Iclepertin: Bridging the Gap in CIAS Treatment – the Answer to an Unmet Need

• Despite the urgent need for novel treatments, drug development for cognitive impairment associated with schizophrenia has been challenging, due to limited understanding, high trial failures, and few potential targets in the treatment regime.
• Iclepertin (BI 425809), an investigational asset, is a GlyT1 inhibitor being developed by Boehringer Ingelheim that modulates the NMDA receptor function, a key aspect of CIAS, addressing the cognitive symptoms that are a significant burden for individuals with schizophrenia.
• A US FDA-designated drug, Iclepertin, has the potential to fill the gap, and positive outcomes from Phase I and II trials that show iclepertin’s safety, tolerability, and pro-cognitive effects in both healthy volunteers and CIAS patients, further strengthen the belief.

Iclepertin (BI 425809) is a glycine transporter 1 (GlyT1) inhibitor being investigated in a Phase III trial for treating cognitive symptoms associated with schizophrenia (CIAS). It blocks the GlyT1 receptor, which increases glycine levels and enhances its ability to modulate the NMDA receptor function. This unique mechanism has an important role in reversing sensory processing deficits and neural network dysfunction, which are associated with cognitive impairment in schizophrenia. Preclinical studies have shown that improved NMDA receptor signaling leads to an increase in long-term potentiation and synaptic plasticity, which improves cognitive function and memory in schizophrenic patients. Therefore, if successful in ongoing Phase III clinical trials, iclepertin may represent the first efficacious medication for cognitive impairment associated with schizophrenia.

Recently, Boehringer Ingelheim presented a poster for its drug candidate, Iclepertin (BI 425809), at the Annual Congress of the Schizophrenia International Research Society (SIRS) held in Florence, Italy, from April 3 to 7, 2024.

Efficacy and safety of iclepertin (BI 425809) in patients with schizophrenia

Iclepertin (BI 425809) is currently being investigated in multiple Phase III CONNEX trials to evaluate the safety and efficacy of Iclepertin in adult patients with schizophrenia, highlighting Boehringer Ingelheim’s commitment to developing innovative treatments for mental health conditions. NCT04846868 (CONNEX-1), NCT04846881 (CONNEX-2), NCT05211947 (CONNEX), and NCT04860830 (CONNEX-3), these studies are currently recruiting with completion expected in Quarter 1 of 2025.

In Phase II clinical trials, iclepertin demonstrated pro-cognitive effects in patients with schizophrenia, leading to greater improvements in processing speed, reasoning, problem-solving, and working memory compared to placebo. In the Phase I trial, the drug was well-tolerated in healthy volunteers with no dose-dependent trends in the overall number of adverse events. Recognizing its potential in treating CIAS, the US FDA has granted a Breakthrough Therapy Designation to Iclepertin, to expedite the development and review of the drug.

However, one needs to be cautious as most large, industry-sponsored studies, to address cognitive function, have failed to show proof of clinical concepts. Therefore, a demonstration of the efficacy of iclepertin in improving cognition in this Phase III program would provide important insight into the role of glutamate in cognitive symptoms that may also have relevance for other cognitive disorders.

Iclepertin is a promising new treatment for CIAS, with a novel mechanism of action that enhances NMDA function and glutamatergic signaling. The drug has shown promising results in Phase I and II trials, demonstrating safety, tolerability, and pro-cognitive effects in healthy individuals and patients with schizophrenia. Since schizophrenia, patients frequently ignore certain symptoms, such as cognitive impairment. Therefore, if approved, BI-425809 will be the first approved pharmacotherapy for the treatment of CIAS.