Novel glycine transporter inhibitor effective for improving cognition in schizophrenia

A novel glycine transporter inhibitor improved cognition after 12 weeks among individuals with schizophrenia, according to results of a double-blind, randomized, placebo-controlled phase 2 study published in The Lancet Psychiatry.

“BI 425809 is a novel, potent and selective GlyT1 inhibitor that has been shown to increase extracellular glycine in the cerebrospinal fluid of rodents and healthy volunteers, showing functional target engagement and supporting a potential therapeutic mechanism for cognitive impairment associated with schizophrenia,” W. Wolfgang Fleischhacker, MD, of the Medical University Innsbruck in Austria, and colleagues wrote. “In addition, BI 425809 was well tolerated at doses up to 75 mg in white and Asian healthy volunteers.”

Although cognitive impairment linked to schizophrenia predicts poor functional outcomes, no approved pharmacotherapy is currently available. In the current study, the investigators aimed to assess whether BI 425809 improved cognition in this patient population. They randomly assigned 509 outpatients with schizophrenia aged 18 to 50 years who were on stable treatment to add-on once-daily oral BI 425809 2 mg, 5 mg, 10 mg or 25 mg or placebo for 12 weeks, with interactive response technology used to assign treatment in blocks. A total of 444 (87%) participants completed the 12-week treatment. Change from baseline in MATRICS Consensus Cognitive Battery (MCCB) overall composite T score at week 12 served as the primary endpoint. Fleischhacker and colleagues evaluated six predefined dose-response models and monitored adverse events.

Results showed a statistically significant benefit of BI 425809 over placebo in five of six dose-response models. The researchers noted greater mean improvement in pairwise comparisons from baseline in MCCB overall composite T score at week 12 with BI 425809 10 mg and 25 mg vs. placebo, with an adjusted mean difference of 1.8 for 10 mg and 1.73 for 25 mg. Across groups, adverse events were balanced and experienced by 59% of patients on BI 425809 2 mg, 52% on 5 mg, 41% on 10 mg, 42% on 25 mg and 44% on placebo.

“BI 425809 was generally well tolerated, with no significant differences in psychiatric adverse events or suicidal ideation and behavior observed between treatment groups,” Fleischhacker and colleagues wrote.