Sep 307 min read

COBENFY (xanomeline + trospium), related meds—and all things muscarinic—to understand and remember

Topics:

Xanomeline
Trospium
Xanomeline + Trospium (Cobenfy)
Medications related to Cobenfy
- Clozapine + metabolite is also an M1 & M4 agonist
Acetylcholine ballicule
Acetylcholine and muscarinic medications in context
"Anticholine" ballicule (context)
Antimuscarinic medications in context

This content in PDF form:

Xanomeline

Component: xanomeline

Pronounced: zuh-NOM-uh-leen

Mnemonic phrase: “The gnome line”

Cost: unavailable as a standalone

Mechanism: M1 & M4 muscarinic acetylcholine receptor agonist

Xanomeline COBENFY mnemonic mascot jason cafer MD salivation

FDA-approved for: Schizophrenia (in combination with trospium)

Xanomeline is an agonist at M1 and M4 cholinergic receptors without affecting dopamine receptors. While not available as a standalone medication, it was approved in 2024 in combination with trospium under the brand name Cobenfy for the treatment of schizophrenia. This approval marks a significant advancement in schizophrenia treatment, offering a novel mechanism rather than the traditional dopaminergic approach.

Xanomeline readily enters the central nervous system (CNS) with a high brain-to-plasma ratio of > 10:1. It directly activates muscarinic acetylcholine receptors, affecting downstream dopamine and glutamate circuits.

Xanomeline shares structural and pharmacological traits with arecoline, the primary psychoactive component in betel nut.

Development of xanomeline as an Alzheimer's medication was abandoned in the 1990s due to cholinergic side effects.

Xanomeline Mechanism

Refer to the acetylcholine ballicule below to understand xanomeline in context. Think of xanomeline as a piece of acetylcholine.

Xanomeline Interactions

Trospium (Sanctura)

FDA-approved for:

❖ Overactive bladder (OAB)

❖ Countering muscarinic side effects of xanomeline (Cobenfy combo)

Pronunciation: TROSE-pee-um (SANK-tur-uh)

Mnemonic: “Trusty pee-in’ Sanctuary”

Mechanism: Antimuscarinic

Special feature: Does not readily cross the blood-brain barrier

Year of FDA approval: 2004 for OAB

Available strengths: 20 mg IR tabs and 60 mg SR capsules

Cost: IR tab $30–$100, ER cap $50–$150

Trospium is FDA approved for overactive bladder mnemonic cafer

"The brain is a Sanctuary"—Trospium is an anticholinergic medication for overactive bladder (OAB) that does not readily cross the blood-brain barrier (BBB) owing to its large size, hydrophilicity, and positive charge. Therefore, it does not have the ability to impair cognition like most other anticholinergics. Trospium is a P-gp substrate, so any molecules that do cross the BBB are promptly expelled from the CNS by P-gp transporters—"pumpers gonna pump."

Central anticholinergic effects have been rarely reported with trospium including dizziness, confusion, hallucinations, and somnolence. CNS effects should not occur unless trospium is combined with a P-gp inHibitor.

Trospium has low oral bioavailability (<10%). Excretion is primarily renal of unchanged drug (60% within 24 hours). Half-life is approximately 20 hours.

Trospium Mechanism

Refer to the "anticholine" ballicule below to understand trospium in context.

Trospium (does not cross blood-brain barrier) mechanism Stahl-style ballicule by Jason Cafer MD

Trospium Interactions

Trospium is a P-gp substrate interactions

Trospium Contraindications

❖ Urinary retention (anticholinergic)

❖ Gastric retention (anticholinergic)

❖ Untreated narrow-angle glaucoma (anticholinergic)

❖ Moderate or severe hepatic impairment

➤ due to potential for drug accumulation

➤ hepatic toxicity is not a concern

Angioedema has occurred as an IgE-mediated hypersensitivity reaction.

Trospium Dosing:

❖ IR tablets: 20 mg BID (20 mg HS if age > 75)

❖ ER capsules: 60 mg QD

❖ With either formulation, give on an empty stomach > 1 hour before meal

Cobenfy (Xanomeline + Trospium)

FDA-approved for: Schizophrenia

Pronunciation: koh-BEN-fee (zuh-NOM-uh-leen + TROS-pee-um)

Mnemonic: “Cob with benefits”

Class: Next-generation antipsychotic

Mechanism: Muscarinic agonist + muscarinic antagonist

FDA approval: September 2024

Anticipated cost: $1,500–$3,000 monthly

Strengths: Capsules 50/20 mg, 100/20 mg, and 125/30 mg

Cobenfy is xanomeline with trospium - mnemonics with anticholinergic and cholinergic effects

Cobenfy, approved in 2024, is the first antipsychotic for schizophrenia that works exclusively through muscarinic receptors. It consists of a fixed-dose combination of two components in capsule form: xanomeline, the active antipsychotic agent, and trospium, an anticholinergic medication included to manage peripheral side effects.

