Xanomeline-Trospium Improves Schizophrenia Symptoms in Phase 2 Trial


Positive and Negative Syndrome Scale (PANSS) total scores dropped an additional 11.6 points in patients with schizophrenia who received combination xanomeline-trospium, compared with placebo, according to a study published in The New England Journal of Medicine.

Biopharmaceutical company Karuma Therapeutics Inc. is developing the novel xanomeline-trospium treatment under the brand name KarXT.


“The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events,” researchers explained in the study. “Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline.”

Some 182 patients with an acute exacerbation of schizophrenia took part in the double-blind, phase 2 trial: 90 were randomized to a flexible dose of twice-daily xanomeline-trospium over 5 weeks and 92 received a placebo. The study’s primary end point was PANSS total score change from baseline to week 5.

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Compared with an average 5.9-point decrease in PANSS total score for patients who received placebo, scores dropped an average 17.4 points for patients who received xanomeline-trospium, according to the study.

In addition, 4 out of 5 secondary endpoints in the study were significantly better with xanomeline-trospium, researchers noted, specifically PANSS positive symptom subscore, PANSS negative symptom subscore, PANSS Marder negative symptom subscore, and Clinical Global Impression-Severity (CGI-S) frequency counts. The percentage of patients with a response according to a CGI-S score did not significantly differ between groups.

The most common adverse events with xanomeline-trospium were constipation, nausea, dry mouth, dyspepsia, and vomiting, researchers reported. Incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar with xanomeline-trospium and placebo.

“These findings support the potential for KarXT to treat symptoms of psychosis in schizophrenia without producing the common problematic side effects of current therapies, such as weight gain and extrapyramidal symptoms,” said lead study author Steve Brannan, MD, chief medical officer of Karuna Therapeutics.

“Given these encouraging results, we have advanced KarXT into phase 3 clinical development in our efforts to provide a meaningful, new, non-dopaminergic treatment option for this serious neuropsychiatric disorder affecting more than 21 million people worldwide.”

—Jolynn Tumolo



Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A. muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. The New England Journal of Medicine. 2021;384(8):717-726.

Karuna Therapeutics announces New England Journal of Medicine publication of data from EMERGENT-1 phase 2 trial evaluating KarXT in schizophrenia [press release]. Boston, Massachusetts: Karuna Therapeutics Inc.; February 24, 2021.


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