Xanomeline/trospium chloride, sold under the brand name Cobenfy, is a

fixed-dose combination A combination drug is a combination of two or more pharmaceutical drugs as active ingredients combined into a single dosage form, typically as a ''fixed-dose combination'', with each constituent standardized to specifications of a fixed dose. Fix ...

medication used for the treatment of

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

. It contains

xanomeline Xanomeline (developmental code name LY-246,708) is a small molecule muscarinic acetylcholine receptor agonist that was synthesized in a collaboration between Eli Lilly and Novo Nordisk as an investigational therapeutic being studied for the tre ...

, a

muscarinic agonist A muscarinic acetylcholine receptor agonist, also simply known as a muscarinic agonist or as a muscarinic agent, is an agent that activates the activity of the muscarinic acetylcholine receptor. The muscarinic receptor has different subtypes, lab ...

; and trospium chloride, a

muscarinic antagonist A muscarinic acetylcholine receptor antagonist, also simply known as a muscarinic antagonist or as an antimuscarinic agent, is a type of anticholinergic drug that blocks the activity of the muscarinic acetylcholine receptors (mAChRs). The muscarin ...

. Xanomeline is a functionally preferring muscarinic M₄ and M₁ receptor agonist. Trospium chloride is a peripherally-acting non-selective muscarinic antagonist. The most common side effects of xanomeline/trospium chloride include

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

indigestion Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier ...

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...

(increased heartbeat),

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

, and

gastroesophageal reflux disease Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is a chronic upper gastrointestinal disease in which stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/or ...

. In September 2024, it was approved for medical use in the United States. It is the first

antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...

drug approved by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) to treat schizophrenia that targets cholinergic receptors as opposed to

dopamine receptor Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diff ...

s, which has long been the standard of care. The FDA considers it to be a

first-in-class medication A first-in-class medication is a prototype drug that uses a "new and unique mechanism of action" to treat a particular medical condition. While the Food and Drug Administration's Center for Drug Evaluation and Research tracks first-in-class medic ...

. Trospium chloride is a peripherally selective non-selective muscarinic antagonist to quell peripheral muscarinic agonist-dependent side effects. Xanomeline's

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

in this context is hypothesized to be via modulating certain

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

circuits, including

acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

, and

glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

, which can provide therapeutic benefits in schizophrenia and related diseases.

Medical uses

Xanomeline/trospium chloride is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of schizophrenia in adults.

Adverse effects

The US

(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. The most common side effects of xanomeline/trospium chloride include

(increased heartbeat),

, and

Mechanism of action

Preclinical data supports the hypothesis that xanomeline's central mechanism of action is mediated primarily through stimulation of brain muscarinic M₄ and M₁ receptors. M₄ muscarinic receptors are most highly expressed in the midbrain, which controls motor and action planning, decision-making, motivation, reinforcement, and reward perception. M₁ 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 D₂ and

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

5-HT_2A blocking antipsychotic medications, M₄ and M₁ receptor stimulation indirectly rebalances

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

and

glutamatergic Glutamatergic means "related to glutamate". A glutamatergic agent (or drug) is a chemical that directly modulates the excitatory amino acid (glutamate/aspartate) system in the body or brain. Examples include excitatory amino acid receptor agonist ...

circuits involved in the symptoms associated with neurological and neuropsychiatric diseases such as schizophrenia and

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. Based on preclinical pharmacological and genetic studies, M₄ receptors appear to modulate both

psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...

and cognitive symptom domains while M₁ 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 The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

. As a result, it is able to counteract the peripheral side effects of xanomeline caused by M₄ and M₁ receptor activation without affecting the central nervous system.

History

Xanomeline was first synthesized in a collaboration between pharmaceutical firms

Eli Lilly Eli Lilly (July 8, 1838 – June 6, 1898) was a Union Army officer, pharmacist, chemist, and businessman who founded Eli Lilly and Company. Lilly enlisted in the Union Army during the American Civil War and recruited a company of men to ...

and

Novo Nordisk Novo Nordisk A/S is a Danish multinational pharmaceutical company headquartered in Bagsværd, with production facilities in nine countries and affiliates or offices in five. Novo Nordisk is controlled by majority shareholder Novo Holdings A/S ...

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

(FDA). In November 2023, the FDA began its review and set the

PDUFA date In United States pharmaceutical regulatory practice, the PDUFA date is the colloquial name for the date by which the Food and Drug Administration must respond to a New Drug Application or a Biologics License Application. It is part of the regime es ...

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 Positive is a property of positivity and may refer to: Mathematics and science * Positive formula, a logical formula not containing negation * Positive number, a number that is greater than 0 * Plus sign, the sign "+" used to indicate a posit ...

(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 The Bristol-Myers Squibb Company, doing business as Bristol Myers Squibb (BMS), is an American multinational pharmaceutical company. Headquartered in Princeton, New Jersey, BMS is one of the world's largest pharmaceutical companies and consist ...

. The FDA approved xanomeline/trospium chloride based on evidence from two clinical trials of 470 adults with schizophrenia. The trials were conducted at 39 sites in the United States and Ukraine. There were 425 trial participants from the United States. The efficacy of the combination (which is a measure of how well the drug works) was evaluated in two clinical trials for 470 participants with schizophrenia, and safety was assessed in the two trials in a total of 504 participants with schizophrenia who received at least one dose of xanomeline/trospium chloride. The same trials were used to assess efficacy and safety. The number of participants representing efficacy findings differs from the number of participants representing safety findings due to different pools of study participants analyzed for efficacy and safety. In the trials, participants were randomly assigned to receive xanomeline/trospium chloride or placebo, and neither participants nor care providers knew which treatment was given during the trial. Symptoms of schizophrenia were measured using a clinician-administered measure of schizophrenia symptoms called the Positive and Negative Syndrome Scale (PANSS). The benefit of COBENFY was assessed in both trials by determining the improvement in schizophrenia symptoms (the difference in PANSS scores before and after five weeks of treatment).

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 The Bristol-Myers Squibb Company, Trade name, doing business as Bristol Myers Squibb (BMS), is an American multinational pharmaceutical company. Headquartered in Princeton, New Jersey, BMS is one of the world's largest pharmaceutical companies ...

purchased Karuna Therapeutics for . 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 Formulation is a term used in various senses in various applications, both the material and the abstract or formal. Its fundamental meaning is the putting together of components in appropriate relationships or structures, according to a formula ...

of xanomeline/trospium chloride is under development for the treatment of

. It is being developed by Terran Biosciences under the developmental code name TerXT or TerXT-LAI. The formulation specifically contains a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

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.

References

External links

* * {{Authority control Carboxylate esters Chlorides Combination psychiatric drugs M1 receptor agonists M1 receptor antagonists M2 receptor antagonists M3 receptor antagonists M4 receptor agonists M4 receptor antagonists M5 receptor antagonists Nitrogen heterocycles Peripherally selective drugs Quaternary ammonium compounds Spiro compounds Tertiary alcohols Tetrahydropyridines Thiadiazoles de:Xanomelin