# Xanomeline/trospium chloride

Xanomeline/trospium chloride, sold under the brand name Cobenfy, is a fixed-dose combination medication used for the treatment of schizophrenia. It contains xanomeline, a muscarinic agonist; and trospium chloride, a muscarinic antagonist. Xanomeline is a functionally preferring muscarinic M$_4$ and M$_1$ receptor agonist. Trospium chloride is a peripherally-acting non-selective muscarinic antagonist.
The most common side effects of xanomeline/trospium chloride include nausea, indigestion, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia (increased heartbeat), dizziness, and gastroesophageal reflux disease.
In September 2024, it was approved for medical use in the United States. It is the first antipsychotic drug approved by the US Food and Drug Administration (FDA) to treat schizophrenia that targets cholinergic receptors as opposed to dopamine receptors, which has long been the standard of care. The FDA considers it to be a first-in-class medication.

## Medical uses

Xanomeline/trospium chloride is indicated for the treatment of schizophrenia in adults.

## Adverse effects

The US Food and Drug Administration (FDA) prescribing information for the combination includes warnings that xanomeline/trospium chloride can cause urinary retention, increased heart rate, decreased gastric movement or angioedema (swelling beneath the skin) of the face and lips.

## Mechanism of action

Preclinical data supports the hypothesis that xanomeline's central mechanism of action is mediated primarily through stimulation of brain muscarinic M$_4$ and M$_1$ receptors. M$_4$ muscarinic receptors are most highly expressed in the midbrain, which controls motor and action planning, decision-making, motivation, reinforcement, and reward perception. M$_1$ muscarinic receptors are most highly expressed in the cerebral cortical regions, which regulate higher-level processes including language, memory, reasoning, thought, learning, decision-making, emotion, intelligence, and personality. Unlike direct dopamine D$_2$ and serotonin 5-HT$_{2A}$ blocking antipsychotic medications, M$_4$ and M$_1$ receptor stimulation indirectly rebalances dopaminergic and glutamatergic circuits involved in the symptoms associated with neurological and neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. Based on preclinical pharmacological and genetic studies, M$_4$ receptors appear to modulate both psychosis and cognitive symptom domains while M$_1$ predominantly modulates cognitive symptom domains and modestly regulates psychosis symptom domains.
Trospium chloride is a non-selective muscarinic antagonist, but does not cross the blood–brain barrier. As a result, it is able to counteract the peripheral side effects of xanomeline caused by M$_4$ and M$_1$ receptor activation without affecting the central nervous system.

## History

Xanomeline was first synthesized in a collaboration between pharmaceutical firms Eli Lilly and Novo Nordisk with the goal of delaying cognitive decline in people with Alzheimer's disease. In a phase II study, significant improvements in cognition were observed in people with Alzheimer's along with surprising improvements in psychotic symptoms. In a follow-up placebo-controlled study in participants with treatment resistant schizophrenia, similar antipsychotic activity was observed with xanomeline. However, cholinergic-mediated side effects prevented advancement of xanomeline into phase III trials.
Xanomeline was licensed to Karuna Therapeutics in 2012 and KarXT was subsequently created as a dual drug formulation by adding trospium. Trospium is a non-brain-penetrant and non-selective muscarinic receptor blocker that may ameliorate the peripheral side effects of xanomeline. In a 2021 placebo controlled phase II clinical trial, KarXT met the primary endpoint. In March 2023, Karuna Therapeutics announced that KarXT had met its primary endpoint in a phase III trial, EMERGENT-3, and that it was submitting the drug for approval by the US Food and Drug Administration (FDA). In November 2023, the FDA began its review and set the PDUFA date for September 2024.
The effectiveness of xanomeline/trospium chloride for the treatment of schizophrenia in adults was evaluated in two studies with identical designs. Study 1 (NCT04659161) and study 2 (NCT04738123) were 5-week, randomized, double-blind, placebo-controlled, multi-center studies in adults with a diagnosis of schizophrenia according to DSM-5 criteria. The primary efficacy measure was the change from baseline in the positive and negative syndrome scale (PANSS) total score at week 5. The PANSS is a 30-item scale that measures symptoms of schizophrenia. Each item is rated by a clinician on a seven-point scale. In both studies, the participants who received xanomeline/trospium chloride experienced a meaningful reduction in symptoms from baseline to week 5 as measured by the PANSS total score compared to the placebo group. The FDA granted the approval of Cobenfy to Bristol-Myers Squibb.

## Society and culture
### Legal status

Xanomeline/trospium chloride was approved for medical use in the United States in September 2024.

### Economics

In 2024, Bristol Myers Squibb purchased Karuna Therapeutics for US$14 billion. Bristol Myers Squibb set the wholesale cost of the combo at $1,850 a month.

## Research
### Long-acting injectable

A long-acting injectable (LAI) formulation of xanomeline/trospium chloride is under development for the treatment of schizophrenia. It is being developed by Terran Biosciences under the developmental code name TerXT or TerXT-LAI. The formulation specifically contains a prodrug of xanomeline and a prodrug of trospium chloride and is expected to have a multi-month duration. As of May 2024, TerXT is in the preclinical stage of development.