Positive Phase 3 Results for New Antipsychotic in Psychosis

Xanomeline-trospium (KarXT, Karuna Therapeutics) — a novel therapy that combines a muscarinic receptor agonist with an anticholinergic agent — led to statistically significant and clinically meaningful improvements in positive and negative symptoms of schizophrenia compared with placebo in the phase 3 EMERGENT-2 trial, a new study showed.

KarXT 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,” wrote 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 Lancet.

Beyond the Dopamine System

Evidence suggested the muscarinic cholinergic system was 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 KarXT 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 (PANSS range 30-210, with higher scores indicating more severe symptoms).

At the end of the treatment period, KarXT 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 KarXT vs 11.6 points with placebo (P

All secondary endpoints were also met, with active treatment demonstrating statistically significant reductions compared with placebo at week 5 (P

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 KarXT were constipation (21%), dyspepsia (19%), nausea (19%), vomiting (14%), headache (14%), hypertension (10%), dizziness (9%), and gastroesophageal reflux disease (6%).

KarXT 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 reported.

Potential ‘Game-Changer’

KarXT is a potential “game-changer” for patients with schizophrenia, Ann Shinn, MD, MPH, director of clinical research, Schizophrenia and Bipolar Disorder Research Program, McLean Hospital, and assistant professor of psychiatry, Harvard Medical School, told Medscape Medical News.

There was a “clear separation between the people who were randomized to KarXT versus placebo. It’s not just a statistically significant but also a clinically significant difference in the reduction in symptoms of psychosis,” said Shinn, who wasn’t involved in the study.

“What’s really exciting” was that the drug did not cause weight gain or extrapyramidal symptoms compared with placebo. “Both from an efficacy and side-effect perspective, I think more patients with schizophrenia are going to be willing to take medication,” Shinn noted.

Also commenting on this research for Medscape Medical News, René Kahn, MD, PhD, professor and chair of psychiatry at the Icahn School of Medicine at Mount Sinai in New York, noted that current antipsychotic medications for schizophrenia work “directly on the dopamine system — either as dopamine antagonists or partial agonist.”

KarXT provides a “new mechanism of action, a new system that’s being targeted in the treatment of schizophrenia, and the effect size was rather large, so the drug didn’t just squeak by,” Kahn said.

Nonetheless, “we’ll have to wait and see whether it’s as effective or more effective than drugs currently on the market. The proof of the pudding will come when it’s marketed and used on 1000s and 1000s of patients,” Kahn added.

The coauthors of an accompanying commentary said the EMERGENT-2 findings “strongly support the possibility that agonism of muscarinic receptors provides the first viable antipsychotic alternative to blocking the dopamine D2 receptor for more than 70 years, and as such encourage further research.”

However, as a regulatory trial, EMERGENT-2 does not provide comparative data on the benefits and harms of KarXT with existing alternatives.

This represents a “missed opportunity to provide patients and clinicians with the information that is clinically needed — what is the treatment of choice for a patient?” wrote Andrea Cipriani, MD, PhD, with Department of Psychiatry, University of Oxford, United Kingdom, and coauthors.

The study was funded by Karuna Therapeutics. Several authors disclosed relationships with the company. Kahn disclosed various relationships with Boehringer Ingelheim International GmbH. Cipriani received research, educational, and consultancy fees from the Italian Network for Paediatric Trials, the CARIPLO Foundation, Lundbeck, and Angelini Pharma and was chief investigator of one trial about seltorexant in adolescent depression, sponsored by Janssen. Shinn had no relevant disclosures.