Posters Share Positive Data on Long-Term Treatment with Xanomeline/Trospium

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Results from the 52-week, open label EMERGENT-4¹ and EMERGENT-5² trials showed that long-term treatment with xanomeline/trospium was safe and generally well tolerated in participants with schizophrenia. Investigators shared the new data in 2 posters presented at the 2024 Psych Congress.

Xanomeline/trospium (Cobenfy), formerly known as KarXT, was recently approved by the US Food and Drug Administration for the treatment of schizophrenia in adults. Unlike most available antipsychotics, xanomeline/trospium utilizes a unique mechanism of action and does not directly block D2 dopamine receptors.³

In the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1, EMERGENT-2, and EMERGENT-3 trials, xanomeline/trospium improved symptoms and was generally well tolerated.

“Building on momentum from the recent US Food and Drug Administration’s approval of Cobenfy for the treatment of schizophrenia in adults, we’re pleased to be sharing additional data at Psych Congress from the EMERGENT clinical trial program that further highlights the differentiated clinical profile of Cobefny, including efficacy, safety, and patient reported outcomes of adults with schizophrenia who participated in our long-term clinical trials,” said Alyssa Johnsen, MD, PhD, senior vice president and head of clinical development, Immunology, Cardiovascular and Neuroscience, at Bristol Myers Squibb. “As we continue to strengthen our neuropsychiatry portfolio, we remain committed to developing and delivering differentiated options for patients.”⁴

EMERGENT-4

Results from the 52-week, open label extension EMERGENT-4 trial showed that long-term treatment with xanomeline/trospium was safe and generally well tolerated in participants with schizophrenia. Investigators did not identify any new safety or tolerability issues.

Participants who enrolled in EMERGENT-2 or EMERGENT-3 were required to be aged 18 to 65 years, have a diagnosis of schizophrenia, be experiencing acute psychosis that warrants hospitalization, have a Positive and Negative Syndrome Scale (PANSS) total score 80-120, and have a Clinical Global Impression–Severity (CGI-S) score greater than or equal to 4. Participants who enrolled in EMERGENT-4 were required to have completed the treatment period of EMERGENT-2 or EMERGENT-3, reside in a stable living situation, and have a reliable caregiver.

All participants started with twice-daily oral doses of xanomeline 50 mg/trospium 20 mg and were titrated to a maximum dose of xanomeline 125 mg/trospium 30 mg for a total of 52 weeks.

A total of 152 participants were included in the safety population for analyses. Overall, 122 of 156 (78.2%) enrolled participants discontinued the trial. Trial discontinuation reasons included withdrawal of consent (34.0%), failure to adhere to treatment protocols (15.4%), and lost to follow-up (12.8%).

Approximately 35.5% of participants experienced 1 or more treatment-related adverse event (AE). The incidence of treatment-related AEs was similar in participants with (35.3%) or without (35.7%) prior xanomeline/trospium exposure in EMERGENT-2 or EMERGENT-3.

Most treatment-related AEs were mild or moderate gastrointestinal (GI) disorders, did not lead to discontinuation of trial medication, and resolved with continued treatment. Incidence of GI disorders was similar between participants with or without prior xanomeline/trospium exposure, witgh the exception of vomiting (2.9% vs 11.9%). Serious treatment-related treatment-emergent AEs were reported by 2 (1.3%) participants and were related to worsening schizophrenia.

Investigators noted continued improvement with xanomeline/trospium treatment in PANSS total, CGI-S, PANSS positive subscale, and PANSS negative subscale scores over 52 weeks. This demonstrates long-term efficacy and durability. Mean change from acute trial baseline to week 52 in PANSS total score was -33.8 in the xanomeline/trospium group and -31.3 in the placebo group. Notably, in participants who received placebo in the acute trials, there was an initial rapid improvement in symptoms once treatment with xanomeline/trospium was initiated.

Investigators noted that by week 4, there were no clinically meaningful differences between the groups who received xanomeline/trospium and placebo in the acute trials. Furthermore, continued improvement in PANSS total score was evident in both treatment groups throughout the 52 weeks of open-label treatment with xanomeline/trospium.

Additionally, at week 52, 68.6% of participants had a 30% or greater reduction from acute trial baseline in floor-adjusted PANSS total score.

EMERGENT-5

EMERGENT-5 was a phase 3, multicenter, outpatient, 52-week, open-label trial in adults with schizophrenia. Eligible participants had to have stable symptoms of schizophrenia, no prior exposure to xanomeline/trospium, a PANSS total score less than or equal to 80, and a CGI-S score less than or equal to 4.

All participants initiated twice-daily oral doses of xanomeline/trospium at xanomeline 50 mg/trospium chloride 20 mg and were titrated to a maximum dose of xanomeline 125 mg/trospium chloride 30 mg for a total of 52 weeks.

The safety population for analysis included a total of 566 participants. Overall, 289 of the 566 (51.1%) enrolled participants discontinued the trial. Most trial discontinuation reasons were participant related including adverse event (17.0%), withdrawal of consent (16.4%), and lost to follow-up (8.1%).

By last dose of xanomeline/trospium, 145 (25.6%) of participants were receiving 100 mg/20 mg twice daily, and 412 (72.8%) were receiving 125 mg/30 mg twice daily.

Overall, 67.1% of participants experienced 1 or more treatment-related treatment-emergent adverse event (TEAE). The majority of treatment-related TEAEs were mild or moderate GI disorders, and did not lead to discontinuation of trial medication. Serious treatment-related TEAEs were reported by 9 (1.6%) participants. Overall, 7 (1.2%) participants reported a TEAE of akathisia and 2 (0.4%) reported a TEAE of tardive dyskinesia.

Over the course of 52 weeks, treatment with xanomeline/trospium led to improvements in PANSS total, CGI-S, PANSS positive subscale, and PANSS negative subscale scores. Mean change from baseline to week 52 in outcome measures were -5.5 PANSS total score, -0.4 CGI-S score, -1.9 PANSS positive subscale score, and -0.8 PANSS negative subscale score. At week 52, 85 out of 283 participants (30.0%) had a 30% or higher reduction from baseline in floor-adjusted PANSS total score.

“Treatment with xanomeline/ trospium led to continued, durable improvements in PANSS total, CGI-S, PANSS positive subscale, and PANSS negative subscale scores, confirming maintenance of efficacy over 52 weeks,” wrote the poster presenters.

References

1. Kaul I, Claxton A, Sauder C, et al. Long-term safety and efficacy of xanomeline and trospium chloride in schizophrenia: results from the 52-week, open-label EMERGENT-4 trial. Poster presented at: Psych Congress; October 29-November 2, 2024; Boston, Massachusetts.

2. Kaul I, Claxton A, Sauder C, et al. Long-term safety, tolerability, and efficacy of xanomeline and trospium chloride in people with schizophrenia: results from the 52-week, open-label EMERGENT-5 trial. Poster presented at: Psych Congress; October 29-November 2, 2024; Boston, Massachusetts.

3. Duerr HA. FDA approves Cobenfy, a first in-class agent for schizophrenia. Psychiatric Times. September 26, 2024. https://www.psychiatrictimes.com/view/fda-approves-cobenfy-for-schizophrenia

4. Bristol Myers Squibb to Present New Clinical and Health Economics and Outcomes Research Data at Psych Congress 2024. News release. October 28, 2024. Accessed October 31, 2024. https://news.bms.com/news/corporate-financial/2024/Bristol-Myers-Squibb-to-Present-New-Clinical-and-Health-Economics-and-Outcomes-Research-Data-at-Psych-Congress-2024/default.aspx