Iclepertin Fails to Improve Cognition in Schizophrenia Phase 3 Study

Shashank Deshpande

Credit: LinkedIn

Boehringer Ingelheim announced today that iclepertin for schizophrenia in their phase 3 trial did not bring statistically significant effects on cognition or functioning.¹ Therefore, the trial failed to meet its primary and secondary endpoints.

“While these findings are disappointing, we remain dedicated to finding effective solutions for those living with serious mental illnesses,” said Shashank Deshpande, a member of the Board Managing Directors and Head of Human Pharma at Boehringer Ingelheim. “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.”

Phase III CONNEX was designed to assess the efficacy and safety of iclepertin, an investigator oral inhibitor of glycine transporter 1, for improving cognitive impairment in adults with schizophrenia. There are currently no approved targeted pharmaceutical treatments for cognitive impairment in schizophrenia despite this being one of the core symptoms of schizophrenia.

A study published in October reported that patients with schizophrenia who have cognitive deficit concerns should avoid antipsychotics, such as dopamine antagonists and clozapine.² The antipsychotics molindone and thioridazine were demonstrated to have the best impact on cognition but the studies had too small sample sizes (n = 15 – 22) and were based only on the speed of processing.

More than 80% of people with schizophrenia experience cognitive impairment, which occurs early in patients’ lives and impairs daily functioning.¹ Cognitive impairment impacts problem-solving abilities, attention, and memory, ultimately making it harder to live independently. This might cause someone to struggle with simple tasks such as attending appointments, which stand in the way of receiving treatment.

Phase III CONNEX was a part of the largest program for cognitive impairment in schizophrenia, which included 3 randomized, double-blind, placebo-controlled parallel trials evaluating the treatment of oral iclepertin 10 mg once daily over 26 weeks in adults with schizophrenia who received stable antipsychotic treatment. The CONNEX program included 1840 patients in 41 counties.

Although iclepertin was demonstrated to be well tolerated with a safety profile consistent with earlier studies, the drug brought no statistically significant effects on cognition or functioning at 6 months compared with placebo.

Due to the results, Boehringer Ingelheim decided to immediately discontinue the long-term extension trial.

“In the near future more can be expected,” Deshpande said. “Our gratitude goes to the patients and clinical investigators whose time and commitment made this research possible.”

References

1. ^{Boehringer provides update on iclepertin Phase III program in schizophrenia. Global Newswire. 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. Accessed January 16, 2025.}
2. ^{Derman, C. Cognitive Deficits in Schizophrenia: Which Antipsychotics Should Be Avoided? HCPLive. October 17, 2024. https://www.hcplive.com/view/cognitive-deficits-schizophrenia-which-antipsychotics-should-be-avoided-. Accessed January 16, 2024.}