The Effect of Iclepertin on Hematological Parameters: An Overview of Nonclinical Studies and Clinical Trials in Healthy Volunteers and Patients with Cognitive Impairment Associated with Schizophrenia

There are currently no approved pharmacotherapies to treat cognitive impairment associated with schizophrenia (CIAS). Iclepertin (BI 425809) is a selective glycine transporter-1 (GlyT1) inhibitor that was investigated for the treatment of CIAS. As hemoglobin reduction is considered a class effect of GlyT1 inhibitors, nonclinical studies and clinical trials were assessed to determine if this effect applied to iclepertin. Nonclinical studies of iclepertin-treated rodents demonstrated a reversible reduction in hemoglobin versus vehicle-control animals. Pooled Phase I data from healthy volunteers (N = 391) showed no clinically relevant changes in hemoglobin. Analysis of Phase II, 12-week, randomized-controlled trials in patients with CIAS (N = 709) receiving placebo or iclepertin 2, 5, 10, or 25 mg demonstrated a small hemoglobin decrease in the 10-mg group and, in the 25-mg group, a dose- and pharmacokinetic-dependent, mild hemoglobin decrease that recovered slightly at post-treatment follow-up (Week 16). Pooled data from the Phase III CONNEX trial program, which included three 26-week, randomized-controlled trials (N = 1835), and one 52-week open-label extension (N = 1356) in patients with CIAS, showed that iclepertin was well-tolerated. In placebo-treated patients, hemoglobin concentration was stable, with small fluctuations over 26 weeks. In iclepertin-treated patients, hemoglobin concentration dropped within the first 18 weeks (mean change vs baseline, -2.4 g/L) and remained stable until the end of treatment (≤78 weeks). As the primary and secondary CIAS efficacy endpoints were not met, the CONNEX trial program was terminated. Findings from these nonclinical studies and clinical trials suggest reversible mean hemoglobin reductions were of limited significance and iclepertin was well-tolerated with a consistent safety profile.