Clinical Trial of an IL-23 Inhibitor for Immune Activation in Clinical Trial of an IL-23 Inhibitor for Immune Activation in People With Schizophrenia

Study Summary

This 16 week clinical trial investigates a precision-medicine approach to schizophrenia by targeting a biologically distinct subgroup,-approximately one-third of patients-characterized by the presence of anti-gliadin antibodies (AGA IgG+) which is associated with elevated inflammation in the IL-23/IL-17 immune axis (Th17 pathway). This specific biotype is associated with pronounced negative symptoms, cognitive deficits, and reduced white matter integrity. Building on evidence that this pathway can be modulated to improve clinical outcomes, we are conducting a randomized, double-blind clinical trial of mirikizumab, an FDA-approved monoclonal antibody targeting IL-23, in addition to current antipsychotics, in schizophrenia patients who are positive for AGA IgG. The primary objective is to determine whether mirikizumab - a repurposed FDA approved monoclonal antibody treatment inhibiting IL-23-- will be superior to placebo in treating experiential (e.g., anhedonia and asociality) negative symptoms and cognitive impairments. Secondary aims will be to assess changes in T-cell subtypes and relative abundance by gene expression, peripheral cytokines, and neuroimaging markers (in a smaller subset). By focusing on this patient subgroup, who are identified by their immune status, the research aims to provide a targeted, revolutionary treatment for symptoms that have traditionally remained resistant to standard antipsychotic therapies. This protocol includes a screening phase, with a separate consent form which is intended to identify those with AGA IgG antibodies. This screening portion will also serve to compare other aspects of immune functioning and the TH17 pathway between patient groups and controls in order to further characterize and show that Th17 (and similar immune cell lines) are different between AGA IgG positive, AGA IgG negative and healthy controls of either status.

Primary Outcome

Change in negative symptoms in schizophrenia, specific experiential negative symptoms (i.e., motivation and pleasure) using The Clinical Assessment Interview for Negative Symptoms (CAINS) is a clinician-rated tool developed to assess the negative symptoms of schizophrenia, aligning with the NIMH's consensus on negative symptom domains. It comprises two main subscales: the Motivation and Pleasure (MAP) scale and the Expression (EXP) scale. The CAINS-MAP subscale specifically evaluates deficits in

Interventions

• DRUG Placebo
• DRUG IL-23