luvadaxistat (NBI-1065844) / Takeda, Neurocrine Biosciences - LARVOL DELTA

In Vivo Rodent Studies with the Novel PET Tracer [18F]PGM028299: An Inhibitor of D-Amino Acid Oxidase. (PubMed, J Med Chem) - "Enzyme occupancy studies in rodents showed that [18F]2 is a displaceable ligand, with binding blocked dose dependently by the DAAO inhibitor luvadaxistat...Human dosimetry estimates indicated a favorable safety profile. These findings support [18F]2 as a promising PET tracer for in vivo DAAO imaging."

Journal • Preclinical • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

Exploratory anchor-based analyses to determine minimal clinically important differences for the Brief Assessment of Cognition in Schizophrenia and the Schizophrenia Cognition Rating Scale. (PubMed, Schizophr Res) - "Results suggest that a 2- to 4-point difference in BACS composite score and a 3- to 5-point difference in SCoRS interviewer total score may be clinically meaningful in cognitive impairment in schizophrenia."

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

Synthesis and evaluation of 18F-PGM028299: A novel PET ligand for in vivo delineation of D Amino Acid Oxidase (SNMMI 2026) - " Ex-vivo enzyme occupancy studies measured by LC-MS/MS were performed in C57BL/6J mice and Sprague Dawley rats using PGM028299 and DAAO inhibitor, luvadaxistat... 18F‑PGM028299 is a selective tracer for in vivo imaging of DAAO in rodents and offers a future tool for imaging DAAO in humans using PET."

Preclinical • CNS Disorders • Mental Retardation • Schizophrenia

D-Amino Acid Oxidase Occupancy and Pharmacodynamic Effects of Luvadaxistat (TAK-831) in the Human Brain: A Combined PET and Functional MRI Study (SNMMI 2026) - "18F‑PGM028299 PET is the only available PET radioligand for the evaluation of DAAO expression in the human brain. The imaging characteristics of 18F‑PGM028299 were sufficient to evaluate the interaction of a novel drug candidate, luvadaxistat, with DAAO in the human brain and produce acceptable occupancy estimates that correlated with functional brain measures."

PK/PD data • CNS Disorders • Mental Retardation • Schizophrenia

Synthesis and evaluation of 18F-PGM028299: A novel PET ligand for in vivo delineation of D Amino Acid Oxidase (SNMMI 2026) - " Ex-vivo enzyme occupancy studies measured by LC-MS/MS were performed in C57BL/6J mice and Sprague Dawley rats using PGM028299 and DAAO inhibitor, luvadaxistat... 18F‑PGM028299 is a selective tracer for in vivo imaging of DAAO in rodents and offers a future tool for imaging DAAO in humans using PET."

Preclinical • CNS Disorders • Mental Retardation • Schizophrenia

A phase 2 randomized controlled trial of luvadaxistat in treatment of adults with cognitive impairment associated with schizophrenia: results from the ERUDITE study. (PubMed, Neuropsychopharmacology) - P2 | "Luvadaxistat 20 mg or 50 mg did not show statistically significant changes in cognitive performance or functioning within the ERUDITE study. Trial registration: ClinicalTrials.gov identifier NCT05182476."

Clinical • Journal • P2 data • Alzheimer's Disease • CNS Disorders • Cognitive 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

Inhibition of D-Amino Acid Oxidase as a Novel Approach to Enhance Cognitive Function in Schizophrenia and Other Cognitive Disorders (WFSBP 2025) - "In addition to sodium benzoate, other DAAO inhibitors are promising; for example, luvadaxistat was also found to improve cognitive function of schizophrenia patients (Kuo et al., CNS Drugs 2022; Murthy et al., Schizophr Res 2024). If these findings can be reconfirmed, DAO inhibition and related pathways may instill hope for the treatment of cognitive impairment in schizophrenia and other cognitive disorders."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Depression • Psychiatry • Schizophrenia • CAT

Symptomatic and cognitive effects of D-amino acid oxidase inhibitors in patients with schizophrenia: a meta-analysis of double-blind randomized controlled trials. (PubMed, Schizophrenia (Heidelb)) - "Four trials utilized sodium benzoate, while one trial employed luvadaxistat...The findings of this meta-analysis suggest that DAOI may be effective in improving clinical symptoms and cognitive function in patients with schizophrenia. Further studies with larger sample sizes are needed to confirm these results."

Clinical • Journal • Retrospective data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Evolution of D-amino acid oxidase inhibitors: From concept to clinic. (PubMed, Adv Pharmacol) - "Some of these inhibitors were investigated in a range of preclinical in vivo studies to assess pharmacokinetics, pharmacodynamics, and behavioral pharmacology. Most importantly, these efforts culminated with the discovery of TAK-831 (luvadaxistat), an orally available brain-penetrant DAAO inhibitor currently under clinical development, representing a true bench-to-bedside success in this field."

