EFFICACY OF XANOMELINE AND TROSPIUM CHLORIDE ACROSS SYMPTOM DOMAINS IN ADULTS WITH SCHIZOPHRENIA: RESULTS FROM THE 52-WEEK, OPEN-LABEL EMERGENT-5 CLINICAL TRIAL

Introduction

Xanomeline and trospium chloride (KarXT), combining the dual M1/M4-preferring muscarinic receptor agonist xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride, is approved for treatment of schizophrenia in adults in the US. KarXT demonstrated significant improvement in Positive and Negative Syndrome Scale (PANSS) total score versus placebo in the pivotal phase 3, 5-week, doubleblind, placebo-controlled, randomized EMERGENT-2 (NCT04659161) and EMERGENT-3 (NCT04738123) clinical trials. Continued long-term improvement in PANSS total score was also observed with KarXT treatment in the 52-week, open-label extension EMERGENT-4 trial (NCT04659174) in participants who completed the treatment period of EMERGENT-2 and EMERGENT-3. In this post hoc analysis, long-term efficacy of KarXT is assessed across schizophrenia symptoms in the phase 3, multicenter, 52-week, open-label, outpatient EMERGENT-5 (NCT04820309) trial using PANSS Marder 5-factor analysis.

Methods

EMERGENT-5 enrolled adults with confirmed schizophrenia who had stable symptoms with antipsychotic (AP) use and no prior exposure to KarXT. Participants were aged 18-65 years with a primary DSM-5 diagnosis of schizophrenia, PANSS total score ≤80, and Clinical Global Impression-Severity (CGI-S) score ≤4. Participants had received oral AP therapy within 30 days of screening and discontinued these medications prior to their baseline visit. After initial assessments, participants were initiated with twice-daily (BID) oral doses of KarXT 50 mg/20 mg and titrated to a maximum dose of KarXT 125 mg/30 mg BID for the remainder of the 52-week treatment period. Change from baseline (CfB) in PANSS total score was examined in the modified intention-to-treat population (mITT; participants with ≥1 dose of trial medication and ≥1 baseline and postbaseline PANSS assessment). Post hoc analysis evaluated CfB in PANSS Marder 5-factor scores. Adverse events (AEs) were assessed in the safety population (participants with ≥1 dose of trial medication).

Results

The safety and mITT populations consisted of 566 and 558 participants treated with KarXT, respectively. The mean±standard error baseline PANSS score in the mITT population was 66.0±0.44, reflecting a mildly ill population. Long-term treatment with KarXT resulted in improvements in PANSS total score (CfB at week 52, −5.5±0.66). Additionally, score reductions from baseline to week 52 were observed in each of the PANSS Marder factors. The largest improvement was in the PANSS Marder positive factor, with a −2.1±0.23-point CfB resulting in a mean score of 18.2±0.28 at 52 weeks. Similarly, score reductions from baseline to week 52 in PANSS Marder negative (15.6±0.29; CFB, −1.1±0.27), uncontrolled hostility (6.3±0.15; CFB, −0.3±0.17), disorganized thought (14.0±0.22; CFB, −0.8±0.20), and depression/anxiety (6.1±0.16; CFB, −1.2±0.18) factors indicate broad and sustained efficacy with KarXT over the 52-week trial period. No new safety signals were observed; additionally, KarXT was not associated with motor symptoms, somnolence, weight gain, or other AEs often reported with D2 receptor-acting AP treatments.

Conclusions

In the long-term, open-label, outpatient EMERGENT-5 trial, KarXT demonstrated consistent efficacy across symptoms among adults with schizophrenia who transitioned from other AP treatments. KarXT was generally well tolerated and no new safety signals were observed.