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

Abstract Introduction Cognitive impairment is a major determinant of poor functional outcome in schizophrenia and there are currently no available pharmacotherapies. Deficits glutamatergic signaling play key role the neuropathology cognitive symptoms. Iclepertin (BI 425809), an inhibitor glycine transporter-1, enhances by increasing synaptic levels N -methyl-D-aspartate receptor co-agonist, glycine. A 12-week, Phase II trial (NCT02832037) 509 patients with demonstrated that iclepertin was well tolerated significantly improved cognition. The III CONNEX program aims to confirm efficacy, safety, tolerability improving cognition functioning larger cohort patients. Methods consists three replicate randomized, double-blind, placebo-controlled parallel-group trials (NCT04846868, NCT04846881, NCT04860830) stable on antipsychotic treatment. Each recruit ~586 patients, 18–50 years old, treated 1–2 medications (≥12 weeks current drug; ≥35 days dose prior treatment), who have day-to-day activities, interact ≥1 hour per week designated study partner. Patients due developmental, neurological, or other disorders, receiving remediation therapy within 12 screening, will be excluded. recruited from multiple centers across 32 countries Asia, North South America, Europe, randomized 1:1 receive either oral 10 mg (n=293), placebo (n=293) once daily over 26 weeks. primary efficacy endpoint change baseline (CfB) MATRICS Consensus Battery overall composite T-score. Key secondary endpoints CfB Schizophrenia Cognition Rating Scale total score adjusted time Virtual Reality Functional Capacity Assessment Tool. Long-term safety data collected open-label extension (CONNEX-X). Results studies recruiting (first enrolled Aug–Sept 2021), completion expected Q2 2024. Here we present overview status, including any information relating screening failures, experience collecting these as part large multi-country, multi-center study. Conclusion To date, most large, industry-sponsored testing various compounds address function failed show proof-of-clinical concept. Demonstration this would provide important insight into glutamate symptoms may also relevance for disorders. represent first efficacious medication associated schizophrenia. Funding Boehringer Ingelheim International GmbH (1346-0011, NCT04846868; 1346-0012, NCT04846881; 1346-0013,