Schizophrenia Drug Approved by FDA Represents First New Treatment Option in Decades

The FDA approved xanomeline and trospium chloride (Cobenfy, formerly KarXT), an oral medication for the treatment of schizophrenia in adults, Bristol Myers Squibb announced in a release.¹ The approval marks a breakthrough in the treatment for the condition, as xanomeline and trospium chloride represents the first new class of medication for schizophrenia in decades.

Xanomeline and trospium chloride’s mechanism of action is distinct from current therapies on the market. By combining 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, the drug selectively targets M₁ and M₄ receptors in the brain without blocking D₂ receptors.

“Schizophrenia is a leading cause of disability worldwide,” Tiffany Farchione, MD, director of the division of psychiatry, office of neuroscience in the FDA’s Center for Drug Evaluation and Research, said in a release.² “It is a severe, chronic mental illness that is often damaging to a person’s quality of life. 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 FDA approval of xanomenline and trospium chloride is supported by data from the EMERGENT clinical program. It includes 3 placebo-controlled trials to assess the efficacy and safety of the medication, as well as 2 open-label trials evaluating the long-term safety and tolerability of xanomeline and trospium chloride for up to a year.

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In the phase 3, five-week, inpatient EMERGENT-2 (NCT04659161) and EMERGENT-3 (NCT04738123) trials, xanomeline and trospium chloride met its primary endpoint by significantly reducing schizophrenia symptoms compared to placebo, as measured by the Positive and Negative Syndrome Scale (PANSS) total score change from baseline to week 5.

Specifically, xanomeline and trospium chloride demonstrated a 9.6-point reduction (-21.2 Cobenfy vs -11.6 placebo, P < .0001) and an 8.4-point reduction (-20.6 Cobenfy vs -12.2 placebo; P < .0001) in PANSS total score compared to placebo at week 5 in EMERGENT-2 and EMERGENT-3, respectively.

In EMERGENT-2, xanomeline and trospium chloride improved overall illness severity, as measured by the Clinical Global Impression-Severity (CGI-S) score. The medication demonstrated a statistically significant 0.6-point change (-1.2 Cobenfy vs -0.7 placebo; P < .0001) in CGI-S score compared to placebo at week 5.

The safety and tolerability of xanomeline and trospium chloride were demonstrated in both short-term and long-term studies. In the phase three EMERGENT-2 and EMERGENT-3 trials, the most common adverse reactions were nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastroesophageal reflux disease.

Schizophrenia is a chronic mental illness that affects how a person thinks, feels, and behaves.¹ When left untreated or inadequately managed, symptoms can severely impact daily life and overall well-being.

However, many individuals with schizophrenia face a frustrating cycle of discontinuing and switching treatments. Research shows that approximately 40% of people with schizophrenia do not respond to therapy, and up to 60% experience partial or insufficient improvement or intolerable side effects.^3,4

“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,” said Rishi Kakar, MD, chief scientific officer and medical director at Segal Trials and investigator in the EMERGENT program, in the same release.¹ “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 pathways in the brain. By leveraging a novel pathway, Cobenfy offers a new option to manage this challenging condition.”

Alongside FDA approval, Bristol Myers Squibb also announced the launch of Cobenfy Cares, a program designed to support patients who have been prescribed xanomeline and trospium chloride.¹ According to the company, patients will be able to enroll in the Cobenfy Cares program in late October corresponding with product availability.

READ MORE: Mental and Behavioral Health Resource Center

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References

1. US 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

2. 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. Diniz E, Fonseca L, Rocha D, et al. Treatment resistance in schizophrenia: a meta-analysis of prevalence and correlates. Braz J Psychiatry. 2023;45(5):448-458. doi:10.47626/1516-4446-2023-3126

3. Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. P T. 2014;39(9):638-645.