Efficacy and Safety of Iclepertin (BI 425809) in Patients With Schizophrenia: CONNEX, a Phase III Randomized Controlled Trial Program

Abstract: Introduction No effective pharmacological treatments are available for cognitive impairments in schizophrenia. Iclepertin (BI 425809), an inhibitor of glycine transporter-1, enhances glutamate N-methyl-D-aspartate receptor signaling by increasing synaptic levels of its co-agonist, glycine. The Phase III CONNEX program aims to confirm efficacy, safety and tolerability of iclepertin in improving cognition and functioning across a large cohort of patients with schizophrenia. Methods The CONNEX program consists of 3 replicate randomized, double-blind, placebo-controlled parallel trials in patients diagnosed with schizophrenia (NCT04846868, NCT04846881, NCT04860830). 586 patients per trial are being recruited from 32 countries and randomized 1:1 to receive iclepertin 10 mg, or placebo daily over 26 weeks. Primary efficacy endpoint: change from baseline (CfB) in overall composite T-score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery. Key secondary efficacy endpoints: CfB in total score on the Schizophrenia Cognition Rating Scale, and CfB in the adjusted total time in the Virtual Reality Functional Capacity Assessment Tool. Long-term safety/tolerability data will be collected in an open-label safety extension study (CONNEX-X). Results The studies are currently recruiting (first patients enrolled August–September 2021), with completion expected in Q2 2024. An overview will be provided of the current study status, including screening failures and data collection experiences. Conclusions Currently, most large industry-sponsored studies testing compounds for cognitive deficits have failed to show proof-of-clinical concept. Demonstration of efficacy in this Phase III program would establish iclepertin as the first efficacious medication to address cognitive impairments and functioning in schizophrenia.Short Description: Cognitive impairment is a major determinant of poor functional outcome in schizophrenia. Currently, studies testing potential treatments for cognitive impairment have failed to demonstrate proof-of-clinical concept. These Phase III multinational CONNEX trials aim to confirm efficacy, safety and tolerability of iclepertin (BI 425809) in improving cognition and functioning across a large cohort of people with schizophrenia. Demonstration of efficacy would establish iclepertin as the first efficacious medication to address cognitive impairment and functioning in schizophrenia.Name of Sponsoring Organization(s): Boehringer Ingelheim International GmbH