Novel Drug Combo for Schizophrenia Works in Acute Psychosis

The investigational combination xanomeline-trospium (KarXT) was effective and well tolerated in individuals with schizophrenia who were experiencing acute psychosis, according to the randomized controlled phase III EMERGENT-3 trial.

Participants randomized to the novel combination therapy had significantly reduced Positive and Negative Syndrome Scale (PANSS) total scores over 5 weeks compared with those on placebo (−20.6 vs −12.2), according to Steven Paul, MD, of Karuna Therapeutics in Boston, and colleagues.

The comparative reduction in PANSS total scores corresponded with a least squares mean difference of −8.4 between the combination therapy and placebo (95% CI −12.4 to −4.3, P<0.001) with a Cohen d effect size of 0.60, they reported in JAMA Psychiatry.

"This study provides further evidence that the combination of xanomeline-trospium is an efficacious therapy for individuals who are experiencing an acute episode of schizophrenia," co-author David Walling, PhD, of CenExel in Garden Grove, California, told MedPage Today in an email. "This is an incredibly exciting time in schizophrenia research as we now have the first non-dopamine medication that has demonstrated efficacy in two pivotal phase III trials -- as well as phase II trials."

Xanomeline-trospium was well tolerated, with few serious treatment-emergent adverse events (TEAEs), and discontinuation rates were similar among both the therapy and placebo groups (6.4% vs 5.5%). TEAEs occurred in 70.4% of the combination therapy group and 50% of the placebo group, and the most common ones were nausea, dyspepsia, vomiting, constipation, hypertension, and diarrhea, the researchers reported.

Regarding secondary endpoints, there was significant reduction in the PANSS positive subscale score from baseline to week 5 for the xanomeline-trospium group compared with the placebo group (−7.1 vs −3.6), but the prespecified PANSS negative subscale score did not meet statistical significance at week 5, although it did meet significance at week 4, as did the PANSS Marder negative factor score, the authors noted.

These findings, taken together with the previously reported results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be "the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity," the authors wrote.

"The fact that they tracked so closely [and] consistently with other studies really does reinforce the efficacy of this treatment," Walling said. "This research adds to the growing body of evidence that xanomeline-trospium provides an effective treatment for acute episodes of schizophrenia," he added. "It is further validation of the phase II and earlier phase III work that has been done."

In November, the FDA accepted Karuna Therapeutics' New Drug Application (NDA) for xanomeline-trospium as treatment for schizophrenia in adults, and set a decision date for September 26, 2024, according to a company press release.

EMERGENT-3 was a randomized, double-blind, multicenter, placebo-controlled trial that enrolled 256 participants ages 18 to 65 who had a diagnosis of schizophrenia based on a comprehensive psychiatric evaluation using the DSM-V. The trial was conducted at 18 inpatient sites in the U.S. and 12 inpatient sites in Ukraine between April 1, 2021, and December 7, 2022, but sites in Ukraine were closed to further enrollment after the beginning of the conflict with Russia in February 2022.

Participants had a mean age of 43.1 and the majority were men (74.6%) and Black or African American (60.9%). Participants were randomized into either the xanomeline-trospium group (n=125) or the placebo group (n=131).

Participants started medication on day 1. Those in the xanomeline-trospium group were given 50 mg xanomeline and 20 mg trospium twice daily for the first 2 days, then 100 mg xanomeline and 20 mg trospium twice daily for days 3 through 7. After day 8, participants in the intervention group received flexible dosing with optional increases to a maximum of twice-daily 125 mg xanomeline and 30 mg trospium.

Researchers assessed the participants at screening, baseline, then weekly throughout the 5-week treatment period. Spontaneous adverse events were recorded at each visit, and vital signs were measured throughout the trial, including 2 hours after the morning dose.

The authors noted that the trial had several limitations, including that the study only investigated results after 5 weeks, which does not reflect the life-long nature of schizophrenia or the long-term durability of the combination therapy's effect and safety.

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