Development of a QSP Platform to Quantify Benefits of DAAO Inhibition in Schizophrenia

Hypofunctioning of the N-methyl-d-aspartate receptor (NMDAR) and reduction of the NMDAR primary coagonist, d-serine, have been associated with the pathophysiology of schizophrenia. Inhibition of d-amino acid oxidase (DAAO) results in increased d-serine and may lead to improvement in negative symptoms of schizophrenia. TAK-831, a highly selective and potent inhibitor of DAAO, increased d-serine levels in the cerebellum of mice and demonstrated a positive effect on cognition and social interaction in rodent cognition and behavioral models. In collaboration with scientists from Rosa, Takeda developed a mechanistic platform that includes plasma, cerebrospinal fluid and brain compartments, the primary site of DAAO inhibition and a cerebellar tripartite synapse for modulation of NMDAR signaling, to enable quantitative assessment of the clinical benefits of TAK-831.This webinar will discuss how the platform was developed, the result that it yielded, and the impact it had on clinical decision making.