in the phase 3 EMERGENT-2 trial, a new study shows.
Xanomeline-trospium treatment was not associated with weight gain compared with placebo, and the incidences of extrapyramidal motor symptoms or akathisia were low and similar between treatment groups.
The EMERGENT-2 results “support the potential for KarXT to represent a new class of effective and well-tolerated antipsychotic medicines based on activating muscarinic receptors, not the D2 dopamine receptor-blocking mechanism of all current antipsychotic medications,” write the authors, led by Inder Kaul, MD, with Karuna Therapeutics, Boston, Massachusetts.
The US Food and Drug Administration has accepted the company’s new drug application for KarXT for the treatment of schizophrenia in adults. The Prescription Drug User Fee Act action date is September 26, 2024.
Results of the EMERGENT-2 trial were published online on December 14, 2023, in The Lancet.
Beyond the Dopamine System
Evidence suggests the muscarinic cholinergic system is involved in the pathophysiology of schizophrenia.
Xanomeline is an oral muscarinic cholinergic receptor agonist that does not have direct effects on the dopamine receptor. Combining it with trospium chloride, an oral pan-muscarinic receptor antagonist, is thought to reduce side effects associated with xanomeline’s activation of peripheral muscarinic receptors in peripheral tissues.
EMERGENT-2 was a multicenter, double-blind, placebo-controlled trial that enrolled 252 adults with schizophrenia who recently experienced a worsening of psychotic symptoms warranting hospitalization.
Patients were treated for 5 weeks, with xanomeline-trospium titrated from 50 mg/20 mg twice daily to 125 mg/30 mg twice daily. Efficacy and safety analyses were conducted in those who had received at least one dose of the study drug.
The primary endpoint was change in baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score (range, 30-210, with higher scores indicating more severe symptoms).
At the end of the treatment period, xanomeline-trospium was associated with a significant 9.6-point reduction in PANSS total scores relative to placebo. PANSS total scores fell by 21.2 points with xanomeline-trospium vs 11.6 points with placebo (P < .0001; Cohen d effect size, 0.61).
All secondary endpoints were also met, with active treatment demonstrating statistically significant reductions compared with placebo at week 5 (P < .05).
These secondary endpoints included change in PANSS positive subscale, PANSS negative subscale, PANSS Marder negative factor, Clinical Global Impression-Severity score, and percentage of participants achieving at least a 30% reduction from baseline to week 5 in PANSS total score.
Rates of discontinuation related to side effects were similar with active treatment and placebo (7% and 6%, respectively). The most common side effects with xanomeline-trospium were constipation (21%), dyspepsia (19%), nausea (19%), vomiting (14%), headache (14%), hypertension (10%), dizziness (9%), and gastroesophageal reflux disease (6%).
Xanomeline-trospium demonstrated a “distinctive safety and tolerability profile and was not associated with many of the adverse events typically associated with current antipsychotic treatments, including extrapyramidal motor symptoms, weight gain, changes in lipid and glucose parameters, and somnolence,” the authors report.