — |
Mechanism of action
Potent, selective, oral inhibitor of D-amino acid oxidase (DAAO / DAO), the peroxisomal flavoenzyme (EC 1.4.3.3) that catabolizes D-serine. Luvadaxistat inhibits oxidative deamination of D-serine by human recombinant DAAO with an IC50 of approximately 14 nM, thereby elevating brain, plasma and CSF D-serine. Because D-serine is an endogenous co-agonist at the glycine modulatory site of the NMDA glutamate receptor, DAAO inhibition is hypothesized to augment NMDAR signaling and address NMDAR hypofunction implicated in the negative and cognitive symptoms of schizophrenia.
| Target | Action | Affinity |
|---|---|---|
| DAAOprimaryDAO | Inhibitor | IC50 14 nMⓘ |
← Full NBI-1065844 compound page (identity, identifiers, all indications)
Sources
- ERUDITE: Phase 2 study of luvadaxistat in cognitive impairment associated with schizophrenia (NCT05182476) — ClinicalTrials.gov
- INTERACT: a randomized phase 2 study of the DAAO inhibitor luvadaxistat in adults with schizophrenia — Schizophrenia Research (PubMed)
- INTERACT: Phase 2 study of luvadaxistat (TAK-831) in negative symptoms of schizophrenia (NCT03382639) — ClinicalTrials.gov
- Luvadaxistat: A Novel Potent and Selective D-Amino Acid Oxidase Inhibitor Improves Cognitive and Social Deficits in Rodent Models for Schizophrenia — Neurochemical Research (PubMed)
- Neurocrine announces top-line results from Phase II INTERACT study of luvadaxistat (NBI-1065844) in negative symptoms and CIAS (2 Mar 2021) — Neurocrine Biosciences (PR Newswire)
- Neurocrine Biosciences Form 8-K Exhibit 99.1 - Takeda grants Neurocrine an exclusive license to seven psychiatry pipeline programs incl. luvadaxistat (Jun 2020) — U.S. Securities and Exchange Commission (EDGAR)
- Neurocrine Biosciences Provides Update on ERUDITE Phase 2 Data for Luvadaxistat — Neurocrine Biosciences (PR Newswire)