Bristol Myers Squibb’s Cobenfy Falls Short in Phase III Trial as Add On Therapy for Schizophrenia

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Results from the Phase III ARISE trial show that Bristol Myers Squibb’s (BMS) Cobenfy (xanomeline and trospium chloride) failed to meet the primary endpoint in adult patients with schizophrenia that was inadequately controlled by prior antipsychotic therapies. The trial found that Cobenfy did not achieve statistical significance based on the change from baseline to week six in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo.¹

"Adjunctive treatment trials in schizophrenia present significant clinical and methodological challenges," said Husseini Manji, MD, FRCPC, co-chair, UK Government Mental Health Goals Program, professor, department of psychiatry, Oxford University, in a press release. "When patients are already receiving treatment, demonstrating additional statistical benefit becomes inherently more difficult. However, it’s common for individuals to continue to experience persistent symptoms, and prescribers have adopted an approach to address this significant unmet need through adjunctive use. 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."

The randomized, double-blind, placebo-controlled, multicenter, outpatient ARISE trial evaluated Cobenfy in adult patients with schizophrenia who had demonstrated inadequate responses to previous antipsychotic treatments. All enrolled patients were on stable background therapy and maintained a PANSS score of 70 at screening and randomization. Key secondary endpoints of the study included changes in personal and social performance (PSP), Clinical Global Impression-Severity (CGI-S), PANSS Marder positive and negative symptom factor scores, categorical response, and preference of medication.

Results showed that Cobenfy demonstrated a two-point reduction in PANSS total score versus placebo at week six, which was not statistically significant. Additionally, Cobenfy demonstrated a 0.6-point change in PSP score and a 0.1-point change in CGI-S score, indicating that the changes in secondary endpoints were also not statistically significant. However, results from a post-hoc subgroup analysis revealed a nominally significant benefit among patients receiving non-risperidone background antipsychotics, with a 3.4-point greater reduction in PANSS score compared to placebo. In contrast, there was no benefit found in patients treated with risperidone, while there was a 1.1-point change in PANSS score, favoring placebo.

Despite limited efficacy findings, in terms of safety, Cobenfy was well tolerated in the ARISE study. The most common adverse events associated with Cobenfy included nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastroesophageal reflux disease.¹

"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, EVP, chief medical officer, head of development, BMS, in a press release. "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 first approved in September 2024 in 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. BMS. April 22, 2025. Accessed April 23, 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

2. FDA Approves Bristol Myers Squibb’s Cobenfy for Schizophrenia. PharmExec. September 27, 2024. Accessed April 23, 2025. https://www.pharmexec.com/view/fda-approves-bristol-myers-squibb-cobenfy-schizophrenia