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Cobenfy as an adjunctive treatment to atypical antipsychotics did not reach the threshold for a statistically significant difference compared to placebo with an atypical antipsychotic for the primary endpoint of the change from baseline to Week 6 in the Positive and Negative Syndrome Scale (PANSS) total score
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Treatment with Cobenfy and an atypical antipsychotic showed a numerical improvement compared to treatment with placebo and an atypical antipsychotic
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Cobenfy’s safety and tolerability profile as an adjunctive therapy was consistent with previous monotherapy trials
April 22, 2025--PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb (NYSE: BMY) today announced topline results from the Phase 3 ARISE trial evaluating the efficacy and safety of Cobenfy (xanomeline and trospium chloride) as an adjunctive treatment to atypical antipsychotics in adults with inadequately controlled symptoms of schizophrenia. In the Phase 3 trial, adjunctive Cobenfy treatment demonstrated a 2.0-point reduction in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo 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 to placebo plus an atypical antipsychotic for certain patients. In a post-hoc subgroup analysis there was a notable difference in response between subjects treated with risperidone as a background therapy compared with the remaining subjects treated with other background antipsychotics (non-risperidone). The initial analyses showed:
APD = Antipsychotic background drug; PANSS = Positive and Negative Syndrome Scale; PSP = Personal and Social Performance Scale; CGI-S = Clinical Global Impressions Severity Scale; mITT = modified intent-to-treat; SE = Standard Error; LSMD = Least Squares Mean Difference; Non-Risperidone group includes paliperidone, aripiprazole, ziprasidone, lurasidone and cariprazine.
*p-value is nominal, not adjusted for multiplicity
Cobenfy’s safety and tolerability profile as an adjunctive treatment was consistent with previous monotherapy trials.
Further analysis will follow, and the company will plan to speak with regulators about potential next steps.
"Adjunctive treatment trials in schizophrenia present significant clinical and methodological challenges," said Husseini Manji, MD, FRCPC, Co-Chair, UK Government Mental Health Goals Program and Professor, Department of Psychiatry, Oxford University. "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."
"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.”
There is a robust clinical development program advancing for this important medicine across multiple neuropsychiatric conditions, including symptoms associated with Alzheimer's disease and autism spectrum disorder, bipolar disorder and other areas of significant clinical need.
Bristol Myers Squibb will complete a full evaluation of the Phase 3 trial data and intends to present detailed results at an upcoming medical conference.
Bristol Myers Squibb thanks the patients, investigators and clinical trial sites who participated in the ARISE clinical trial.
About the Phase 3 ARISE Trial
The ARISE clinical trial (KAR-012) is a Phase 3, 6-week, randomized, double-blind, placebo-controlled, multicenter, outpatient study evaluating Cobenfy (xanomeline and trospium chloride) as an adjunctive treatment in adults with schizophrenia who have inadequate response to their current antipsychotic treatment. The trial 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 ≥70 at screening and randomization. The primary objective is to assess the efficacy of Cobenfy as an adjunctive treatment to one of several atypical antipsychotics compared to placebo 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 (PSP), Clinical Global Impression-Severity (CGI-S), PANSS Marder Positive and Negative symptom factor scores, categorical response (defined as the proportion of subjects achieving ≥30% improvement in PANSS total score at Week 6), and Preference of Medication (POM).
Following completion of the ARISE study, eligible participants may continue in a 52-week open-label extension (OLE) study to evaluate the long-term safety and tolerability of adjunctive Cobenfy treatment.
About Schizophrenia
Schizophrenia is a persistent and often disabling mental illness impacting how a person thinks, feels and behaves. There are three symptom domains of schizophrenia, which include positive symptoms (e.g., hallucinations, delusions, disordered thinking and speech), negative symptoms (e.g., lack of motivation, lack of emotional expression/flat affect, social withdrawal) and cognitive dysfunction (e.g., impaired attention, deficits in memory, concentration and decision-making). The symptoms of schizophrenia can affect all areas of people’s lives, making it difficult to maintain employment, live independently and manage relationships. Schizophrenia affects nearly 24 million people worldwide, including 2.8 million people in the United States, and is one of the top 15 leading causes of disability worldwide.
Bristol Myers Squibb: Transformational Research Advancing Neuroscience
Bristol Myers Squibb is inspired by a single vision – transforming patients’ lives through science. Neurological and neuropsychiatric conditions represent some of the greatest challenges of our time, bringing life-altering hardships to patients, caregivers and families throughout the course of these devastating diseases. Our researchers are committed to the pursuit of breakthrough science to develop life-changing medicines that modify disease and treat symptoms to improve quality of life. We have established a diverse neuroscience portfolio, including assets across a wide range of therapeutic modalities and mechanisms in conditions such as Alzheimer’s disease, schizophrenia, multiple sclerosis and more. With industry-leading capabilities, including our in-house neuroimaging program, we seek bold solutions to improve the treatment landscape. Evolution is in our DNA at Bristol Myers Squibb. We are motivated by the rapid progress of scientific knowledge within neuroscience and have an unwavering commitment to advance the most promising innovations to deliver transformational results for patients.
About Cobenfy™ (xanomeline and trospium chloride)
Cobenfy™ (xanomeline and trospium chloride), formerly KarXT, is an oral medication for the treatment of schizophrenia in adults. Cobenfy combines xanomeline, a dual M1- and M4-preferring muscarinic receptor agonist, with trospium chloride, a muscarinic receptor antagonist that does not appreciably cross the blood-brain barrier, primarily confining its effects to peripheral tissues. While the exact mechanism of action of Cobenfy is unknown, its efficacy is thought to be due to the agonist activity of xanomeline at M1 and M4 muscarinic acetylcholine receptors in the central nervous system.
About Bristol Myers Squibb
Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases.