Cobenfy as an Adjunctive Agent in Schizophrenia: Peter J. Weiden, MD, Shares Insights on the Latest Findings

In an exclusive interview with Psychiatric Times, Peter J. Weiden, MD, clinical professor of psychiatry at SUNY Stony Brook, offered key clinical insights into the recently released study results evaluating Cobenfy (xanomeline/trospium) as an adjunct treatment for schizophrenia.^1,2

Approved by the US Food and Drug Administration (FDA) in 2024, Cobenfy represents the first schizophrenia treatment to target muscarinic acetylcholine receptors rather than dopamine pathways.³ “The FDA does not call it an antipsychotic because it is not a dopamine medicine,” said Weiden. Its approval was based on phase 3 trial data showing efficacy as monotherapy in adult patients with schizophrenia, with effect sizes on par with established agents such as olanzapine and risperidone.

The recent trial data, announced via a Bristol Myers Squibb press release,¹ evaluated Cobenfy’s efficacy as an adjunctive therapy when there is suboptimal response to a first-line antipsychotic. The results did not meet the prespecified threshold for statistical significance.

“The results did not meet statistical significance in patients who were stayed on their primary antipsychotic and were randomized to Cobenfy versus placebo,” Weiden told Psychiatric Times. “However, it was numerically better than the placebo group.”

Weiden attributed part of the outcome to a high placebo response, which often complicates the interpretation of adjunctive studies. “These studies are very hard to do,” he added. “So the fact that it did not separate, at least to me, is not a surprise… it's disappointing, but it happens.” He also noted the press release had limited data, so it is difficult to make grand conclusions without knowing more.

From a regulatory perspective, Weiden said unless there are additional studies or data, these findings make it unlikely that Cobenfy will receive an expanded label for treatment resistance or adjunctive use at this time. “This is not clozapine, and this has not helped us think of it as a kind of clozapine.”

Still, the results are far from conclusive in clinical practice, where antipsychotic combination strategies are common, albeit debated. “In my experience, it's almost like a religion—either you believe in it, or you don't,” he said. “If you're a clinician who likes to combine antipsychotics for partial responders… where would Cobenfy fit in that? There, the answer is still unclear.”

In good news, Weiden explained the safety findings were reassuring. “Nothing weird happened over the 6 weeks when patients were combined with Cobenfy and their current antipsychotic,” he reported.

Looking ahead, Weiden emphasized that there is still more to learn. “This is just the beginning of our understanding of the muscarinic system as a potential treatment approach for patients with schizophrenia.”

Although the trial results may not lead to immediate regulatory changes, Weiden urged clinicians to stay engaged. “I think it's going to be a very important study no matter what,” he said. “And there's still a lot more to be told.”

Dr Weiden is a clinical professor of psychiatry at the Renaissance School of Medicine at Stony Brook University in New York. He is Psychiatric Times' Schizophrenia and Psychosis Section Editor.

Disclosure: Dr Weiden is a former employee of Karuna Therapeutics and is currently on the speakers bureau for Bristol-Myers Squibb.

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. Accessed April 25, 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. Kuntz L. Cobenfy as Add-On Treatment for Schizophrenia Fails to Meet Primary Endpoint in Phase 3 ARISE Trial. Psychiatric Times. April 22, 2025. Accessed April 25, 2025. https://www.psychiatrictimes.com/view/cobenfy-as-add-on-treatment-for-schizophrenia-fails-to-meet-primary-endpoint-in-phase-3-arise-trial

3. Duerr HA. FDA Approves Cobenfy, A First In-Class Agent for Schizophrenia. Psychiatric Times. September 26, 2024. Accessed April 25, 2025. https://www.psychiatrictimes.com/view/fda-approves-cobenfy-for-schizophrenia