ONSET, DURATION, AND INCIDENCE OF ADVERSE EVENTS BY DOSE AND TITRATION SCHEDULE OF XANOMELINE AND TROSPIUM CHLORIDE

Introduction

Xanomeline and trospium chloride (KarXT) is approved by the U.S. Food and Drug Administration for the treatment of schizophrenia in adults. KarXT combines the dual M1/M4-preferring muscarinic receptor agonist xanomeline with the peripherally restricted pan muscarinic receptor antagonist trospium chloride to reduce side effects related to xanomeline activation of peripheral muscarinic receptors. The efficacy and safety of KarXT have been demonstrated in the EMERGENT clinical trials and a phase 4 trial with slower titration to evaluate tolerability of administration with and without food. The aim of this post hoc analysis was to compare the onset, duration, and incidence of treatment-emergent adverse events (TEAEs) by KarXT dose (100 mg/20 mg and 125 mg/30 mg twice daily [BID]) and titration schedule with data from these completed trials.

Methods

The phase 4, inpatient, open-label “food effect” trial (NCT06572449) enrolled adults with schizophrenia, Positive and Negative Syndrome Scale (PANSS) total score ≤80, and Clinical Global Impression-Severity (CGI-S) score ≤4. Over weeks 1-4, participants began KarXT treatment at 50 mg/20 mg BID (days 1-7), followed by 100 mg/20 mg (days 8-14), and then increased to a maximum of 125 mg/30 mg (cohort 1) or continued with 100 mg/20 mg (cohort 2) (days 15-28). The phase 2 EMERGENT-1 (NCT03697252) and phase 3 EMERGENT-2 (NCT04659161) and EMERGENT-3 (NCT04738123) inpatient, 5-week, randomized, double-blind, placebo-controlled trials enrolled adults with a confirmed DSM-5 diagnosis of schizophrenia and a recent worsening of psychosis warranting hospitalization, PANSS total score ≥80, and CGI-S score ≥4. BID dosing of KarXT began at 50 mg/20 mg (days 1-2), followed by 100 mg/20 mg (days 3-7), and increased to a maximum of 125 mg/30 mg (days 8-35). Food effect trial analyses of TEAEs by maximum KarXT dose and titration schedule were restricted to weeks 1-4; results from the EMERGENT trials were pooled. Efficacy was measured as a decrease in PANSS total score.

Results

In the food effect trial, TEAEs occurred in 69.9% (KarXT maximum dose: 100 mg/20 mg) and 59.0% (KarXT maximum dose: 125 mg/30 mg) of participants; in pooled EMERGENT, rates were 77.8% and 67.1%, respectively. Peak incidence of procholinergic and anticholinergic TEAEs coincided with transition to the KarXT 100 mg/20 mg dose (food effect: week 2; pooled EMERGENT: days 3-7); incidence of TEAEs plateaued or decreased with transition to the KarXT 125 mg/30 mg dose. Duration of nausea was longer for those maintained on KarXT 100 mg/20 mg in both data sets. PANSS total score decreases were observed with the 100 mg/20 mg and 125 mg/30 mg doses in both study populations.

Conclusions

Overall, the incidence and duration of TEAEs appear to be similar regardless of titration speed to KarXT 125 mg/30 mg BID. However, the data suggest that the duration of certain TEAEs is longer when individuals remain at 100 mg/20 mg BID, potentially due to the higher ratio of X to T of 5:1 vs 4.1:1. In some circumstances, potential improvements in tolerability may be seen with a more rapid titration and/or uptitration to KarXT 125 mg/30 mg BID.