Long-term data from the phase III EMERGENT-4 trial indicates that xanomeline and trospium chloride (Cobenfy) demonstrates sustained efficacy and safety in treating schizophrenia. The findings, presented at the Psych Congress in Boston, offer additional support for the drug, which was approved in September as the first new class of medication for schizophrenia in over 30 years.
Participants who continued Cobenfy after an initial 5-week treatment period showed a 33.8-point drop in their Positive and Negative Syndrome Scale (PANSS) total score after 52 weeks. Those who switched to xanomeline and trospium chloride from placebo saw a 31.3-point improvement from baseline, according to Inder Kaul, MD, MPH, of Bristol Myers Squibb.
EMERGENT-4 Trial Results
Of the 35 participants who completed the 52-week EMERGENT-4 trial, 68.6% experienced a 30% or greater reduction from acute trial baseline in floor-adjusted PANSS total score. Similar improvements were observed in the PANSS positive and negative subscales, as well as Clinical Global Impression-Severity (CGI-S) scores. By week 4, efficacy measures were similar between the two groups.
EMERGENT-5 Trial Results
The open-label EMERGENT-5 trial included adults with schizophrenia who had stable symptoms on a prior antipsychotic and no prior exposure to xanomeline and trospium. After 52 weeks, participants had the following mean changes from baseline:
- PANSS total score: -5.5 points
- CGI-S score: -0.4 point
- PANSS positive subscale score: -1.9 points
- PANSS negative subscale score: -0.8 point
Of the 283 participants who completed EMERGENT-5, 30% achieved a 30% or greater reduction from baseline in floor-adjusted PANSS total score.
Expert Commentary
"The long-term findings should provide additional confidence to healthcare providers when deciding to prescribe Cobenfy, as this data reinforces the efficacy and tolerability seen in previous short-term trials," said EMERGENT program investigator Rishi Kakar, MD, chief scientific officer and medical director of Segal Trials. He noted the importance of long-term data given the chronic nature of schizophrenia.
Safety and Tolerability
In EMERGENT-4, the safety profile of xanomeline and trospium chloride was consistent with previous reports. 35.5% of participants experienced at least one treatment-related adverse event, primarily mild to moderate gastrointestinal events that did not lead to discontinuation. A small decrease in body weight (-1.9 kg) was observed by week 52, along with minor increases in blood pressure and heart rate, peaking at week 2.
- Systolic blood pressure: +1.9 mm Hg
- Diastolic blood pressure: +0.7 mm Hg
- Heart rate: +3.9 bpm
There were no clinically meaningful changes in prolactin levels or movement disorder scales, and no reports of akathisia or tardive dyskinesia.
Novel Mechanism of Action
Cobenfy targets the M1 and M4 muscarinic receptors, differing from traditional antipsychotics that act on dopaminergic and serotonergic receptors. This unique mechanism may benefit patients who do not respond to or tolerate dopamine-blocking agents. The drug's approval was based on the 5-week EMERGENT-2 and EMERGENT-3 trials, which both met their primary endpoint, demonstrating significantly greater reductions in PANSS total score compared with placebo (P < 0.0001 for both).
Study Details
When the 152 participants from EMERGENT-4 were enrolled in EMERGENT-2 and -3, all had a primary schizophrenia diagnosis with an acute exacerbation of psychosis warranting hospitalization. Their mean age was 44.9, 75% were men, 61.2% were Black or African American, and 36.8% were white. All had a baseline PANSS total score of 80-120 and a CGI-S score of 4 or higher. Participants were started on twice-daily oral doses of xanomeline 50 mg/trospium 20 mg and were titrated up to a maximum dose of 125 mg/30 mg for 52 weeks.
In a qualitative interview-based survey, the average satisfaction score for xanomeline and trospium was 8.1 out of 10, compared to 5.7 for past treatments. 78.3% indicated they would continue taking the drug after the trial.
