Iclepertin Found Ineffective in Treating Cognitive Impairment Associated With Schizophrenia

In an analysis of 3 phase 3 trials, iclepertin showed no significant improvement in cognitive impairment for adults with schizophrenia.¹ The drug was well tolerated but did not result in significant changes in cognition in patients with schizophrenia.

The analysis included the CONNEX 1, 2, and 3, trials—all randomized, double-blind, placebo-controlled phase 3 studies conducted across 41 countries. Patients included were aged 18 to 50 years (mean 34.7 years), with 1835 patients receiving at least 1 dose of the medication and 1602 patients completing treatment. Of the total number of recruited patients across all 3 trials, 1207 (66%) were male and 629 (34%) were female, 903 (49%) were White, 558 (30%) were Asian, and 67% were not Hispanic or Latino.

Eligible patients had a diagnosis of schizophrenia based on the DSM-5, functional impairment (as judged by the investigator), a mild to moderate severity of positive symptoms on the Positive and Negative Syndrome Scale, and were being treated with a stable dose of 1 or 2 antipsychotic medications (excluding clozapine). At baseline, 70% of patients were taking 1 antipsychotic, and 30% were taking 2 antipsychotics. Some patients were taking other medications in addition to study medication/placebo, including antidepressants (27%), anticholinergics (15%), benzodiazepines and their derivatives (20%), and antiepileptics (5%). Patients were excluded who had a DSM-5 diagnosis other than schizophrenia, cognitive impairment for reasons other than schizophrenia, suicidal behavior in the last year, suicidal ideation type 5 on the Columbia Suicide Severity Rating Scale in the last 3 months, or a history of moderate to severe substance use disorder (as defined by the DSM-5).

Patients were randomized 1:1 to oral iclepertin 10 mg or placebo once daily for 26 weeks. The primary endpoint was change from baseline at week 26, as measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) overall composite T-score. Efficacy analysis was conducted on randomly selected patients, and safety and tolerability assessments included monitoring adverse events. Secondary endpoints included change from baseline at week 26 in the Schizophrenia Cognition Rating Scale (SCoRS) and Virtual Reality Functional Capacity Assessment Tool adjusted total time T-score, as well as change in Patient Reported Experience of Cognitive Impairment in Schizophrenia total score at week 24.

At week 26, there was no significant difference between treatment and placebo groups in individual trials or the pooled population. The adjusted mean difference for drug vs placebo in MCCB overall composite T-score was 0.127 (P=0.63). Primary analysis showed adjusted mean change from baseline MCCB score was 2.293 for iclepertin vs 2.166 for placebo. Secondary analysis of SCoRS total score was not statistically different between treatment and placebo groups in individual trials or pooled trial data. Adverse effects were reported in 66% of the treatment group and 69% of the placebo group. The most common adverse events reported were nervous system disorders (headache, insomnolence, dizziness), and psychiatric disorders (schizophrenia, insomnia). One patient in the placebo group died during the trial due to antipsychotic overdose, and 2 died during the follow-up period due to cardiorespiratory arrest and drug overdose, respectively; all mortality was deemed unrelated to the trial. Iclepertin was tolerated in the treatment group, with a safety profile consistent with phase 2 research findings.²

Iclepertin is a novel selective glycine transporter-1 (GlyT1) inhibitor that has been associated with procognitive effects in rodents, like improvement and working and social recognition memory.¹ Schizophrenia symptoms like cognitive impairment have been hypothesized to be related to NMDA receptor hypofunction leading to excitatory-inhibitory imbalance.³ With GlyT1 inhibitors, the goal is to increase synaptic glycine levels and therefore enhance glutaminergic signaling by blocking glycine reuptake.³

Investigators stated that “increasing the NMDA receptor co-agonists glycine or D-serine to normalize deficits in NMDA receptor function may not be sufficient for treating cognitive impairment in schizophrenia in the broad population of patients with schizophrenia.”¹ There are currently no approved pharmacological treatments for cognitive impairment in schizophrenia.

References

1. Keefe RSE, Harvey PD, Correll CU, et al. Efficacy and safety of iclepertin for cognitive impairment associated with schizophrenia (CONNEX programme): results from the three phase 3 randomised controlled trials. Lancet Psychiatry. 2025;12(12):906-920.

2. Fleischhacker WW, Podhorna J, Groschl M, et al. Efficacy and safety of the novel glycine transporter inhibitor BI 425809 once daily in patients with schizophrenia: a double-blind, randomized, placebo-controlled phase 2 study. Lancet Psychiatry. 2021;8(3):191-201.

3. Rosenbrock H, Desch M, Wunderlich G. Development of the novel GlyT1 inhibitor, iclepertin (BI 425809), for the treatment of cognitive impairment associated with schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2023;273(7):1557-1566.