Luvadaxistat was an investigational oral medication studied for its potential effects on brain function. It aimed to address certain neurological conditions by targeting specific brain pathways involved in information processing.
Mechanism of Action
Luvadaxistat functions as a D-amino acid oxidase (DAAO) inhibitor. DAAO is an enzyme found in the brain, particularly in areas like the cerebellum and prefrontal cortex, which breaks down a substance called D-serine. D-serine acts as a co-agonist for N-methyl-D-aspartate (NMDA) receptors, which are specialized proteins on nerve cells. These receptors are involved in various brain processes, including learning, memory formation, and overall cognitive function.
By blocking DAAO, luvadaxistat was designed to increase D-serine levels in the brain, particularly in the synaptic cleft where nerve cells communicate. This increase was intended to boost the activity of NMDA receptors, which are hypothesized to be underactive in certain neurological disorders. Early studies showed luvadaxistat could significantly increase D-serine levels in rodent brains, plasma, and cerebrospinal fluid.
Investigated Medical Uses
The primary condition luvadaxistat was developed to treat was Cognitive Impairment Associated with Schizophrenia (CIAS). CIAS refers to the difficulties with memory, attention, problem-solving, and other mental processes that many individuals with schizophrenia experience. These cognitive deficits can significantly impact a person’s ability to function in daily life, affecting employment, social interactions, and overall independence.
Current treatments for schizophrenia primarily target positive symptoms, such as hallucinations and delusions, but often do not adequately address these cognitive challenges. This creates a substantial unmet medical need, and luvadaxistat was investigated as a potential new approach to improve cognitive function in people living with schizophrenia.
Clinical Trial Findings
Early-phase trials, specifically the INTERACT Phase 2 study, showed results for luvadaxistat in improving cognitive function. While the INTERACT study did not meet its primary endpoint for negative symptoms of schizophrenia, a 50 mg dose of luvadaxistat showed statistically significant improvement in secondary endpoints related to cognitive performance, as measured by the Brief Assessment of Cognition in Schizophrenia (BACS) and the Schizophrenia Cognition Rating Scale (SCoRS). These initial findings suggested a potential benefit for cognitive impairment associated with schizophrenia, encouraging further investigation.
Later, a second Phase 2 trial, known as the ERUDITE study, was conducted to further evaluate luvadaxistat for CIAS, with cognitive improvement as its primary endpoint. However, this study failed to meet its primary endpoint, meaning luvadaxistat did not show a statistically significant improvement in cognitive function compared to placebo in this larger trial. The inability to replicate the earlier positive cognitive results was attributed in part to significant variability in cognitive measures across the study population and potential imbalances in baseline characteristics among the treatment groups.
Safety and Side Effects
Throughout its clinical development, luvadaxistat was well-tolerated by participants in the trials. The safety profiles observed were consistent across various studies, indicating no new or unexpected safety signals.
Commonly reported side effects were mild to moderate in severity, including headache, dizziness, and nausea. The discontinuation of luvadaxistat’s development was not due to significant safety concerns or severe adverse events, but rather a lack of demonstrated effectiveness in its later-stage clinical trials.
Current Development Status
The development of luvadaxistat was officially discontinued by Neurocrine Biosciences, in collaboration with Takeda Pharmaceutical Company, in 2024. This decision came after the ERUDITE Phase 2 clinical study failed to meet its primary endpoint for improving cognitive impairment associated with schizophrenia.
The inability to consistently replicate the cognitive benefits seen in earlier studies led to the halt of further development. As a result, luvadaxistat is no longer being pursued as a treatment and is not available for clinical use.