Development of the novel GlyT1 inhibitor, iclepertin (BI 425809), for the treatment of cognitive impairment associated with schizophrenia

• Published in: European archives of psychiatry and clinical neuroscience Vol. 273; no. 7; pp. 1557 - 1566
• Main Authors: Rosenbrock, Holger, Desch, Michael, Wunderlich, Glen
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2023; Springer; Springer Nature B.V
• Subjects: Antipsychotic drugs; Antipsychotics; Cognitive ability; Delusional disorder; Delusions; Drug therapy; Executive function; Glycine; Glycine transporter; Invited Review; Medicine; Medicine & Public Health; Mental disorders; Neurophysiology; Neurosciences; Psychiatry; Schizophrenia; Short term memory; Withdrawal; Schizophrenia; BI 425809; NMDA receptor; GlyT1 inhibitor; Iclepertin; Cognitive impairment
• ISSN: 0940-1334; 1433-8491
• DOI: 10.1007/s00406-023-01576-z

Schizophrenia is a psychiatric disorder characterised by symptoms in three domains: positive (e.g. delusions, hallucinations), negative (e.g. social withdrawal, lack of motivation) and cognitive (e.g. working memory and executive function impairment). Cognitive impairment associated with schizophrenia (CIAS) is a major burden for patients and negatively impacts many aspects of a patient’s life. Antipsychotics are the standard-of-care treatment for schizophrenia but only address positive symptoms. So far there are no approved pharmacotherapies for the treatment of CIAS. Iclepertin (BI 425809) is a novel, potent and selective glycine transporter 1 (GlyT1) inhibitor, under development by Boehringer Ingelheim for the treatment of CIAS. Phase I studies have shown it to be safe and well tolerated in healthy volunteers, and central target engagement (inhibition of GlyT1) was achieved in a dose-dependent manner from 5 to 50 mg in healthy volunteers. A Phase II study has demonstrated that iclepertin is safe and well tolerated in patients with schizophrenia and improves cognition at doses of 10 mg and 25 mg. Phase III studies are ongoing to confirm these initial positive safety and efficacy findings with the 10 mg dose, and if successful, iclepertin could become the first approved pharmacotherapy used to treat CIAS.