Journal • Review • CNS Disorders • Neuralgia • Pain • Psychiatry • Schizophrenia

Therapeutic potential of D-amino acid oxidase inhibitors for cognitive impairment associated with schizophrenia: learnings from luvadaxistat. (PubMed, Int J Neuropsychopharmacol) - "In this review, we provide an overview of the evidence supporting the potential of NMDAR modulators in general, and DAAO inhibitors in particular, as potential adjunctive treatments for schizophrenia. We also discuss the preclinical and clinical data related to luvadaxistat, an investigational highly selective and potent DAAO inhibitor that was under development for the treatment of the cognitive impairment associated with schizophrenia."

Biomarker • Clinical • Journal • Observational data • Retrospective data • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

ERUDITE: Study to Evaluate the Efficacy, Safety, and Tolerability of Luvadaxistat in Participants With Cognitive Impairment Associated With Schizophrenia (clinicaltrials.gov) - P2 | N=216 | Terminated | Sponsor: Neurocrine Biosciences | Active, not recruiting ➔ Terminated; Failed to meet the primary endpoint

Trial termination • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

A Systematic Literature Review on the Efficacy of Pharmacological Interventions in Ataxia (ISPOR-EU 2024) - "Across these, idebenone and riluzole (2 studies each) were the most commonly assessed interventions, followed by one study each for amantadine hydrochloride, deferiprone, luvadaxistat, omaveloxolone, rovatirelin, and troriluzole. Limited therapeutic options are available for ataxia, often focusing on symptomatic management rather than addressing the underlying cause. This SLR underscores a notable gap in treatments that directly target ataxia and highlights the potential pharmacological treatments in treating ataxia or slowing its progression."

Clinical • Review • Ataxia • CNS Disorders • Friedreich ataxia • Movement Disorders

Neurocrine Biosciences Provides Update on ERUDITE Phase 2 Data for Luvadaxistat in Adults with Cognitive Impairment Associated with Schizophrenia (PRNewswire) - P2 | N=216 | ERUDITE (NCT05182476) | Sponsor: Neurocrine Biosciences | "Neurocrine Biosciences, Inc...today announced that its ERUDITE Phase 2 clinical study of investigational compound luvadaxistat (NBI-1065844) failed to meet its primary endpoint as a potential treatment to improve cognitive impairment in patients with schizophrenia....The ERUDITE study was the second Phase 2 trial for luvadaxistat. It failed to replicate the cognitive endpoints data seen in the earlier INTERACT study, due in part to the large variability seen in the cognitive measures across the population studied and a potential imbalance in the baseline characteristics of subjects enrolled across the treatment arms....We therefore plan to halt further development of luvadaxistat at this time and instead will focus our efforts and resources on the advancement into Phase 3 clinical development of NBI-1117568 for schizophrenia and NBI-1065845 for major depressive disorder."

New P3 trial • P2 data • Major Depressive Disorder • Schizophrenia

Finding the right dose: NMDAR modulating treatments for cognitive and plasticity deficits in schizophrenia and the role of pharmacodynamic target engagement. (PubMed, Biol Psychiatry) - "A range of direct and indirect NMDAR modulators will be covered, including d-serine, d-cycloserine, memantine, glycine and "first generation" glycine transport inhibitors (GTI, e.g. sarcosine and bitopertin), as well as recent positive studies of iclepertin, a novel GTI and luvadaxistat, a D-amino acid oxidase inhibitor (DAAO-I) that increases brain d-serine levels and indirect non-invasive brain stimulation NMDAR modulating treatments. Several examples of successful use of pharmacodynamic target engagement biomarkers for dose/drug discovery will be emphasized, including mismatch negativity (MMN), auditory steady state (ASSR) and time-frequency event-related potential (TF-ERP) approaches."

Journal • PK/PD data • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Pharmacological Treatment of Cognitive Impairment Associated With Schizophrenia: State of the Art and Future Perspectives. (PubMed, Schizophr Bull Open) - "In particular, the effects on CIAS of antipsychotic medications, anticholinergic medications, benzodiazepines, which are currently commonly used in the treatment of SSD, and of iclepertin, d-serine, luvadaxistat, xanomeline-trospium, ulotaront, anti-inflammatory molecules, and oxytocin, which are undergoing regulatory trials or can be considered as experimental agents, will be reported and discussed. Some molecules that are currently being investigated in Phase 2 and Phase 3 trials have provided very promising preliminary results, but more information is currently required to assess their effectiveness in real-world contexts and to provide clear recommendations regarding their use in clinical practice. The results of ongoing and future studies will reveal whether any of these molecules represents the awaited pharmacological game-changer in the treatment of CIAS."

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

INTERACT: a randomized phase 2 study of the DAAO inhibitor luvadaxistat in adults with schizophrenia. (PubMed, Schizophr Res) - P2 | "Luvadaxistat was well-tolerated in INTERACT, with no new safety signals observed. ClinicalTrials.gov: NCT03382639."

