FDA Approves Cobenfy, A First In-Class Agent for Schizophrenia

The US Food and Drug Administration approved Cobenfy, formerly known as KarXT (xanomeline-trospium), a first in-class agent for the treatment of schizophrenia.¹ Cobenfy is the first new agent with a novel mechanism of action for schizophrenia more than 50 years.

In a statement to the press, Tiffany Farchione, MD, director of the Division of Psychiatry, Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research said, “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.”¹

Farchione added, "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.”¹

"The FDA approval of Cobenfy is an exciting and possibly quantum leap forward for psychiatry and individuals that suffer from schizophrenia," John J. Miller, MD, Psychiatric Times editor in chief said in an exclusive statement. "For decades we have understood that schizophrenia is a complex syndrome that involves many different neurotransmitter systems, yet all of our antipsychotic medications since our very first in 1954 work by blocking the dopamine-2 receptors in the brain."

"Cobenfy brings to our treatment armamentarium a novel mechanism of action that modulates the acetylcholine muscarinic receptors, which putatively decrease presynaptic dopamine release only at the neuronal circuits that are involved in the pathophysiology of schizophrenia," he added. "This allows for a treatment approach that targets the source of the excess dopamine while not affecting the dopamine circuits involved in movement and endocrine functions. Additionally, all of the phase 3 studies of Cobenfy have consistently demonstrated no effect on weight, lipids, glucose, insulin levels, or alertness. Finally, its novel mechanism of action may improve symptoms in the 30 to 40% of individuals with schizophrenia that do not respond to dopamine-2 receptor blocking drugs."

The decision was based on data from the EMERGENT trials, which looked at safety and efficacy data across multiple studies. The most recent, EMERGENT-4 and EMERGENT-5 were phase 3 open label trials, looking at 718 participants who received at least 1 dose and 134 participants who completed a year of treatment over 52 weeks. The data indicated the drug was generally well tolerated, with no significant changes in prolactin and movement disorder scale scores and stabilization or improvement in key metabolic parameters, including weight and total cholesterol, triglyceride and HbA1c levels.² About 65% of participants saw a decrease in weight; the mean decrease in weight over a year was 2.6 kg. The most common treatment-related adverse events were mild or moderate and transient in nature, and included gastrointestinal issues (ie, nausea, vomiting, dyspepsia, constipation, diarrhea), dry mouth, dizziness, and hypertension.

The first 3 EMERGENT trials consistently found favorable efficacy for the agent. In EMERGENT-3, for example, the drug demonstrated demonstrating a “statistically significant and clinically meaningful 8.4-point reduction” in the Positive and Negative Syndrome Scale (PANSS) total score compared with placebo (-20.6 KarXT vs -12.2 placebo; p<0.0001) at Week 5, meeting its primary endpoint. In addition, patients saw “an early and sustained statistically significant reduction of symptoms from Week 2 (p<0.05).” ³

Earlier this year, after presenting data at the 2024 Annual Congress of the Schizophrenia International Research Society, Roland Chen, MD, senior vice president and head, Immunology, Cardiovascular and Neuroscience development, Bristol Myers Squibb, shared optimism about the drug. “The long-term safety results and metabolic outcomes from the EMERGENT program are extremely encouraging, allowing us to further understand the tolerability profile of KarXT in people living with schizophrenia,” he said in a press statement. “It is promising to see that over one year of treatment, KarXT was not associated with burdensome side effects, specifically weight gain and metabolic dysfunction, as well as extrapyramidal symptoms, which underscores its potential to provide a meaningful and differentiated option for people living with schizophrenia.”² BMS completed acquisition Karuna Therapeutics in March 2024, the company that began work on KarXT.⁴

Previous Coverage and Expert Insights

Much Ado About Something: Why There’s Excitement Behind Novel Mechanism of Action in Schizophrenia

Changing the Way Schizophrenia Is Treated

Post Hoc Analysis Explores Risk-Benefit Profile of KarXT

New Data Demonstrates KarXT’s Positive Long-Term Metabolic Profile

Medication Pipeline: Schizophrenia and PTSD

NDA Submitted for Investigational Muscarinic Antipsychotic in the Treatment of Schizophrenia

“A New and Differentiated Approach for Schizophrenia”: Positive Results for Phase 3 Trial

Journal Publication Brings Good News for Novel Schizophrenia Treatment

Promising New Data Announced on In-the-Works Schizophrenia Treatment

As Miller explained, the excitement over Cobenfy involves its novel mechanism of action. Research has shown that patients with schizophrenia have fewer M1 receptors than healthy patients, and postmortem studies have found lower levels of M1 and M4 receptor expression in brain regions implicated in schizophrenia.⁵ As a muscarinic acetylcholine receptor (mAChR) agonist preferring M1/ M4, the xanomeline portion of the drug duo works to improve positive and negative symptoms of schizophrenia.⁶ Because muscarinic receptors are present in the peripheral nervous system, activation via xanomeline can lead to gastrointestinal side effects. Thus, trospium was added to the drug to counter those effects. It cannot cross the blood brain barrier and can prevent xanomeline’s effects in the peripheral nervous system.

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

4. Bristol Myers Squibb Completes Acquisition of Karuna Therapeutics, Strengthening Neuroscience Portfolio. Press release. BMS. March 18, 2024. Accessed September 25, 2024. https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Completes-Acquisition-of-Karuna-Therapeutics-Strengthening-Neuroscience-Portfolio/default.aspx

5. Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC. Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia. Am J Psychiatry. 2022;179(9):611-627.

6. Howes OD, Dawkins E, Lobo MC, Kaar SJ, Beck K. New Drug Treatments for Schizophrenia: A Review of Approaches to Target Circuit Dysfunction. Biol Psychiatry. 2024;96(8):638-650.