Development of the novel GlyT1 inhibitor, iclepertin (BI 425809), for the treatment of cognitive impairment associated with schizophrenia

Abstract

Schizophrenia is a psychiatric disorder characterised by symptoms in three domains: positive (e.g. delusions, hallucinations), negative (e.g. social withdrawal, lack of motivation) and cognitive (e.g. working memory and executive function impairment). Cognitive impairment associated with schizophrenia (CIAS) is a major burden for patients and negatively impacts many aspects of a patient's life. Antipsychotics are the standard-of-care treatment for schizophrenia but only address positive symptoms. So far there are no approved pharmacotherapies for the treatment of CIAS. Iclepertin (BI 425809) is a novel, potent and selective glycine transporter 1 (GlyT1) inhibitor, under development by Boehringer Ingelheim for the treatment of CIAS. Phase I studies have shown it to be safe and well tolerated in healthy volunteers, and central target engagement (inhibition of GlyT1) was achieved in a dose-dependent manner from 5 to 50 mg in healthy volunteers. A Phase II study has demonstrated that iclepertin is safe and well tolerated in patients with schizophrenia and improves cognition at doses of 10 mg and 25 mg. Phase III studies are ongoing to confirm these initial positive safety and efficacy findings with the 10 mg dose, and if successful, iclepertin could become the first approved pharmacotherapy used to treat CIAS.

Keywords: BI 425809; Cognitive impairment; GlyT1 inhibitor; Iclepertin; NMDA receptor; Schizophrenia.

Fig. 1

The three symptom domains of schizophrenia [2, 3]

Fig. 2

Iclepertin mode of action. AMPA-R α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, Ca²⁺ calcium, GlyT1 glycine transporter 1, NMDA-R N-methyl-D-aspartate receptor. Figure reused with permission from Moschetti V et al. (2016) Br J Clin Pharmacol 82(5):1315–24. 10.1111/bcp.13060

Fig. 3

Chemical structure of iclepertin. Figure reused with permission from Rosenbrock H et al. (2022) J Pharmacol Exp Ther 382(2):223–32. https://doi.org/10.1124/jpet.121.001071. Wiley (Publisher)

Fig. 4

a Effects of BI 425809 on glycine levels in rat cerebrospinal fluid (CSF)* and b Percentage change from baseline in individual and mean E₃₁₂ of glycine in CSF after multiple dosing of BI 425809 in healthy male subjects^ꝉ. *Data are expressed as mean ± SEM of eight animals per group; *p < 0.05, **p < 0.01 as compared with vehicle, Dunnett’s post hoc analyses. ^ꝉThe dotted line represents a 50% increase from baseline in CSF glycine concentration E₃₁₂, effect of glycine at the time point 312 h before the last dose is given. CSF cerebrospinal fluid, SEM standard error of measurement. Figures reused with permission from Rosenbrock H, Desch M, Kleiner O et al. (2018) Clin Transl Sci 11:616–23. https://doi.org/10.1111/cts.12578, Wiley (Publisher)

Fig. 5

a, b Best-fitting dose–response curve and adjusted mean change from baseline for MCCB overall composite T-score; c, d MCCB neurocognitive composite T-score. CI confidence interval, MCCB Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, MCPMod multiple comparison procedure and modelling, MMRM mixed model repeated measures. Figure reused with permission from Fleischhacker, WW et al. (2021) Lancet Psychiatry 8(3): 191–201

Fig. 6

Study diagram for the ongoing Phase III trials (CONNEX 1/NCT04846868; CONNEX 2/NCT04846881; CONNEX 3/NCT04860830). Note: patients were stratified by screening MCCB score at randomisation. ^aPatients from CONNEX-1 and 3 can go directly into the open-label study; patients from CONNEX-2 must complete discontinuation and follow-up first. Broken grey arrow, optional follow-up; solid blue arrow, must complete follow-up. MCCB, Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery; R, Randomisation; S, Screening; SCoRS, Schizophrenia Cognition Rating Scale; VRFCAT, Virtual Reality Functional Capacity Assessment Tool