Iclepertin

Cognitive impairment associated with schizophrenia (CIAS) represents a persistent and disabling domain of symptoms that remains largely unaddressed by current antipsychotic treatments. Iclepertin (BI 425809), a novel and selective glycine transporter 1 (GlyT1) inhibitor, is being developed as a potential pharmacological solution for CIAS. Cognitive symptoms in schizophrenia—such as deficits in working memory, attention, and executive function—often precede the onset of psychosis and continue despite symptomatic remission of positive symptoms. Unlike antipsychotics that target delusions and hallucinations, iclepertin aims to restore NMDA receptor function by increasing synaptic glycine availability, thus enhancing glutamatergic neurotransmission and synaptic plasticity. Preclinical studies demonstrated that iclepertin improves cognitive performance and normalizes cortical network dysfunction in rodent models. In a large Phase II randomized controlled trial involving 509 patients across 11 countries, iclepertin (10 mg and 25 mg daily) significantly improved cognition compared to placebo, as measured by the MCCB and SCoRS scales. No added benefit was seen with the higher dose. Phase III trials (CONNEX 1–3) and an open-label safety extension (CONNEX-X) are currently ongoing, involving 586 participants over 26 weeks of treatment. These trials will further evaluate the cognitive and functional benefits of iclepertin in a real-world schizophrenia population. If successful, iclepertin would become the first approved medication specifically indicated for CIAS, addressing a major unmet clinical need and potentially improving the daily functioning and quality of life of patients living with schizophrenia.