Bristol Myers Squibb (BMS) announced that its novel schizophrenia medication Cobenfy (xanomeline and trospium chloride) failed to meet the primary endpoint in the Phase 3 ARISE trial evaluating its efficacy as an adjunctive treatment for adults with schizophrenia who had inadequate response to their current antipsychotic therapy.
The trial showed Cobenfy produced a 2.0-point greater reduction in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo when added to atypical antipsychotics, but this difference did not reach statistical significance (-14.3 vs -12.2; least squares mean difference, -2.0; 95% confidence interval, -4.5 to 0.5; P = .11).
"Adjunctive treatment trials in schizophrenia present significant clinical and methodological challenges," said Husseini Manji, MD, FRCPC, Co-Chair of the UK Government Mental Health Goals Program and Professor in the Department of Psychiatry at Oxford University. "When patients are already receiving treatment, demonstrating additional statistical benefit becomes inherently more difficult."
Differential Response Based on Background Therapy
A notable finding emerged in post-hoc subgroup analysis, which revealed a significant difference in response based on the background antipsychotic medication. Patients receiving non-risperidone antipsychotics showed significantly greater PANSS reductions with adjunctive Cobenfy compared to placebo (-15 vs -11.7; LSMD, -3.4; -6.3 to -0.5; P = .03). In contrast, patients on risperidone showed no additional benefit from Cobenfy.
This differential response suggests potential for targeted use of Cobenfy as an adjunctive therapy in specific patient populations, though further analysis is needed to understand these findings.
Novel Mechanism of Action
Cobenfy represents the first new pharmacological approach to treating schizophrenia since the 1970s. Unlike traditional antipsychotics that target dopamine receptors, Cobenfy works through a novel mechanism as a dual M1- and M4-preferring muscarinic receptor agonist.
The FDA approved Cobenfy as a monotherapy for schizophrenia in September 2024 based on positive results from the EMERGENT clinical trial program. The ARISE trial was designed to evaluate whether Cobenfy could provide additional benefits when added to existing antipsychotic treatments.
Trial Design and Patient Population
The ARISE study was a 6-week, randomized, double-blind, placebo-controlled trial that enrolled adults aged 18 to 65 years with schizophrenia who were on stable background therapy with a PANSS score of ≥70 at screening and randomization.
The primary endpoint was the change from baseline in PANSS total score at Week 6. Secondary endpoints included changes in Personal Social Performance (PSP), Clinical Global Impression-Severity (CGI-S), PANSS Marder Positive and Negative symptom factor scores, and other measures.
Safety Profile Consistent with Previous Studies
According to the company, Cobenfy's safety and tolerability profile as an adjunctive treatment aligned with earlier trials. The most common adverse reactions observed in previous studies included nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastroesophageal reflux disease.
Expert Perspectives on the Results
Despite not meeting the primary endpoint, some experts see potential value in the findings. Dr. Manji noted, "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."
Samit Hirawat, MD, executive vice president, chief medical officer and head of development at Bristol Myers Squibb, acknowledged the challenges in adjunctive treatment studies: "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."
Future Directions
BMS plans to complete a full evaluation of the Phase 3 trial data and intends to present detailed results at an upcoming medical conference. The company will also engage with regulators to discuss potential next steps.
"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," said Dr. Hirawat.
The company noted that Cobenfy's development program continues to advance across multiple neuropsychiatric conditions, including symptoms associated with Alzheimer's disease, autism spectrum disorder, and bipolar disorder.
Unmet Needs in Schizophrenia Treatment
Schizophrenia affects nearly 24 million people worldwide, including 2.8 million in the United States, and is one of the top 15 leading causes of disability globally. Despite available treatments, many patients continue to experience persistent symptoms that significantly impact their quality of life and ability to function.
The search for effective adjunctive treatments remains an important goal in addressing the complex symptomatology of schizophrenia, particularly for patients who show inadequate response to current antipsychotic medications.
