Cobenfy, a combination of xanomeline and trospium chloride, has been approved for oral use in the treatment of schizophrenia in adults as of September 26, 2024, by the U.S. Food and Drug Administration (FDA). This marks it as the first antipsychotic medication designed to target cholinergic receptors rather than the traditional dopamine receptors, which have dominated schizophrenia treatment for decades.
Schizophrenia is a chronic mental disorder that disrupts an individual’s thoughts, emotions, and behaviors. The spectrum of symptoms typically falls into three categories: psychotic, negative, and cognitive.
– Psychotic symptoms may include hallucinations, delusions, and thought disorders.
– Negative symptoms are reduced motivation, lack of interest in daily activities, and social withdrawal.
– Cognitive symptoms involve attention, concentration, and memory difficulties, impacting decision-making and information retention.
For over 70 years, treatments for schizophrenia have primarily focused on dopamine pathways, which, while effective for some patients, can lead to significant side effects, including weight gain and drowsiness.
Mechanism of Action
Cobenfy includes two active components. The first, xanomeline, stimulates muscarinic acetylcholine receptors (M1 and M4) in the brain, which helps decrease dopamine activity without the typical side effects associated with other antipsychotics. The second component, trospium, acts as a peripheral muscarinic acetylcholine antagonist, reducing gastrointestinal side effects, such as nausea, vomiting, and diarrhoea, that can arise from xanomeline.
Drug Trial
The approval of Cobenfy was based on results from two Phase 3 clinical trials that were randomized, double-blind, and placebo-controlled, conducted across multiple centres. Participants who took Cobenfy twice daily for five weeks showed an average reduction of about 21 points in their Positive and Negative Syndrome Scale (PANSS) score, a 30-item assessment of schizophrenia symptoms. In contrast, the placebo group experienced only a 12-point decrease.
Indication and Contraindications
Cobenfy is indicated for patients who have partial responses to atypical antipsychotics or cannot tolerate the associated side effects like weight gain, sedation, or movement disorders. However, it is contraindicated in individuals with liver impairment, severe kidney issues, urinary retention, untreated narrow-angle glaucoma, or a history of allergic reactions to its components.
Side Effects
Common side effects reported for Cobenfy include nausea, indigestion, constipation, vomiting, hypertension, abdominal pain, diarrhea, increased heart rate (tachycardia), dizziness, and gastroesophageal reflux disease.
The drug is expected to be available in late October at a list price of approximately $22,500 per year.
Ongoing Research
Several pharmaceutical companies are exploring treatments that target the muscarinic pathway for schizophrenia. There are seven products in various clinical development stages (Phases I-III) aimed at muscarinic acetylcholine receptors. Notably, AbbVie’s emraclidine is a positive modulator at the M4 receptors and is in Phase II trials, while Neurocrine Biosciences has shared promising Phase II results for its M4 receptor agonist.
Cobenfy’s approval represents a significant advancement in the treatment landscape for schizophrenia. Additionally, it is being investigated for its potential efficacy in addressing neuropsychiatric symptoms in patients with bipolar disorder and Alzheimer’s disease, with results anticipated in 2026.
