Xanomeline-Trospium (COBENFY): A Schizophrenia Drug With a Novel Mechanism of Action

In September 2024 the Food and Drug Administration (FDA) approved xanomeline-trospium (COBENFY), a first-in-class drug to treat schizophrenia in adults.[1] The fixed-dose combination product (a preset dose ratio of each active ingredient) is formulated as a capsule and taken orally twice daily. In contrast to previous antipsychotic drugs that block dopamine receptors in the nervous system, xanomeline-trospium acts on muscarinic receptors.[2]

Xanomeline-trospium is contraindicated in people with urinary retention and moderate or severe liver impairment, among other contraindications, and can cause urinary retention and decreased gastrointestinal motility, among other adverse effects.

Good-quality clinical trial data about xanomeline-trospium is limited to the study of patients with active schizophrenia. These trials were short in duration (five weeks) and the studies did not compare xanomeline-trospium to second-generation antipsychotic drugs such as olanzapine (ZYPREXA and generics), quetiapine (SEROQUEL and generics) and risperidone (RISPERDAL and generics). For these reasons, and because xanomeline-trospium has important contraindications, warnings and precautions, Public Citizen’s Health Research Group has classified it as Do Not Use for Seven Years.

About schizophrenia and antipsychotic drugs

Schizophrenia is a serious and chronic mental illness that affects how a person thinks, feels and behaves.[3] The condition is characterized by substantial distortions in cognition, emotion and other behaviors that impair social and self-care functions and the ability to work. Symptoms include hallucinations (false sensory perceptions), delusions (persistent false beliefs), disorganized thinking, diminished verbal and emotional expression, and apathy (lack of usual motivation). Because schizophrenia is difficult to diagnose and there are no biological tests to confirm its presence, keep in mind that the diagnosis of schizophrenia is not appropriate if the predominant symptoms of concern are depression, mania or both (bipolar).

Approximately 1% of the population has schizophrenia. Each year, new cases emerge in 1.5 of every 10,000 persons.[4] The condition often is first diagnosed in adolescents or young adults and typically requires many years of treatment.[5] The causes and pathophysiology of schizophrenia are mostly unknown.

Along with individualized psychosocial treatments (for example, case management, family and employment supports, and psychotherapy), antipsychotic medications are a recommended first-line treatment for schizophrenia.[6]

First-generation antipsychotics such as chlorpromazine (generics only) are less frequently used than second-generation drugs such as olanzapine because long-term use of the first-generation drugs greatly increases a person’s risk of developing debilitating movement disorders. These disorders include akathisia (restlessness, feeling jittery), parkinsonism (slowness, rigidness, tremors), dystonia (twitching, involuntary movements) and tardive dyskinesia (multiple, chronic involuntary movements of the face, arms and legs).[7]

Second-generation antipsychotics increase the risk of weight gain and metabolic illnesses such as diabetes and high cholesterol (hyperlipidemia). Although beneficial for many people with schizophrenia, second-generation antipsychotics may have serious adverse effects, similar to those from first-generation drugs, or fail to ease some psychotic symptoms, especially cognitive impairment and apathy.[8]

The new antipsychotic drug

Xanomeline-trospium was developed as an alternative to the dopaminergic drugs that have long been the mainstay of schizophrenia treatment. Xanomeline is a muscarinic receptor agonist, which means it activates cell membrane switches controlled by acetylcholine (a different neurotransmitter than dopamine).[9] Trospium is a muscarinic receptor antagonist, meaning that it blocks acetylcholine activity. Although the FDA has not previously approved xanomeline, trospium alone (generics only) was approved in 2004 as a treatment for overactive bladder.[10]

Xanomeline was previously developed by Eli Lilly as a potential treatment for Alzheimer’s disease. The drug development was abandoned because of the intolerable adverse effects it caused when used alone. Bristol Myers Squibb, the developer of xanomeline-trospium for schizophrenia, added trospium to limit the adverse effects of xanomeline in the peripheral tissues, meaning nerve cells outside of the brain and spinal cord.

Clinical trials

The FDA approved xanomeline-trospium for the treatment of schizophrenia in adults[11] based on the results of three randomized, placebo-controlled clinical trials, only two of which are highlighted in the prescribing information.[12] As part of the approval, the FDA also required the manufacturer to conduct post-marketing studies to assess the effects of xanomeline-trospium use on pregnancy and lactation and in people aged 18 or younger. It also required studies to clarify concerns about adverse effects the drug may cause to the kidneys, liver and pancreas.[13]

The three pivotal trials compared xanomeline-trospium with a placebo and had nearly identical designs.[14] All were double-blinded, five-week trials in which the xanomeline-trospium dosages were adjusted upward to a maximum of 125 milligrams (mg) of xanomeline and 30 mg of trospium twice daily. Each trial included adults aged 18-65 years experiencing an acute episode of schizophrenia that resulted in hospitalization. Adults with alcohol use disorder, major depression, post-traumatic stress disorder and obsessive-compulsive disorder were excluded.

