Mechanism of Action of Cobenfy
Cobenfy (xanomeline-trospium) works through a dual mechanism: xanomeline acts as a preferential agonist at muscarinic M1 and M4 acetylcholine receptors in the central nervous system to provide antipsychotic efficacy, while trospium chloride acts as a peripheral muscarinic antagonist to mitigate cholinergic side effects. 1, 2
Central Mechanism: Xanomeline
Xanomeline is a muscarinic receptor agonist with preferential activity at M1 and M4 receptors in the brain, representing the first FDA-approved antipsychotic that does not primarily target dopamine receptors. 2
The M1 and M4 receptor agonism is thought to confer the therapeutic antipsychotic effects by modulating cholinergic neurotransmission in brain regions relevant to schizophrenia pathophysiology. 1, 3
This represents a mechanistically novel approach to treating schizophrenia, as it targets the cholinergic system rather than the traditional dopaminergic pathway used by all other approved antipsychotics. 3
Peripheral Mechanism: Trospium Chloride
Trospium chloride is a quaternary ammonium muscarinic antagonist that does not cross the blood-brain barrier, allowing it to selectively block peripheral muscarinic receptors. 2
By antagonizing peripheral muscarinic receptors, trospium reduces the cholinergic adverse events (such as gastrointestinal effects, salivation, and sweating) that would otherwise be caused by xanomeline's systemic muscarinic agonism. 1, 2
This peripheral antagonism allows the central therapeutic effects of xanomeline to be maintained while minimizing tolerability issues. 2
Clinical Implications
The combination received FDA approval on September 26,2024, for treatment of schizophrenia in adults, with demonstrated efficacy in reducing positive and negative symptoms (Cohen's d effect size approximately 0.60 in phase 3 trials). 1, 2
The most common adverse events were rated as mild-to-moderate, with the medication being generally well-tolerated across clinical trials. 1
This mechanism avoids direct dopamine blockade, potentially reducing the risk of extrapyramidal symptoms, metabolic syndrome, and other adverse effects associated with traditional antipsychotics. 3