NEW ORLEANS–The xanomeline-trospium (KarXT) research group improved both positive and negative symptoms of schizophrenia in the EMERGENT-2 Phase III trial.
When the primary endpoint was met, twice-daily inpatients experienced a 21.2-point reduction in PANSS total positive and negative syndrome scale (PANSS) compared to a 11.6-point reduction with placebo by week 5 (Cohen) Dr= 0.61), according to Christoph U. Corell, 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 the poster presented in Psychological Conference 2022.
Some of the trial’s main secondary endpoints were also met, which included separate positive subscales for PANSS – a measure of symptoms such as hallucinations and delusions – and subscales for negative symptoms, and a measure of symptoms such as social withdrawal and difficulty enjoying life:
- Positive subscale for PANSS: -6.8 with xanomeline-trospium vs -3.9 with placebo at week 5
- Negative sub-range of PANSS: -3.4 vs -1.6, respectively
- PANSS Negative Marder Factor Subrange: -4.2 vs -2.0, respectively
Oral therapy works by combining two factors: Double M1/ M4 The muscarinic receptor agonist prefers xanomeline, originally developed by Eli Lilly in the 1990s, and trospium, the only peripherally restricted muscarinic receptor antagonist, which neutralizes some peripheral M.1Related pro-muscarinic effects. The latter has been used for years by urologists to treat an overactive bladder, Angel Angelov, MD, MBA, chief medical officer at Karuna Therapeutics, developer of KarXT, explained to MedPage today.
During the poster presentation, Correll noted that “all currently approved therapies for schizophrenia contain direct D-dopamine.2 receptor-blocking efficacy and also has issues with efficacy and tolerability in some patients.”
“As you know from clinical care, there is a high unmet medical need for some patients [to have] More effective and better-tolerated therapies for schizophrenia with new mechanisms of action.
After the 2-week screening phase, empiric therapy was started with 50 mg xanomeline and 20 mg trospium twice daily for the first 2 days, titrated to 100 mg/20 mg on days 3 through 7, to a maximum dose of 125 mg/30 mg for days 8 to 35.
Xanomeline-trospium was well tolerated, with all adverse events most commonly rated as mild to moderate in severity. The most common of these (occurring in 5% or more of patients) are constipation, indigestion, nausea, vomiting, headache, increased blood pressure, dizziness, gastroesophageal reflux disease, abdominal discomfort, and diarrhoea.
There was no significant difference in mean blood pressure values between treatment groups or from baseline. However, there was an increase in heart rate observed in the active treatment at the start of the trial, but this decreased again by the fifth week.
Of note, treatment was not associated with common side effects of other schizophrenia agents, such as weight gain, drowsiness, and extrapyramidal symptoms such as tardive dyskinesia.
Over the course of the trial, 25% and 21% of those treated with zanomyelin-tropium and placebo discontinued, respectively.
In this study, 252 acute psychotic patients with a confirmed DSM-5 diagnosis of schizophrenia were recruited across 22 experimental sites, all of whom currently had symptoms of psychosis requiring hospitalization. All had a PANSS score of 80 to 120 and a clinical global impression severity score of 4 or higher indicating at least moderate disease at baseline.
Those who had received another diagnosis in the DSM-5 within the previous year, along with those with a history of antipsychotic treatment resistance or a decrease in their PANSS total score of 20% or more between screening and baseline, were excluded.
Participants’ ages ranged from 18 to 65 (median age 46), and 75% were men, and 75% were black. The average PANSS baseline score was 98.
Karuna Treatments He announced plans to submit a new drug application to the Food and Drug Administration in mid-2023 in search of an indication for schizophrenia after collecting more long-term safety data as part of the EMERGENT-3, -4, and -5 trials.
This trial was funded by Karuna Therapeutics.
Corel has mentioned several relationships, including with Karuna.