Iclepertin Fails to Show Statistically Significant Effects on Cognition and Functioning in Patients With Schizophrenia

Results from the CONNEX phase 3 clinical trial program demonstrated that compared with placebo, iclepertin (BI 425809; Boehringer Ingelheim) did not have statistically significant effects on cognition or functioning in patients with schizophrenia after 6 months of treatment. Although iclepertin did not meet the trials’ primary or secondary end points, the investigational drug was generally well-tolerated by patients and demonstrated a consistent profile as shown in prior studies.¹

Schizophrenia affects approximately 24 million people worldwide. One of the core symptom domains is cognitive impairment, which affects over 80% of people who have the condition. It manifests early in patients’ lives and represents a leading cause of disability and impairment in day-to-day functioning. Individuals with schizophrenia often face cognitive challenges that can affect their problem-solving abilities, attention, and memory, making it difficult to maintain an independent and productive life, according to experts.¹

Iclepertin is an investigational oral inhibitor of glycine transporter 1 (GlyT1) undergoing evaluation as a potential treatment for cognitive impairment in adult patients with schizophrenia.¹ In a randomized, double-blind, placebo-controlled, parallel-group phase 2 clinical trial (NCT02832037), iclepertin demonstrated improvements in cognition of adults with schizophrenia after 12 weeks of treatment.^2,3

Compared with placebo, all evaluated doses (2 mg, 5 mg, 10 mg, and 25 mg) of iclepertin presented statistically significant benefit according to 5 of 6 dose-response models. Additionally, 10 mg and 25 mg of iclepertin demonstrated the largest separation from placebo. Adverse events (AEs) were balanced across all groups (2 mg: 59%, n = 50; 5 mg: 52%, n = 44; 5 mg: 41%, n = 35; 25 mg: 42%, n = 36; and placebo: 44%, n = 74), according to the investigators.^2,3

Following the positive results from the phase 2 trial, investigators established the phase 3 CONNEX clinical trial program, consisting of 3 randomized, double-blind, placebo-controlled, parallel-group trials—CONNEX-1 (NCT04846868), CONNEX-2 (NCT04846881), and CONNEX-3 (NCT04860830)—to confirm the safety, efficacy, and tolerability of once-daily 10 mg of oral icelpertin in improving the cognition and functioning of a larger cohort of adults with schizophrenia over a 26-week period.^4-6 All 3 trials had the same primary and secondary end points: change in baseline in overall composite T-score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia consensus cognitive battery (primary end point); and changes from baseline in Schizophrenia Cognition Rating Scale, Virtual Reality Functional Capacity Assessment Tool, Patient Reported Experience of Cognitive Impairment in Schizophrenia total scores (secondary end points).^1,4-7

The investigators reported that in these 3 trials, icelpertin did not meet the primary or secondary end points and that statistical significance was not reached compared with placebo. Despite this, the therapy showed a consistent safety profile with other studies and was well-tolerated by patients. Further, the investigators reported that full safety and efficacy data will be submitted for presentation at an upcoming medical meeting, and these results will still be significant in informing future research featuring adults with schizophrenia-related cognitive impairment.¹

“While these findings are disappointing, we remain dedicated to finding effective solutions for those living with serious mental illnesses,” said Shashank Deshpande, member of the Board of Managing Directors and head of Human Pharma at Boehringer Ingelheim, in a news release. “In the near future, more can be expected.”¹

REFERENCES

1. Boehringer Ingelheim. Boehringer provides update on iclepertin Phase III program in schizophrenia. News release. January 16, 2025. Accessed January 30, 2025. https://www.boehringer-ingelheim.com/human-health/mental-health/schizophrenia/update-phase-iii-connex-clinical-program-schizophrenia

2. Clinical Trial of BI 425809 Effect on Cognition and Functional Capacity in Schizophrenia. ClinialTrials.gov identifier: NCT02832037. Updated February 24, 2021. Accessed January 30, 2025. https://clinicaltrials.gov/study/NCT02832037

3. Fleischhacker WW, Podhorna J, Gröschl M, et al. Efficacy and safety of the novel glycine transporter inhibitor BI 425809 once daily in patients with schizophrenia: a double-blind, randomised, placebo-controlled phase 2 study. Lancet Psychiatry. 2021;8(3):191-201. doi:10.1016/S2215-0366(20)30513-7

4. Clinical Trial of Iclepertin Effect on Cognition and Functional Capacity in Schizophrenia (CONNEX-1). ClincialTrials.gov identifier: NCT04846868. Updated November 13, 2024. Accessed January 30, 2025. https://clinicaltrials.gov/study/NCT04846868

5. Clinical Trial of Iclepertin Effect on Cognition and Functional Capacity in Schizophrenia (CONNEX-2). ClinialTrials.gov identifier: NCT04846881. Updated December 24, 2024. https://clinicaltrials.gov/study/NCT04846881

6. CONNEX-3: A Study to Test Whether Iclepertin Improves Learning and Memory in People With Schizophrenia. CLinicalTrials.gov identifier: NCT04860830. Updated January 9, 2025. Accessed January 30, 2025. https://clinicaltrials.gov/study/NCT04860830

7. Falkai P, Reuteman-Fowler C, Blahova Z, Ikezawa S, Marder SR, Krystal JH. Efficacy and safety of iclepertin (BI 425809) in patients with schizophrenia: CONNEX, a Phase III randomised controlled trial programme. Eur Psychiatry. 2023;66(S1):S637-S637. doi:10.1192/j.eurpsy.2023.1325