CYP2D6 metaboliser status impact on xanomeline and trospium chloride efficacy and tolerability in adults with schizophrenia: a post hoc analysis

Introduction: CYP2D6 is a highly polymorphic member of the cytochrome P450 family of enzymes involved in drug metabolism. The combination of CYP2D6 alleles predict several metaboliser phenotypes: poor metaboliser without enzymatic activity, intermediate metaboliser with decreased enzymatic activity, normal metaboliser, and ultrarapid metaboliser with increased enzymatic activity. Xanomeline and trospium chloride (KarXT) was approved by the US Food and Drug Administration for the treatment of schizophrenia in adults in 2024. KarXT employs a novel mechanism of action, combining the dual M1/M4-preferring muscarinic receptor agonist xanomeline with the peripherally restricted pan-muscarinic receptor antagonist trospium chloride. In EMERGENT-2 (NCT04659161) and EMERGENT-3 (NCT04738123), KarXT demonstrated superior efficacy compared with placebo in adults with schizophrenia. While P450 pathways are not expected to contribute significantly to trospium elimination, population pharmacokinetic analysis showed that xanomeline exposure was higher in intermediate metabolisers compared with normal metabolisers.

Aims: The current post hoc analysis of data pooled from the randomized, double-blind, placebo-controlled EMERGENT-2 and EMERGENT-3 trials evaluated the impact of CYP2D6 metaboliser status on the efficacy and tolerability of KarXT.

Methods: DNA was isolated from whole blood samples collected from participants who consented for genetic testing in the EMERGENT 2 and EMERGENT 3 clinical trials. Whole genome sequencing was performed using Illumina NovaSeq S4 flow cell platform. CYP2D6 variants were evaluated using consensus sequences from 3 separate analysis tools: StellarPGx, Aldy, and Cyrius. Metaboliser status for CYP2D6 was then determined by a CYP2D6 genotype to phenotype translation method following guidelines from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Changes from baseline to weeks 2, 3, and 5 of the Positive and Negative Syndrome Scale (PANSS) total and PANSS subscale (positive, negative, and general psychopathology) scores, and frequency of adverse events were compared among participants with different CYP2D6 metaboliser status using the Mann-Whitney U test.

Results: CYP2D6 metaboliser status was evaluated for 324 participants (KarXT: n=169; placebo: n=155). Most participants were normal (n=168) or intermediate metabolisers (n=116); there were few poor (n=7) or ultrarapid metabolisers (n=10). The changes from baseline to day 35 for PANSS total and all subscale (positive, negative, or general psychopathology) scores at all visits were similar in normal and intermediate metaboliser groups. Decreases in PANSS total, positive subscale, and general psychopathology subscale scores were greater in the KarXT treatment group compared with the placebo group regardless of normal or intermediate metaboliser status. Adverse events were generally mild or moderate, and frequencies were not significantly different in both metaboliser groups.

Conclusions: In this post hoc analysis of data from the EMERGENT-2 and EMERGENT-3 trials, no consistent impact of CYP2D6 metaboliser status on the efficacy of KarXT or the incidences of adverse events was observed. CYP2D6 metaboliser status does not significantly affect the efficacy and tolerability of KarXT in adults with schizophrenia, indicating a consistent treatment effect across genetic variations.

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