The U.S. Food and Drug Administration (FDA) has approved xanomeline-trospium (Cobenfy), capsules for oral use for the treatment of schizophrenia in adults. Xanomeline-trospium is a dual M1/M4 orthosteric muscarinic agonist combined with a peripheral antimuscarinic to mitigate pro-cholinergic side effects. Xanomeline is a dual M1/M4 muscarinic acetylcholine receptor agonist; it does not directly block any dopamine (DA) receptors. Trospium is a nonselective muscarinic antagonist that has limited CNS penetration.
The approval is based on two positive studies with identical designs (EMERGENT 2 and 3). EMERGENT-2 was a randomized, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase III trial in people with schizophrenia. In the EMERGENT-2 trial, xanomeline-trospium was effective in reducing positive and negative symptoms and was generally well tolerated. It screened 407 participants and enrolled 252 participants who met criteria. 126 participants were randomly assigned to the xanomeline-trospium and 126 participants assigned placebo. The baseline Positive and Negative Syndrome Scale (PANSS) total scores were 98·3 (xanomeline-trospium; n=126) and 97·9 (placebo; n=125). The trial met the primary endpoint with a mean change from baseline to week 5 in PANSS total score that favored xanomeline-trospium (-21·2 points, SE 1·7) versus placebo (-11·6 points, 1·6; least squares mean difference -9·6; 95% CI -13·9 to -5·2; p<0·0001, Cohen's d effect size=0·61). All secondary endpoints were also met, and favored xanomeline-trospium versus placebo (p<0·05).
The EMERGENT-3 phase III, double-blind, randomized, placebo-controlled trial included 256 people with schizophrenia. Xanomeline-trospium was associated with a statistically significant and clinically meaningful reduction in PANSS total score compared with placebo. Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis.
There are ongoing, long-term safety studies. EMERGENT-4 is a 52-week, outpatient, open-label extension trial evaluating the long-term safety and tolerability of xanomeline-trospium in patients who completed EMERGENT-2 or 3. EMERGENT-5 is a 52-week, outpatient, open-label trial evaluating the long-term safety and tolerability of xanomeline-trospium in outpatients on another first-line antipsychotic.
The magnitude of response suggests xanomeline-trospium (Figure) will be among the most efficacious of first-line (non-clozapine) antipsychotics, with relative efficacy for cognitive and negative symptoms theoretically possible but not yet shown. Side effects consistent with those of known muscarinic agonists consistent with parasympathetic nervous system activation. They are usually tolerated and do not include any cardiac signal. It has no direct dopamine receptor activity and no clinical evidence of side effects related to dopamine antagonism.
Mechanism of Action
Effects of M4 agonism by xanomeline
- Cholinergic stimulation of ventral tegmental (VTA) neurons stimulates DA release
- Stimulation of M4 autoreceptors by xanomeline decreases ACh release, which in turn decreases VTA firing and VTA dopamine release
- This decreased DA outflow occurs selectively in striatal areas related to psychosis and not in motor systems controlled by M2 autoreceptors
Effects of M1 agonism by xanomeline
- GABA-ergic inhibitory interneurons in the prefrontal cortex (PFC) regulate glutamate release from excitatory PFC neurons that project to the VTA to stimulate DA release
- Stimulation of M1 receptors on GABA-ergic interneurons in the PFC inhibits glutamate release, which in turn decreases VTA firing and VTA dopamine release
- This also occurs selectively in striatal areas related to psychosis and not in motor systems
Effects of peripheral muscarinic antagonism by trospium
- Xanomeline induces peripheral adverse effects, primarily related to M1 agonism; blockade of peripheral M1 receptors by trospium mitigates these adverse effects