Cobenfy as Add-On Treatment for Schizophrenia Fails to Meet Primary Endpoint in Phase 3 ARISE Trial

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According to topline results from the phase 3 ARISE study, xanomeline and trospium chloride (Cobenfy) as an adjunctive treatment to atypical antipsychotics did not show a statistically significant difference compared with placebo in adults with inadequately controlled symptoms of schizophrenia. However, treatment with Cobenfy and an atypical antipsychotic showed a numerical improvement compared with treatment with placebo and an atypical antipsychotic.

“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. These findings warrant additional follow up and may provide valuable direction in our ongoing search for complementary approaches to address these persistent treatment gaps,” Husseini Manji, MD, FRCPC, cochair of the UK Government Mental Health Goals Program and professor in the Department of Psychiatry at Oxford University.

In the phase 3 trial, adjunctive Cobenfy treatment demonstrated a 2.0-point reduction in the Positive and Negative Syndrome Scale (PANSS) total score when compared with placebo combined with an atypical antipsychotic at week 6, which did not reach the threshold for statistical significance for the primary endpoint (P = 0.11). Preliminary analyses suggest that Cobenfy as an adjunctive treatment to an atypical antipsychotic was associated with improvements in symptoms of schizophrenia compared with placebo plus an atypical antipsychotic for certain patients. In a post-hoc subgroup analysis, there was a notable difference in response between participants treated with risperidone as a background therapy compared with the remaining participants treated with other background antipsychotics (nonrisperidone).

"Adjunctive treatment trials in schizophrenia present significant clinical and methodological challenges," said Manji. "When patients are already receiving treatment, demonstrating additional statistical benefit becomes inherently more difficult. However, it is common for individuals to continue to experience persistent symptoms, and prescribers have adopted an approach to address this significant unmet need through adjunctive use.”

In the 6-week, randomized, double-blind, placebo-controlled, multicenter, outpatient ARISE study evaluating Cobenfy, investigators enrolled adults aged 18 to 65 years with schizophrenia who were on stable background therapy at the time of enrollment, with a Positive and Negative Syndrome Scale (PANSS) score of greater than or equal to 70 at screening and randomization. The primary objective was to assess the efficacy of Cobenfy as an adjunctive treatment to atypical antipsychotics compared with placebo combined with an atypical antipsychotic as measured by change from baseline in PANSS total score at week 6. The study also evaluated several secondary endpoints, including changes in Personal Social Performance, Clinical Global Impression-Severity, PANSS Marder Positive and Negative symptom factor scores, categorical response (defined as the proportion of subjects achieving greater than or equal to 30% improvement in PANSS total score at week 6), and Preference of Medication.

"Historically, the development of an effective, adjunctive treatment for schizophrenia has been difficult due to inherent challenges like variable patient response, stringent trial design requirements, and the complexities of demonstrating incremental benefits beyond established antipsychotics," said Samit Hirawat, MD, executive vice president, chief medical officer, and head of development at Bristol Myers Squibb. "Despite the complex and challenging nature of adjunctive studies, we wanted to pursue research in this area to help more patients struggling with this condition. While the primary endpoint in this trial did not meet statistical significance, we need to complete our analysis and will plan to engage with the medical community and regulators to discuss these results and potential next steps. Cobenfy monotherapy has shown positive efficacy and safety in four pivotal studies, and provides a meaningful, differentiated treatment for people living with schizophrenia.”

Cobenfy was approved by the US Food and Drug Administration on September 20, 2024, making it the first new agent with a novel mechanism of action for schizophrenia more than 50 years, and had been described as a “quantum leap” for care of patients with schizophrenia.²

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. News release. April 22, 2025. https://news.bms.com/news/details/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

2. 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