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NEW ORLEANS -- The investigational combination xanomeline-trospium (KarXT) succeeded in improving positive and negative symptoms of schizophrenia in the phase III EMERGENT-2 trial.

Meeting its primary endpoint, inpatients on the twice-daily treatment saw a 21.2-point reduction in the Positive and Negative Syndrome Scale (PANSS) total score compared with an 11.6-point reduction with placebo by week 5 (Cohen's d=0.61), reported Christoph U. Correll, MD, of Zucker Hillside Hospital in New York, and colleagues.

This difference was statistically significant as early as the second week of treatment, according to their poster presented at Psych Congress 2022.

Some of the trial's key secondary endpoints were met as well, which included separate PANSS positive subscales -- measuring symptoms such as hallucinations and delusions -- and negative symptom subscales, measuring symptoms like social withdrawal and difficulty enjoying life:

• PANSS positive subscale: -6.8 with xanomeline-trospium vs -3.9 with placebo by week 5
• PANSS negative subscale: -3.4 vs -1.6, respectively
• PANSS negative Marder factor subscale: -4.2 vs -2.0, respectively

These positive phase III findings build upon the phase II EMERGENT-1 trial results, presented earlier this year at the American Psychiatric Association meeting.

The oral treatment acts by combining two agents: the dual M₁/M₄ preferring muscarinic receptor agonist xanomeline, originally developed by Eli Lilly in the 1990s, and trospium, the only peripherally restricted muscarinic receptor antagonist, which neutralizes some of the peripheral M₁-related pro-muscarinic effects. The latter has been used for years by urologists to treat overactive bladder, Angel Angelov, MD, MBA, head of medical affairs at Karuna Therapeutics, the developer of KarXT, explained to 名媛直播.

During the poster presentation, Correll noted that "all currently approved treatments for schizophrenia have direct dopamine D₂ receptor blocking efficacy and also have issues related to efficacy and tolerability in some patients."

"As you know from clinical care, there's a high unmet medical need for certain patients [to have] more effective, better-tolerated treatments for schizophrenia with novel mechanisms of action," he added.

After a 2-week screening phase, the investigational treatment was initiated at a dose of 50 mg of xanomeline and 20 mg of trospium twice daily for the first 2 days, titrated up to 100 mg/20 mg for days 3 to 7, reaching a maximum dose of 125 mg/30 mg for days 8 to 35.

Xanomeline-trospium was well-tolerated, with all of the most common treatment-emergent adverse events rated as mild to moderate in severity. The most common of these (occurring in 5% or more of patients) included constipation, dyspepsia, nausea, vomiting, headache, increases in blood pressure, dizziness, gastroesophageal reflux disease, abdominal discomfort, and diarrhea.

There wasn't a significant difference in average blood pressure values between the treatment groups or from baseline. However, there was a heart rate increase seen on active treatment at the beginning of the trial, but this dropped back down by week 5.

Of note, the treatment wasn't associated with side effects typically common of other schizophrenia agents, such as weight gain, somnolence, and extrapyramidal symptoms like tardive dyskinesia.

Over the course of the trial, 25% and 21% of those on xanomeline-trospium and placebo discontinued treatment, respectively.

For this study, 252 acutely psychotic patients with a confirmed DSM-5 diagnosis of schizophrenia were recruited across 22 trial sites, all of whom were currently experiencing symptoms of psychosis warranting hospitalization. All had a PANSS total score of 80 to 120 and a Clinical Global Impression-Severity score of 4 or higher indicating at least moderate illness at baseline.

Those who received another DSM-5 diagnosis within the prior year were excluded, along with those who had a history of antipsychotic treatment resistance or a drop in PANSS total score of 20% or more between screening and baseline.

Participants ranged in age from 18 to 65 (average age 46), 75% were men, and 75% were Black. Baseline PANSS total score averaged 98.

announced plans to submit a new drug application to the FDA in mid-2023 seeking an indication for schizophrenia after gathering more long-term safety data as part of the EMERGENT-3, -4, and -5 trials.

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