Xanomeline–trospium quells acute psychosis in people with schizophrenia

The experimental drug combination of xanomeline and trospium chloride appears to be efficacious and well tolerated in individuals with schizophrenia who are experiencing acute psychosis, according to the results of the phase III EMERGENT-3 trial.

Five weeks of treatment with xanomeline–trospium led to a significantly greater reduction in the primary endpoint of Positive and Negative Syndrome Scale (PANSS) total score compared with placebo (−20.6 vs −12.2; mean difference, −8.4, 95 percent confidence interval [CI], −12.4 to −4.3; p<0.001; Cohen’s d effect size, 0.60). [JAMA Psychiatry 2024;doi:10.1001/jamapsychiatry.2024.0785]

The improvement seen among participants on xanomeline–trospium became evident at week 2 and was enhanced through week 5, as the investigators noted.

Additionally, xanomeline–trospium conferred significant benefits for positive symptoms, with a decrease of 7.1 in the PANSS positive subscale score as opposed to a decrease of 3.6 with placebo (mean difference, −3.5, 95 percent CI, −4.7 to −2.2; p<0.001).

Negative symptoms, on the other hand, did not significantly differ between the two arms at week 5. Nevertheless, the mean difference in PANSS negative subscale score and PANSS Marder negative factor score achieved statistical significance at week 4, the investigators pointed out.

Other secondary endpoints such as Clinical Global Improvement-Severity (CGI-S) and the percentage of PANSS responders (at least 30-percent improvement from baseline) at week 5 were also more favourable in the xanomeline–trospium arm than in the placebo arm (mean difference, −0.5; p<0.001; rate difference, 35.4 percent; p<0.01).

As for safety, “xanomeline–trospium was well tolerated with an adverse effect profile substantially consistent with [previous reports],” the investigators said. [N Engl J Med 2021;384:717-726; Lancet 2024;403:160-170]

Discontinuation rates due to treatment-emergent adverse events (TEAEs) did not significantly differ between the two treatment arms (6.4 percent vs 5.5 percent). Nausea was the most frequent TEAE reported among participants on xanomeline-trospium (19.2 percent), followed by dyspepsia (16.0 percent), vomiting (16.0 percent), and constipation (12.8 percent).

Results for extrapyramidal symptoms, weight gain, and somnolence were comparable between the treatment arms.

“The efficacy, safety, and tolerability of xanomeline–trospium in EMERGENT-3 were substantially consistent with the results reported for the EMERGENT-1 and EMERGENT-2 trials,” the investigators said.

The drug combines the dual M₁/M₄ preferring muscarinic receptor agonist xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation, they added.

In the phase II EMERGENT-1 trial and phase III EMERGENT-2 trial, xanomeline–trospium was associated with significant improvements in positive and negative symptoms compared with placebo in people with schizophrenia experiencing acute psychosis. This benefit was obtained without many of the problematic adverse effects associated with currently approved antipsychotic medications (eg, extrapyramidal motor symptoms, weight gain, somnolence, and hyperprolactinemia), the investigators pointed out. [N Engl J Med 2021;384:717-726; Lancet 2024;403:160-170]

“Together, these results … support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity,” they concluded.

EMERGENT-3 included 256 participants (mean age 43.1 years, 74.6 percent men, 60.9 percent Black or African American) who had been randomly assigned to receive either xanomeline 125 mg/trospium 30 mg (n=125) or placebo (n=131) for 5 weeks. Of these participants, 253 were included in the safety population and 234 in the modified intention-to-treat population.

Xanomeline-trospium dosing began with 50 mg xanomeline twice daily plus 20 mg trospium for 2 days, then increased 100 mg xanomeline twice daily plus 20 mg trospium for days 3–7. At day 8, a flexible dosing regimen allowed for dose adjustments up to a maximum (125 mg xanomeline twice daily plus 30 mg trospium) based on tolerability, with the option to return to the previous dose. No dose changes were permitted in the final 2 weeks.