First Schizophrenia Treatment Approved in Decades Targets Cholinergic Receptors

While existing antipsychotic drugs primarily target dopamine receptors to manage schizophrenia symptoms, xanomeline-trospium chloride offers a novel approach by modulating cholinergic receptors.

FDA approval | Image Credit: Tada Images - stock.adobe.com

The FDA approved xanomeline and trospium chloride (Cobenfy) capsules, the first antipsychotic medication for schizophrenia that targets cholinergic receptors instead of the traditional dopamine receptors, for adults with schizophrenia.¹ The therapy, developed by Bristol Myers-Squibb, offers a new treatment option for patients affected by the debilitating mental condition, and is the first new drug approved for schizophrenia in decades.

“Schizophrenia is a leading cause of disability worldwide. It is a severe, chronic mental illness that is often damaging to a person’s quality of life,” Tiffany Farchione, MD, director of the Division of Psychiatry, Office of Neuroscience, Center for Drug Evaluation and Research, FDA, said in a statement. “This drug takes the first new approach to schizophrenia treatment in decades. This approval offers a new alternative to the antipsychotic medications people with schizophrenia have previously been prescribed.”

The agency's approval of xanomeline-trospium chloride is based on phase 3 EMERGENT data, which included a pair of identical 5-week randomized, double-blind, placebo-controlled, multicenter studies. These studies enrolled adult patients diagnosed with schizophrenia based on DSM-5 criteria and measured efficacy using the Positive and Negative Syndrome Scale (PANSS). PANSS is a 30-item scale that evaluates the severity of schizophrenia symptoms.

Xanomeline-trospium chloride exhibited meaningfully improved symptoms at Week 5, suggesting the drug’s potential as a valuable tool in managing schizophrenia.² In both studies, patients who received the therapy demonstrated a significant reduction in symptoms, as measured by the PANSS total score, compared with those in the placebo group (–20.6) vs –2.2; least squares mean difference, –8.4; 95% CI, –12.4 to –4.3; P < .001).

Despite its efficacy, the prescribing information of xanomeline-trospium chloride warns that the drug can cause urinary retention, elevated heart rate, slowed gastric movement, and angioedema, a type of swelling beneath the skin.¹ It is also linked to potential liver damage and should not be used by patients with known liver impairment. Additionally, xanomeline-trospium chloride is not recommended for individuals with moderate to severe kidney issues.

Common side effects include nausea, indigestion, constipation, vomiting, high blood pressure, abdominal pain, diarrhea, and dizziness. The statement noted that patients experiencing symptoms of liver disease—such as yellowing of the skin or eyes, dark urine, or unexplained itching—are advised to discontinue use immediately. The drug is contraindicated for patients with conditions like urinary retention, untreated narrow-angle glaucoma, or a history of hypersensitivity to the drug or its components.

By providing an alternative to dopamine-targeting therapies, xanomeline-trospium chloride opens up new possibilities for the management of this complex and chronic mental illness.

“Due to its heterogeneous nature, schizophrenia is not a one-size-fits-all condition, and people often find themselves in a cycle of discontinuing and switching therapies,” Rishi Kakar, MD, chief scientific officer and medical director at Segal Trials and investigator in the EMERGENT program, said in a statement.³ “The approval of COBENFY is a transformative moment in the treatment of schizophrenia because, historically, medicines approved to treat schizophrenia have relied on the same primary pathways in the brain. By leveraging a novel pathway, Cobenfy offers a new option to manage this challenging condition.”

References

1. FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia. News release. FDA. September 26, 2024. Accessed September 27, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia

2. Kaul I, Sawchak S, Walling DP, et al. Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry. 2024;81(8):749–756. doi:10.1001/jamapsychiatry.2024.0785

3. U.S. Food and Drug Administration Approves Bristol Myers Squibb’s COBENFY™ (xanomeline and trospium chloride), a First-In-Class Muscarinic Agonist for the Treatment of Schizophrenia in Adults. News release. Bristol Myers Squibb. September 26, 2024. Accessed September 27, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibbs-COBENFY-xanomeline-and-trospium-chloride-a-First-In-Class-Muscarinic-Agonist-for-the-Treatment-of-Schizophrenia-in-Adults/default.aspx