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

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

The D-amino acid oxidase inhibitor luvadaxistat improves mismatch negativity in patients with schizophrenia in a randomized trial. (PubMed, Neuropsychopharmacology) - "Thus, MMN responses after a short treatment period may predict cognitive function improvement. MMN and ASSR should be considered as biomarkers in early trials addressing NMDA receptor hypofunction."

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

Study to Evaluate the Efficacy, Safety, and Tolerability of Luvadaxistat in Subjects With Cognitive Impairment Associated With Schizophrenia Estudio para evaluar la eficacia, la seguridad y la tolerabilidad del Luvadaxistat en pacientes con deterioro cognitivo asociado a la esquizofrenia (clinicaltrialsregister.eu) - P2 | N=308 | Ongoing | Sponsor: Neurocrine Biosciences, Inc.

New P2 trial • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Mental Retardation • Psychiatry • Schizophrenia

Clinical Efficacy and Safety of Therapeutic Interventions Used in Friedreich Ataxia: A Systematic Review (ISPOR 2022) - "These publications investigated idebenone (n=11), recombinant erythropoietin (n=6), omaveloxolone (n=3), amantadine hydrochloride (n=2), and A0001, CoQ10, creatine, deferiprone, interferon-γ-1b, L-cartinine levorotatory form of 5-hydroxytryptophan, luvadaxistat, resveratrol, RT001, vatiquinone (all n=1). This SLR highlighted a considerable unmet need for treatments that improve symptoms related to ataxia and neurological symptoms in FA. Currently, novel efficacious drugs are being investigated that aim to improve these symptoms or slow down the progression of the disease."

Clinical • Review • Ataxia • Atrial Fibrillation • Cardiovascular • CNS Disorders • Friedreich ataxia • Movement Disorders • Pain • Ventricular Tachycardia • IFNG

Luvadaxistat, an Investigational D-Amino Acid Oxidase inhibitor, Was Associated with Signals of Efficacy in Cognitive Impairment Associated with Schizophrenia but Not Negative symptoms: Results from the Interact Study - P2 | "In line with past clinical experience, luvadaxistat was generally well tolerated. Study funded by Takeda Pharmaceutical Company, Ltd and Neurocrine Biosciences, Inc."

Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Insomnia • Mental Retardation • Pain • Psychiatry • Schizophrenia • Sleep Disorder

Luvadaxistat, an Investigational D-Amino Acid Oxidase inhibitor, Was Associated with Signals of Efficacy in Cognitive Impairment Associated with Schizophrenia but Not Negative symptoms: Results from the Interact Study - P2 | "In line with past clinical experience, luvadaxistat was generally well tolerated. Study funded by Takeda Pharmaceutical Company, Ltd and Neurocrine Biosciences, Inc."

Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Insomnia • Mental Retardation • Pain • Psychiatry • Schizophrenia • Sleep Disorder

Regional Comparison of Paired Ratings in a Study of Negative Symptom Schizophrenia (SIRS 2022) - P2 | " The data came from a Phase 2, 12-week, randomized, double-blind study to evaluate the efficacy and safety of 3 Dose Levels of TAK-831 in the adjunctive treatment of adult subjects with negative symptoms of schizophrenia (TAK-831-2002: ClinicalTrials.gov Identifier: NCT03382639)... The ICC was r= 0.839 for paired PANSS ratings (n=1006) and r= 0.871 for paired BNSS ratings (n=892). Bland-Altman scatterplots revealed that 4.8% of paired PANSS scores and 4.7% of paired BNSS scores were outside the confidence intervals. For all pairs, the site-based mean total BNSS and PANSS scores were significantly lower than the paired site-independent scores (p<0.0001 and p= 0.006 respectively)."

CNS Disorders • Schizophrenia

Luvadaxistat, an Investigational D-Amino Acid Oxidase inhibitor, Showed Signals of Efficacy in Cognitive Impairment Associated with Schizophrenia but Not Negative symptoms: Results from the Interact Study (SIRS 2022) - P2 | "Of the 256 participants randomized 3:2:2:2 to receive placebo, luvadaxistat 50 mg, 125 mg and 500 mg, respectively, 228 (89.1%) completed the study. Baseline demographics and characteristics were evenly distributed across treatment groups. No significant improvements in PANSS NSFS versus placebo were observed with luvadaxistat 50 mg, 125 mg or 500 mg at Week 12 (p = 0.426, p = 0.362 and p = 0.808, respectively)."

Clinical • CNS Disorders • Schizophrenia

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

Clinical • New P2 trial • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Luvadaxistat, an Investigational D-Amino Acid Oxidase Inhibitor, was Associated With Signals of Efficacy in Cognitive Impairment Associated With Schizophrenia but Not Negative Symptoms: Results From the Interact Study (ACNP 2021) - P2 | "Luvadaxistat did not show significant efficacy in the treatment of negative symptoms of schizophrenia at the three doses evaluated. For CIAS, an inverted U-shaped dose response was observed with luvadaxistat 50 mg, 125 mg and 500mg. Only luvadaxistat 50 mg showed a signal of efficacy as measured by the BACS composite score and the SCoRS interviewer total score, with a clinically meaningful effect size of 0.4 for each."

Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Insomnia • Mental Retardation • Pain • Psychiatry • Schizophrenia • Sleep Disorder