Disappointing Data From Phase III CONNEX for Iclepertin in Addressing Cognition Impairment in Schizophrenia

Author(s):

Heidi Anne Duerr, MPH

Key Takeaways

Iclepertin showed no significant cognitive or functional improvement in schizophrenia patients compared to placebo in the phase III study.
Despite disappointing results, iclepertin was well tolerated, and Boehringer Ingelheim continues to pursue psychiatric disorder treatments.
The CONNEX-3 trial was a double-blind, placebo-controlled study focusing on iclepertin's efficacy and safety in stable schizophrenia patients.
Addressing cognitive impairment in schizophrenia remains a critical unmet need, with GlyT1 inhibitors showing potential in earlier studies.

Although iclepertin was found to be well tolerated, the agent did not meet endpoints.

Chepko Danil/Adobestock

BREAKING NEWS

Data from the phase III study for iclepertin in addressing cognition impairment in adults with schizophrenia found “no statistically significant effects on cognition or functioning were observed in patients treated with iclepertin versus placebo at six months,” according to Boehringer Ingelheim.¹ On the positive side, all 3 studies of CONNEX indicated iclepertin was well tolerated. Iclepertin (BI 425809) is an investigational oral inhibitor of glycine transporter 1 (GlyT1) thought to influence brain biology and address cognition deficits in schizophrenia and potentially other disorders.

Although the results were not as expected, Boehringer Ingelheim remains committed to addressing psychiatric disorders and improving the care and lives of patients. “While these findings are disappointing, we remain dedicated to finding effective solutions for those living with serious mental illnesses,” Shashank Deshpande, member of the board of Managing Directors and head of Human Pharma at Boehringer Ingelheim, said in a press release.¹ “Our innovative pipeline includes over 20 additional investigative therapies in all stages of development and in different disease areas including schizophrenia and major depressive disorder."

CONNEX-3 was a randomized, double-blind, placebo-controlled, parallel group trial looking at the efficacy and safety of iclepertin 10 mg once daily in patients with schizophrenia and cognitive impairment.² To be included in the trial, patients had to be clinically stable (not in an acute phase of their illness). Participants had to be maintained on an antipsychotic for at least 12 weeks and on their current dose for at least 35 days prior to randomization. Onset of disease for patients was between the ages of 18 years and 50. All women of childbearing potential were required to be on highly effective birth control; those who were pregnant or nursing were excluded from the study. Similarly, patients with suicidal ideation or behavior were excluded. The study excluded patients who had received clozapine, stimulants, ketamine, or electroconvulsive therapy within 6 months before to randomization. Additional inclusion and exclusion criteria were noted.

In the study, patients were randomized to receive the agent or a similarly looking placebo once daily over a 26 week period. Efficacy was measured using changes from baseline on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus cognitive battery (MCCB). Patients were allowed to continue any other medicatoion for schizophrenia throughout the trial.

Last year, Psychiatric Times editor in chief, John. J. Miller, MD, discussed the clinical signifance of iclerpertin in the medication pipeline for schizophrenia, noting the need for agents that address cognitive impairment associated with schizophrenia. “Progressive cognitive impairment can occur in most serious mental illnesses and is a primary subsyndrome in schizophrenia,” he said. “With a trail of failed clinical trials by other agents, the GlyT1 inhibitors have demonstrated some efficacy with 2 earlier members of this class: sarcosine and bitopertin. It would be a huge step forward if iclepertin demonstrated statistical clinical efficacy in the improvement of cognitive symptoms in schizophrenia, which remains a significant unmet need.”³

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References

1. Boehringer provides update on iclepertin Phase III program in schizophrenia. Press release. January 16, 2025. Accessed January 16, 2025. https://www.globenewswire.com/news-release/2025/01/16/3010915/0/en/Boehringer-provides-update-on-iclepertin-Phase-III-program-in-schizophrenia.html

2. CONNEX-3: A Study to Test Whether Iclepertin Improves Learning and Memory in People With Schizophrenia. Accessed January 16, 2025. https://clinicaltrials.gov/study/NCT04860830.

3. Miller JJM. Medication Pipeline: Schizophrenia and PTSD. Psychiatric Times. 2024; 41(1).