Long-term metabolic and cardiovascular safety and tolerability with xanomeline and trospium chloride: pooled results from EMERGENT-4 and EMERGENT-5

Introduction

Currently approved treatments for schizophrenia are associated with a variety of cardiometabolic risks. Xanomeline and trospium chloride (KarXT) is a novel agent that combines the dual M₁/M₄-preferring muscarinic receptor agonist xanomeline and the peripherally restricted pan-muscarinic receptor antagonist trospium chloride. KarXT is approved in the US for the treatment of schizophrenia in adults. The efficacy and safety of KarXT in schizophrenia were demonstrated in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials. KarXT was not generally associated with clinically meaningful weight gain or adverse metabolic side effects compared with placebo in the acute trials; increases in blood pressure (systolic/diastolic) and heart rate were small and transient.

Aims

In this analysis, we examined long-term metabolic and cardiovascular safety and tolerability from data pooled from two 52-week, open-label, phase 3 trials in adults with schizophrenia.

Methods

EMERGENT-4 (NCT04659174) and EMERGENT-5 (NCT04820309) enrolled adults aged 18-65 years with schizophrenia. Participants had either rolled over from the short-term trials (EMERGENT-4) or had stable symptoms appropriate for outpatient care a Positive and Negative Syndrome Scale total score ≤80, a Clinical Global Impression-Severity score ≤4, and no prior exposure to KarXT (EMERGENT-5). Eligible participants received KarXT orally starting at 50 mg/20 mg (xanomeline/trospium) twice daily (BID) and increasing to a maximum of 125 mg/30 mg BID as tolerated. Data from EMERGENT-4 and EMERGENT-5 were pooled. Descriptive analyses were conducted in the safety population, defined as all participants who received ≥1 dose of KarXT.

Results

A total of 718 adults were included in the pooled safety population. At baseline, participants had a mean body mass index of 29.5 kg/m² and hemoglobin A1c (HbA1c) of 5.8%, indicating some baseline cardiometabolic risk. A general decrease in body weight was observed over time on KarXT, with a mean±standard deviation (SD) change from baseline to week 52 of -2.13±6.1 kg. Cholesterol and triglyceride levels remained stable after 52 weeks (mean±SD change, cholesterol: −0.07±0.79 mmol/L; triglycerides: −0.07±0.83 mmol/L). Fewer participants had cholesterol or triglycerides above the upper limit of normal at their last assessment compared with baseline. HbA1c remained stable over the course of treatment. Prolactin decreased by 3.1±15.0 μg/L from baseline to week 52. KarXT was associated with small increases in supine systolic (mean±SD change from baseline to week 52: 1.7±13.4 mmHg) and diastolic blood pressure (BP; mean±SD change from baseline to week 52: 1.3±8.4 mmHg); peak changes in systolic and diastolic BP occurred at day 8. KarXT was also associated with a small increase in heart rate (HR; mean±SD change from baseline to week 52: 2.3±12.5 beats/min) that was not clinically significant; peak change was observed at day 14. Peak changes in BP and HR partially attenuated with continued treatment.

Conclusions

KarXT exhibited a long-term favorable cardiometabolic profile; all metabolic parameters either improved or remained stable over 52 weeks of treatment. KarXT was associated with a low risk for cardiovascular TEAEs with small, generally transient increases in BP and HR. No substantial weight gain was observed over time.

References

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