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

Introduction: No effective pharmacological treatments are available for cognitive impairments in schizophrenia. Iclepertin (BI 425809), a glycine transporter-1 inhibitor, enhances N-methyl-D-aspartate receptor signaling by increasing synaptic levels of its co-agonist, glycine. In a Phase II proof-of-clinical-concept trial (NCT02832037) iclepertin was well tolerated and improved cognition in schizophrenia.

Aims: The Phase III CONNEX program aims to confirm efficacy and safety of iclepertin in improving cognition/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 with schizophrenia. 586 patients/trial will be recruited across 41 countries, and randomized 1:1 to receive daily iclepertin 10 mg or placebo 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 Schizophrenia Cognition Rating Scale score; 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 participants enrolled Aug–Sept 2021), with completion expected in Q1 2025. Current study status, including screening failures and data collection experiences, are presented.

Conclusions: Most industry-sponsored studies testing compounds for cognitive deficits have failed to show proof-of-clinical-concept. If successful, the CONNEX program would provide evidence for iclepertin as the first efficacious medication addressing cognitive impairments in schizophrenia.

Funding: Boehringer Ingelheim Pharmaceuticals, Inc. (NCT04846868/1346-0011, NCT04846881/1346-0012, NCT04860830/1346-0013).