What is Cobenfy?
Cobenfy (xanomeline-trospium chloride) is the first FDA-approved medication for schizophrenia that works through muscarinic receptor modulation rather than dopamine blockade, receiving approval on September 26,2024 for treatment of schizophrenia in adults. 1
Mechanism of Action
- Cobenfy is a fixed-dose combination of xanomeline (a muscarinic M1 and M4 receptor agonist) and trospium chloride (a peripheral muscarinic antagonist). 1
- Xanomeline provides therapeutic efficacy by acting as a partial agonist at M1 and M4 muscarinic acetylcholine receptors in the brain, representing a fundamentally different mechanism than traditional antipsychotics that block dopamine receptors. 1, 2
- Trospium chloride is included specifically to reduce peripheral cholinergic adverse events (such as gastrointestinal effects) associated with xanomeline, as it does not cross the blood-brain barrier. 1, 2
Clinical Efficacy
- Two phase 3 trials demonstrated significant reductions in PANSS (Positive and Negative Syndrome Scale) total scores, with Cohen's d effect sizes of approximately 0.60 for the primary endpoint. 3
- The medication showed improvements in both positive symptoms (hallucinations, delusions) and negative symptoms (social withdrawal, flat affect) of schizophrenia, with significant reductions in PANSS positive and negative subscales compared to placebo. 3
- Long-term open-label studies showed that after 52 weeks of treatment, more than 75% of participants achieved greater than 30% improvement on PANSS total score, with a mean decrease of 33.3 points. 3
- Patients who switched from placebo to active treatment achieved statistically significant improvements on all efficacy measures starting at week 2. 3
Dosing
- The approved dosing is up to 125 mg xanomeline/30 mg trospium twice daily. 3
- Gradual dose titration is recommended to minimize adverse effects. 3
Safety Profile
- The most common adverse events were rated as mild-to-moderate in severity. 3
- Unlike dopamine-blocking antipsychotics, Cobenfy does not appear to cause depressogenic effects or increased suicidality based on data from adults with schizophrenia. 4
- The medication was well-tolerated across all clinical trials, with the peripheral anticholinergic blocker (trospium) successfully mitigating many of the cholinergic side effects that would otherwise occur with xanomeline alone. 1, 3
Potential Future Applications
- Preliminary evidence suggests xanomeline-trospium may improve measures of cognition in both Alzheimer's disease and schizophrenia, though it is currently only FDA-approved for schizophrenia. 4
- The drug is being investigated for potential efficacy in manic episodes, mixed features, and cognitive impairment in bipolar disorder, though these remain investigational uses. 4