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Results of the EMERGENT-3 trial confirm that the novel investigational antipsychotic xanomeline-trospium (KarXT, Karuna Therapeutics) is effective and well tolerated in adults with schizophrenia experiencing acute psychosis.

The EMERGENT-3 findings, coupled with findings from EMERGENT-1 and EMERGENT-2, "support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity," wrote the authors, led by Inder Kaul, MD, MPH, with Karuna Therapeutics.

"The effect size of 0.60 for improvement in total psychopathology versus placebo in EMERGENT-3 is impressive and in keeping with the results from the prior studies," Christoph U. Correll, MD, professor of psychiatry at the Zucker School of Medicine at Hofstra/Northwell, New York City, told Medscape Medical News.

"Similarly encouraging is the safety profile that does not consist of the usual clusters that we are used to, albeit to varying degrees, with currently available dopamine receptor blockers," said Correll, who was involved in EMERGENT-2 but not EMERGENT-3.

Results of EMERGENT-2 were published late last year in The Lancet.

The EMERGENT-3 results were published online on May 1 in JAMA Psychiatry.

Clinically Meaningful Improvement

EMERGENT-3 enrolled 256 adults (mean age 43, 75% men) with schizophrenia experiencing acute psychosis from 30 inpatient sites in the United States and Ukraine. They were randomly allocated 1:1 to KarXT (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks.

The primary endpoint was a change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at week 5. Results showed a statistically significant and clinically meaningful 8.4-point reduction in the PANSS total score in participants taking KarXT compared with those taking placebo (−20.6 vs −12.2, respectively; P < .001; Cohen d effect size, 0.60).

Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between KarXT and placebo groups (6.4% and 5.5%, respectively).

The most common TEAEs in the KarXT group were nausea (19.2% vs 1.6% placebo), dyspepsia (16.0% vs 1.6%), vomiting (16.0% vs 0.8%), and constipation (12.8% vs 3.9%). There were no between-group differences in measures of extrapyramidal symptoms, weight gain, and somnolence.

"Across all three trials, KarXT was not associated with relevant adverse effects regarding Parkinsonism and akathisia, weight gain and metabolic abnormalities, sedation or insomnia, and prolactin elevation or sexual dysfunction," Correll told Medscape Medical News.

"Instead, the M1/M4-preferring muscarinic agonist was mainly associated with gastrointestinal adverse effects, such as nausea, dyspepsia, constipation, and vomiting. However, there was a low discontinuation rate overall as well as due to adverse effects that each did not differ from placebo," he noted.

"Based on the novel mechanism of action, it is hoped that KarXT and other members of the family of muscarinic receptor activators that are currently in development will help treat patients better who are not served well enough by the currently available treatments," Correll said.

The Food and Drug Administration (FDA) Decision Expected This Fall

Last month, the company released interim long-term efficacy data from the open-label EMERGENT-4 trial, which shows that KarXT was associated with continued improvements in symptoms of schizophrenia over 52 weeks.

At 1 year, more than 75% of participants achieved at least a 30% improvement in symptoms, with an average reduction of 33.3 points from baseline in the PANSS total score and an average 1.7-point change (improvement) in Clinical Global Impression-Severity score from baseline, "representing an average shift from 'markedly ill' at baseline to 'moderately' or 'mildly' ill at 1 year," according to a news release from Bristol Myers Squibb (BMS), which acquired Karuna Therapeutics in March.

The US FDA is expected to decide on KarXT for schizophrenia in September.

KarXT will be a "good addition" to the psychiatrist's treatment toolkit for schizophrenia, Robert Buchanan, MD, professor of psychiatry at the University of Maryland School of Medicine, Baltimore, and director of the Maryland Psychiatric Research Center, who wasn't involved in this research, told Medscape Medical News.

"In light of the limitations of the currently available antipsychotic medications, when something comes along that seems to be novel and offers advantages to what is currently available, there will be a lot of excitement, and I think to some extent, it's partially justified with KarXT," Buchanan said.

With further studies, said Buchanan, "KarXT may be shown to have some benefit for the negative symptoms of schizophrenia and cognitive impairments. But those are still open questions because none of the three EMERGENT studies were designed to directly assess effects for negative symptoms or cognition."

The trial was sponsored by Karuna Therapeutics. Several authors disclosed relationships with the company. Correll has been a consultant and/or advisor to Karuna Therapeutics, BMS, and other pharmaceutical companies. Buchanan provided a one-time consultation to Karuna in 2022.