Journal • P2 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Novel Treatment with Multi-targets for Clozapine-resistant Schizophrenia: Modulation of NMDA Receptor, D-Amino Acids, and Related Pathways (WFSBP 2024) - "In addition to sodium benzoate, other DAAO inhibitors are promising; for example, luvadaxistat was found to be able to improve cognitive function of schizophrenia patients (Kuo et al., CNS Drugs 2022). If these findings can be reconfirmed, modulation of NMDAR, D-amino acids, and related pathways may instill hope for the treatment of the most resistant schizophrenia. However, 6-week benzoate treatment (at doses of 1 and 2 gm/day) still didn’t improve cognitive function of clozapine-resistant patients (Lin et al., Biol Psychiatry 2018). More novel approaches are needed to develop effective therapies for the cognitive dysfunction in clozapine-resistant patients (Lin & Lane, Schizophr Res 2023 [Invited Commentary])."

CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Meta-Analysis of Adjunctive Treatment Trials for Cognitive Deficits in Schizophrenia (SOBP 2024) - "For NMDAR-modulators, the largest significant effects were for luvadaxistat (d=0.44, p=0.01) and iclepertin (d=0.34, p=0.01). Published results for the alpha-7 encenicline (d=1.04, p<0.001) were highly significant, but results for the subsequent negative phase III studies are unavailable... These results highlight the potential efficacy of specific add-on mechanisms and encourage further clinical development. Overall effect sizes were similar across MoA, suggesting that significance for NMDAR modulators is presumably driven by the larger number of studies. Nevertheless, effect sizes were generally small, suggesting possible ceiling effects or the need for combined behavioral/pharmacological treatments."

Retrospective data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

ERUDITE: Study to Evaluate the Efficacy, Safety, and Tolerability of Luvadaxistat in Participants With Cognitive Impairment Associated With Schizophrenia (clinicaltrials.gov) - P2 | N=200 | Active, not recruiting | Sponsor: Neurocrine Biosciences | Recruiting ➔ Active, not recruiting | Trial primary completion date: Feb 2024 ➔ Jul 2024

Enrollment closed • Trial primary completion date • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Incorporating Digital Health Technology Tools in Study Design to Assess Medication Adherence in Schizophrenia Trials (SIRS 2024) - "Of the 304 enrolled subjects, 256 subjects were randomized and 169 subjects were assigned to take luvadaxistat. Of the 256 randomized subjects, 254 (83.5%; 254/304) have Platform data for analysis. Within the SLBI period, the average adherence to Platform use of those who did not qualify for the DB period was ~71%."

Adherence • CNS Disorders • Schizophrenia

Novel Compounds in the Treatment of Schizophrenia-A Selective Review. (PubMed, Brain Sci) - "We discuss ten novel drugs, three of which have been approved by the FDA (Olanzapine/Samidorphan, Lumateperone, and Pimavanserin). The rest are under clinical trial investigation (Brilaroxazine, Xanomeline/Trospium, Emraclidine, Ulotaront, Sodium Benzoate, Luvadaxistat, and Iclepertin). However, additional basic and clinical research is required not only to improve our understanding of the neurobiology and the potential novel targets in the treatment of schizophrenia, but also to establish more effective therapeutical interventions for the syndrome, including the attenuation of negative and cognitive symptoms and avoiding dopamine blockade-related adverse effects."

Journal • Review • CNS Disorders • Psychiatry • Schizophrenia

ERUDITE: Study to Evaluate the Efficacy, Safety, and Tolerability of Luvadaxistat in Participants With Cognitive Impairment Associated With Schizophrenia (clinicaltrials.gov) - P2 | N=200 | Recruiting | Sponsor: Neurocrine Biosciences | N=308 ➔ 200

Enrollment change • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Luvadaxistat: A Novel Potent and Selective D-Amino Acid Oxidase Inhibitor Improves Cognitive and Social Deficits in Rodent Models for Schizophrenia. (PubMed, Neurochem Res) - "While luvadaxistat ameliorated the deficit seen in sociability in two different negative symptom tests of social interaction, it failed to show an effect in endpoints of negative symptoms in clinical trials. These results suggest that luvadaxistat potentially could be used to improve cognitive impairment in patients with schizophrenia, which is not well addressed with current antipsychotic medications."

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

Clinical evidence of interventions assessed in Friedreich ataxia: a systematic review. (PubMed, Ther Adv Rare Dis) - "The most frequently identified therapeutic intervention was idebenone (n = 11), followed by recombinant erythropoietin (n = 6), omaveloxolone (n = 3), and amantadine hydrochloride (n = 2). Other therapeutic interventions were investigated in one publication: A0001, CoQ10, creatine, deferiprone, interferon-γ-1b, the L-carnitine levorotatory form of 5-hydroxytryptophan, luvadaxistat, resveratrol, RT001, and vatiquinone (EPI-743)...Identified literature showed a considerable unmet need for therapeutic interventions that halt or slow the deteriorating nature of FA. Novel efficacious drugs should be investigated that aim to improve symptoms or slow disease progression."

Journal • Review • Ataxia • Atrial Fibrillation • Cardiovascular • CNS Disorders • Friedreich ataxia • Movement Disorders • Rare Diseases • Ventricular Tachycardia • IFNG