Cobenfy Falls Short in Phase 3 ARISE Trial as Adjunctive Schizophrenia Therapy

Topline results from the Phase 3 ARISE trial showed xanomeline and trospium chloride (Cobenfy) added no significant benefit over placebo as an adjunctive treatment to typical antipsychotics for schizophrenia treatment, announced Bristol Myers on April 22, 2025.1

“Although Cobenfy did not demonstrate a statistically significant improvement as an adjunctive treatment in this trial, the data are encouraging, showing a noteworthy improvement for the majority of patients in the trial, as well as a tolerable safety profile,” said Husseini Manji, MD, FRCPC, co-chair of the UK Government Mental Health Goals Program and a psychiatry professor at Oxford University, in a statement.

The US Food and Drug Administration (FDA) approved Cobenfy for schizophrenia back on September 26, 2024, marking it as the first pharmacological approach to treating schizophrenia since the 1970s and the first antipsychotic drug to target cholinergic, not dopamine, receptors.2 After those pivotal phase 3 EMERGENT trials, the company conducted ARISE (KAR-012), a phase 3, 6-week, randomized, double-blind, placebo-controlled, multicenter, outpatient study evaluating the efficacy and safety of xanomeline and trospium chloride vs placebo as an adjunctive treatment to atypical antipsychotics in adults with schizophrenia.1 The trial included adults aged 18 to 65 years with schizophrenia who were on a stable antipsychotic at the time of enrollment, with a stable Positive and Negative Syndrome Scale (PANSS) score of ≥ 70 at screening.

In ARISE, xanomeline and trospium chloride demonstrated a 2.0-point reduction in the PANSS total score compared to placebo with an atypical antipsychotic at week 6. Preliminary analyses demonstrated that xanomeline and trospium chloride vs placebo as an adjunctive treatment was linked to improvements in schizophrenia symptoms.

Despite numerical reductions, xanomeline and trospium chloride as an adjunctive treatment to typical antipsychotics did not reach a statistically significant difference in the PANSS total score, compared to taking typical antipsychotics with placebo (-14.3 vs -12.2; least squares mean difference [LSMD], -2.0; 95% confidence interval [CI], -4.5 to 0.5; P = .11).

A post-hoc subgroup analysis also showed a notable difference between participants treated with risperidone and those treated with a different background antipsychotic. When patients took risperidone with xanomeline and trospium chloride or placebo, patients had slightly more PANSS total score reductions on risperidone and adjunctive placebo (-12.3 vs 11.3; LSMD, 1.1, 3.7 to 5.9; P = .66. However, when patients took an antipsychotic other than risperidone, participants had signficantly greater PANSS reductions on the antipsychotic plus xanomeline and trospium chloride than the antipsychotic plus placebo (-15 vs -11.7; LSMD, -3.4; -6.3 to -0.5; P = .03).

Xanomeline and trospium chloride’s safety and tolerability profile as an adjunctive treatment aligned with earlier trials.

“These findings warrant additional follow up and may provide valuable direction in our ongoing search for complementary approaches to address these persistent treatment gaps,” Manji said.

References

1. Bristol Myers Squibb Announces Topline Results from Phase 3 ARISE Trial Evaluating Cobenfy (xanomeline and trospium chloride) as an Adjunctive Treatment to Atypical Antipsychotics in Adults with Schizophrenia. Bristol Myers Squibb. April 22, 2025. https://news.bms.com/news/corporate-financial/2025/Bristol-Myers-Squibb-Announces-Topline-Results-from-Phase-3-ARISE-Trial-Evaluating-Cobenfy-xanomeline-and-trospium-chloride-as-an-Adjunctive-Treatment-to-Atypical-Antipsychotics-in-Adults-with-Schizophrenia/default.aspx. Accessed April 22, 2025.

2. Derman, C. Bristol Myers Squibb Shares EMERGENT-4, EMERGENT-5 Results on Cobenfy for Schizophrenia. HCPLive. November 1, 2024. https://www.hcplive.com/view/fda-approves-xanomeline-and-trospium-chloride-cobenfy-for-schizophrenia. Accessed April 22, 2025.