Xanomeline is a compound developed for complex neuropsychiatric conditions. It represents a new class of medication, distinct from existing therapies used for mental health disorders. This drug has progressed through various stages of clinical research to evaluate its safety and effectiveness. Its development has drawn attention due to its unique approach to treating symptoms of serious brain disorders.
The Targeted Conditions
Xanomeline is primarily being studied for the treatment of schizophrenia and psychosis associated with Alzheimer’s disease. Schizophrenia is a chronic mental disorder characterized by a range of symptoms, including hallucinations, delusions, and disorganized thinking, which are collectively known as psychosis. Psychosis in Alzheimer’s disease involves symptoms like delusions and agitation.
For decades, the mainstays of treatment for these conditions have been antipsychotic medications that primarily work by blocking dopamine receptors in the brain. While these drugs can be effective, a significant number of patients do not respond adequately. Others experience disruptive side effects, such as motor control problems and weight gain, which can lead to nonadherence with treatment. This has created a need for new therapeutic options with different mechanisms of action.
A Novel Mechanism of Action
Xanomeline functions differently from conventional antipsychotics by targeting the body’s muscarinic acetylcholine system. Specifically, it acts as an agonist, meaning it activates M1 and M4 muscarinic receptors in the brain. This approach is a departure from the dopamine receptor blockade that has been the standard for over 50 years. The M1 and M4 receptors are involved in controlling cognition and emotional processing.
Activation of these specific receptors is thought to address symptoms in a new way. The stimulation of M4 receptors is believed to modulate neurotransmitter systems, including dopamine, which may contribute to its antipsychotic-like effects. The action on M1 receptors is primarily associated with improvements in cognitive function.
This distinct mechanism avoids the direct blockade of dopamine D2 receptors, the action responsible for many motor side effects associated with older antipsychotic drugs. By bypassing this direct dopamine interaction, xanomeline offers the potential for managing psychosis and cognitive deficits without inducing movement disorders like tardive dyskinesia.
The Role of Trospium
While xanomeline’s action in the brain is therapeutically beneficial, its effects on muscarinic receptors in the rest of the body, or the periphery, can cause side effects. Activating these peripheral receptors leads to a range of cholinergic adverse events, including nausea, vomiting, and gastrointestinal distress. During initial clinical trials, these side effects were so pronounced that a high percentage of participants had to discontinue treatment.
To solve this problem, xanomeline is combined with a second medication called trospium chloride. Trospium is a muscarinic antagonist, meaning it blocks the action of these receptors. Crucially, trospium is peripherally restricted; it does not readily cross the blood-brain barrier.
This allows it to counteract the unwanted effects of xanomeline in the body without interfering with its intended therapeutic action in the brain. This fixed-dose combination, known as KarXT, was developed to improve the drug’s tolerability, pairing the brain-active agonist with a body-focused antagonist to deliver psychiatric benefits while minimizing physical side effects.
Clinical Trial Outcomes and Side Effects
The efficacy and safety of the xanomeline-trospium combination have been evaluated in a series of clinical studies, including the EMERGENT trials. Across these randomized, placebo-controlled trials, the combination drug demonstrated a statistically significant reduction in the symptoms of schizophrenia compared to a placebo. The trials showed improvements in both positive and negative symptoms of the condition.
In the EMERGENT-2 and EMERGENT-3 trials, for example, the combination was found to be superior to placebo in reducing the total score on the Positive and Negative Syndrome Scale (PANSS) by week five. The most commonly reported side effects associated with the combination therapy were related to its cholinergic activity. These included:
- Dry mouth
- Constipation
- Nausea
- Indigestion
Because trospium mitigates the peripheral effects, the rates of discontinuation due to these adverse events were much lower than in earlier studies of xanomeline alone. The side effect profile is different from traditional antipsychotics, particularly concerning motor and metabolic effects.
Regulatory Status and Availability
The combination of xanomeline and trospium, under the brand name Cobenfy (formerly KarXT), has completed the regulatory approval process. Following successful Phase 3 clinical trials, a New Drug Application (NDA) was submitted to the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia in adults.
The FDA approved xanomeline-trospium for the treatment of schizophrenia in adults in the latter half of 2024. This approval introduces a new class of antipsychotic medication for a condition that has not seen such innovation in over 50 years. This treatment offers an alternative for patients who may not have responded to or tolerated existing dopamine-blocking therapies.
Research is ongoing to evaluate its effectiveness for other conditions, as Phase 3 trials are underway to assess its use for psychosis associated with Alzheimer’s disease.