Efficacy and safety of xanomeline/trospium chloride during transition from atypical antipsychotics in participants with stable schizophrenia symptoms in EMERGENT-5

Introduction

Medication switching is common in schizophrenia; however, clinicians may be concerned about decompensation when switching medications in clinically stable adults. The most frequent reasons for switching antipsychotic (AP) medications may include adverse events (AEs) or lack of efficacy. Xanomeline/trospium chloride (KarXT), approved by the US Food and Drug Administration for schizophrenia treatment, provides a novel mechanism of action, exerting effects through M₁ and M₄ muscarinic receptor agonism, which has the potential to reduce the AE burden associated with atypical APs. Previous results from EMERGENT-5 (NCT04820309) have demonstrated that KarXT was safe, with a trend toward symptom improvement over 1 year in clinically stable adults with schizophrenia who switched from a prior AP.

Aims

This analysis evaluated symptom stability during the 2-week treatment transition period from a previous atypical AP to KarXT and safety following KarXT initiation in participants in EMERGENT-5.

Methods

EMERGENT-5 was a phase 3, 52-week, multicenter, outpatient, open-label trial in adults with schizophrenia with stable symptoms, no prior KarXT use, Positive and Negative Syndrome Scale (PANSS) total score ≤80, and Clinical Global Impression-Severity (CGI-S) score ≤4. Prior APs were washed out 2 weeks before or 5 half-lives between the screening and baseline visits. Participants initiated KarXT 50 mg/20 mg (xanomeline/trospium) twice daily and uptitrated to a maximum dose of 125 mg/30 mg (xanomeline/trospium) twice daily for 52 weeks. Outcomes assessed included change from screening to baseline in PANSS total, PANSS positive, and PANSS negative scores and incidence of new-onset treatment emergent AEs (TEAEs) in the 8 weeks following KarXT initiation.

Results

Most (91.4%) participants had ≥1 prior AP, most commonly quetiapine (26.3%), risperidone (21.5%), aripiprazole (13.8%), and olanzapine (13.4%). Overall mean (standard deviation [SD]) washout duration was 6.0 (29.2) days. Mean (SD) PANSS total score change from screening to baseline was 0.3 (7.0); this change was similar between groups when stratifying by prior AP (quetiapine: 0.0; risperidone: 0.4; aripiprazole: −0.3; olanzapine: 0.0). Overall mean (SD) PANSS positive score change from screening to baseline was −0.3 (2.6); this change was similar between groups when stratifying by prior AP (quetiapine: −0.3; risperidone: −0.1; aripiprazole: −0.8; olanzapine: −0.2). Overall mean (SD) PANSS negative score change from screening to baseline was 0.3 (3.0); this change was similar between groups when stratifying by prior AP (quetiapine: 0.2; risperidone: 0.1; aripiprazole: 0.3; olanzapine: 0.7). KarXT was generally well tolerated and no new safety or tolerability issues emerged during the transition from prior AP to KarXT. Following KarXT initiation (weeks 1-8), the most common TEAEs were procholinergic and anticholinergic in nature: nausea (18.9%), vomiting (15.4%), and constipation (12.5%). Incidence rates for these new-onset AEs decreased over time.

Conclusions

Switching APs is common among individuals with schizophrenia. PANSS total, PANSS positive, and PANSS negative scores remained stable when transitioning participants from a previous atypical AP to KarXT, regardless of the prior AP used. Incidence rates for new-onset TEAEs declined over time. These data suggest that stable individuals can be safely transitioned from previous APs to KarXT without destabilisation of schizophrenia symptoms.

References

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