Across the three trials, 610 subjects were randomized equally to receive either xanomeline-trospium or a placebo. The smallest trial included 182 subjects, the largest 252 subjects. The trials were all multi-site and concentrated in the United States, although one study included many sites in Ukraine. Notably, the trial participants were mostly Black (over 58%) and male (over 69%).

The primary prespecified endpoint for the pivotal trials was change from baseline on the Positive and Negative Syndrome Scale (PANSS), a standardized score that is composed of 30 brief questions assessing the severity (from 1 = absent to 7 = extreme) of positive (for example, hallucinations), negative (for example, social withdrawal) and general psychopathological (for example, anxiety or depression) symptoms characterizing schizophrenia. A PANSS score can range from 30 to 210, with higher scores indicating worse schizophrenia symptoms.

All three trials showed that after five weeks subjects in both the xanomeline-trospium and placebo groups had significant improvements in their PANSS scores. However, the subjects receiving the drug had a greater, though small, symptom improvement from baseline (on average, about 8 to 12 points more than those in the placebo group). Importantly, lower maximum dosing (100 mg of xanomeline and 20 mg of trospium) was found to be similarly effective to higher doses.

To assess safety, the FDA reviewed data from about 1,600 subjects who were exposed to at least one dose of xanomeline-trospium; 340 of these subjects were part of the pivotal randomized trials. Of all subjects in the safety assessments, only 145 were exposed to the drug for 12 months or longer. Four deaths were observed, all in subjects in the xanomeline-trospium group. Two deaths were related to methamphetamine use and two were unexplained; the FDA determined that these deaths were “unlikely” to be related to acute xanomeline-trospium exposure.

Adverse events that were significantly more common in the xanomeline-trospium group were nausea, vomiting, constipation, hypertension and dry mouth. Each of these adverse effects occurred in 5% to 19% of patients receiving xanomeline-trospium. Akathisia was evident in 2.1% of those on xanomeline-trospium and 0.6% of those on placebo. Metabolic illnesses (for example, weight gain or high cholesterol) did not differ markedly between subjects in the xanomeline-trospium and placebo groups. Urinary retention, which was in rare cases severe, was observed in nearly 4% of all subjects exposed to xanomeline-trospium.

What You Can Do

If you suffer from the serious symptoms of schizophrenia or you are involved in the care or support of an adult with schizophrenia, xanomeline-trospium is a novel treatment that you should be aware of. Do not start, stop or otherwise change your antipsychotic drug regimen without the direct involvement of a licensed mental health clinician.

The clinical trials of xanomeline-trospium were only five weeks in duration and did not compare the drug to second-generation antipsychotic drugs. For these reasons and because the drug has important contraindications and safety concerns, Public Citizen’s Health Research Group has classified xanomeline-trospium as Do Not Use for Seven Years.
 

References

[1] Food and Drug Administration. News release: FDA approves drug with new mechanism of action for treatment of schizophrenia. September 26, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia?os=wtmb&ref=app. Accessed January 6, 2025.

[2] Xanomeline-trospium (Cobenfy) for schizophrenia. The Medical Letter. 2024;66(1715)177-8.

[3] Fischer BA, Buchanan RW. Schizophrenia is adults: clinical features, assessment, and diagnosis. UpToDate. July 5, 2023.

[4] Ibid.

[5] Stroup TS, Marder S. Schizophrenia in adults: maintenance therapy and side effect management. UpToDate. June 27, 2024.

[6] Ibid.

[7] Vasan S, Padhy RK. Tardive Dyskinesia. Statpearls. April 24, 2023. https://www.ncbi.nlm.nih.gov/sites/books/NBK448207/. Accessed January 6, 2025.

[8] U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Integrated review for NDA 216158: xamomeline and traspium chloride (Cobenfy). September 26, 20234. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/216158Orig1s000IntegratedR.pdf. Accessed January 6, 2025. December 12, 2024.

[9] Ibid.

[10] Actavis Pharma. Label: trospium. August 2014. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8b8d434c-daa2-4bf2-bde6-3e59f81bd88b&type=display. Accessed January 7, 2025.

[11] Bristol Myers Squibb. Label: xanomeline-trospium chloride (COBENFY). September 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216158s000lbl.pdf. Accessed January 6, 2025.

[12] Food and Drug Administration. Center for Drug Evaluation and Research. Integrated review for NDA 216158: xamomeline and traspium (Cobenfy). September 26, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/216158Orig1s000IntegratedR.pdf. Accessed January 6, 2025.

[13] Food and Drug Administration. Approval letter for Cobenfy (NDA 216158). September 26, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/216158Orig1s000ltr.pdf. Accessed January 8, 2025.

[14] Food and Drug Administration. Center for Drug Evaluation and Research. Integrated review for NDA 216158: xamomeline and traspium (Cobenfy). September 26, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/216158Orig1s000IntegratedR.pdf. Accessed January 6, 2025.