Schizophrenia is a serious and complex syndrome with heterogeneous symptoms. As one of the leading causes of disability worldwide, it often results in significant emotional burden for those who experience symptoms, as well as their family and friends. It impacts 3.5 million people in the U.S. alone and more than 20 million people worldwide. In the U.S., there are approved treatment options for patients who experience positive symptoms of schizophrenia. Yet, roughly 50% of individuals diagnosed with schizophrenia remain untreated.
The symptoms of schizophrenia fall into three categories:
Positive symptoms – characterized by the addition of something not normally present – include sensory changes, hallucinations, and delusions. Such symptoms can result in psychotic behavior, suggesting lost sense of reality.
Negative symptoms – characterized by the absence of something – include emotional and physical disruptions, such as lack of facial expression, slowed speech patterns, decreased motivation, and withdrawal.
Cognitive impairment – include difficulty paying attention, processing information, remembering, and making decisions.
Cognitive Symptoms of Schizophrenia
Mood stabilizers, antidepressants, and stimulants are sometimes prescribed to mitigate the negative and cognitive symptoms of schizophrenia, but they have been shown to have limited effect and are not specifically indicated by the U.S. Food and Drug Administration (FDA) for this purpose. This represents a tremendous unmet need, given an estimated 80% of people with schizophrenia experience clinically relevant cognitive impairment, which is directly related to overall impact of the condition.
Luvadaxistat: An Investigational Therapy for Cognitive Impairment Associated with Schizophrenia
Luvadaxistat is a potential first-in-class, investigational selective d-amino acid oxidase (DAAO) inhibitor for the treatment of cognitive symptoms of schizophrenia. It targets glutamate, an abundant neurotransmitter in the brain. In schizophrenia, N-methyl D-aspartate (NMDA) receptor hypofunction on PV+ gamma-aminobutyric (GABA) interneurons results in disinhibition of cortical or hippocampal glutamate neurons projecting to the pyramidal neurons. The cortical disturbances account for cognitive impairment associated with schizophrenia (CIAS), while the downstream subcortical dopamine release manifests as the positive symptoms of the disorder.
Clinical Trials: Cognitive Impairment Associated with Schizophrenia
Luvadaxistat (NBI-1065844/TAK-831) was developed by Takeda Pharmaceutical Company Limited for the treatment of schizophrenia and has completed several Phase 1 trials in healthy participants. In the Phase 2 INTERACT study of adults with negative and cognitive symptoms of schizophrenia, luvadaxistat met secondary endpoints of cognitive assessment. Neurocrine Biosciences plans to initiate a Phase 2 study of luvadaxistat in adults with cognitive impairment associated with schizophrenia (CIAS) in 2021 designed to replicate the signal of cognitive improvement seen in the INTERACT study.
Valbenazine: An Investigational Add-On Treatment for Schizophrenia
Neurocrine Biosciences is developing valbenazine as an add-on treatment for schizophrenia. Increased dopamine release is known to be associated with symptoms of schizophrenia. Valbenazine’s mechanism of action may reduce dopamine release in the striatum.
NBI-1117568: An Investigational Therapy for Schizophrenia
NBI-1117568 is an oral, investigational muscarinic M4 agonist. Muscarinic receptors are central to brain function and validated as drug targets in psychosis and cognitive disorders. As a selective M4 orthosteric agonist, NBI-1117568 offers the potential for an improved safety profile without the need of combination therapy to minimize side effects and avoids the need of cooperativity with acetylcholine (ACh) when compared to non-selective muscarinic agonists and positive allosteric modulators in development.
Neurocrine Biosciences is developing NBI-1117568 as a part of a strategic collaboration and licensing agreement with Sosei Heptares, announced in November 2022. NBI-1117568 has completed multiple Phase 1 studies and Neurocrine Biosciences will initiate Phase 2 studies in patients with schizophrenia in 2022.