It is worth noting that the two most effective antipsychotics available in the US—clozapine and olanzapine—have M4 agonist effects, while other available (generally less effective) antipsychotics do not possess this property. This observation provides a rationale for excitement about Cobenfy, which also demonstrated superior efficacy in clinical trials. Notably, Cobenfy stands in stark contrast to clozapine and olanzapine in that it does not cause significant weight gain, a common and problematic side effect of those medications. This favorable side effect profile, combined with its efficacy, makes Cobenfy a promising new option in the treatment of schizophrenia.

The name Cobenfy reflects the dual benefits of xanomeline as both an antipsychotic and cognitive enhancer, as well as the co-administration of xanomeline and trospium.

Developed by Karuna as KarXT, the company was acquired by Bristol Myers Squibb for ~$14 billion. Analysts project Cobenfy as a 2025 blockbuster, with estimated annual sales over $1 billion.

Xanomeline is unlikely to cause tardive dyskinesia (TD), though long-term data is unavailable. While not a D2 receptor blocker, it indirectly affects dopamine circuits. Normal motor function requires dopamine-acetylcholine balance. Extrapyramidal symptoms (EPS) result from relative dopamine deficiency and acetylcholine excess in the nigrostriatal pathway. EPS can be relieved by antimuscarinics like benztropine, but these do not improve or prevent TD. Animal studies showed no TD-like symptoms with longer-term xanomeline use.

Cobenfy Mechanism of Action

Mechanism of Cobenfy visualized M1 Agonist, M4 agonist, M2 antagonist, M3 antagonist

Cobenfy Interactions

Cobenfy Efficacy

Although not directly compared, Cobenfy's effect size (0.6 on PANSS) appears larger than many antipsychotics (0.3-0.5) but smaller than clozapine. Cobenfy's NNT is around 4, compared to 3-10 for older antipsychotics.

Cobenfy showed remarkable efficacy for negative symptoms, with a large effect size of 1.18 and NNT of 2 in this subgroup. It improved negative symptoms beyond secondary effects from positive symptom improvement, unlike most traditional antipsychotics.

Statistically significant benefit seen by week 3; maximal by week 5. Clozapine remains the gold standard for efficacy in schizophrenia (effect size 0.76–1.0, NNT as low as 3 for treatment-resistant cases). Xanomeline's efficacy for treatment-resistant schizophrenia is unknown.

Cobenfy effectiveness efficacy graph for negative symptoms

Cobenfy Side Effects

Does Cobenfy cause headache or weight gain?

Cobenfy Monitoring

❖ Liver enzymes and bilirubin

❖ Heart rate

❖ Urinary retention symptoms

➤ Hesitancy, weak stream, incomplete emptying, dysuria

Conbenfy FDA warning

❖ Risk of urinary retention, higher in geriatric patients

Conbenfy Contraindications

❖ Urinary retention

❖ Gastric retention

➤ Caution: ulcerative colitis, intestinal atony, myasthenia gravis

❖ Untreated narrow-angle glaucoma

❖ Moderate/severe hepatic impairment

➤ Trospium accumulation risk

➤ Not hepatotoxic; biliary obstruction risk

➤ Discontinue if signs of substantial liver injury

Cobenfy Cautions

❖ See dosing for renal/hepatic details

❖ Active biliary disease (e.g., symptomatic gallstones): not

recommended

➤ Assess for gallbladder/biliary disorders, pancreatitis if vomiting

or upper abdominal pain occurs

Cobenfy in Pregnancy

❖ No detrimental effects in animal studies (rats and rabbits)

Cobenfy Dosing

❖ Take 1h before or 2h after meals

❖ Start 50/20 mg BID for 2+ days

❖ Increase to 100/20 mg BID for 5+ days

❖ Max 125/30 mg BID based on tolerability/response

➤ In trials, Cobenfy was increased to max dose on day 8

❖ Geriatric: Same start, slower titration, max 100/20 mg BID

❖ Hepatic:

➤ Contraindicated in mod/severe hepatic impairment

➤ Not recommended in mild hepatic impairment (↑ xanomeline

exposure)

❖ Renal:

➤ Not recommended if eGFR <60 mL/min

➤ Increased exposure to both drugs with eGFR 60 to <90 mL/min

but safety profile unaffected

Medications Related to Cobenfy:

❖ Cevimeline (Evoxac) shares the -meline suffix

➤ Muscarinic agonist for treating dry mouth in Sjögren's syndrome

➤ Does not cross BBB, limiting central effects

❖ Clozapine (Clozaril): Gold standard for antipsychotic efficacy

➤ Primarily works through non-D2 blocking mechanisms

➤ Clozapine (parent drug):

● M1, M2, M3, and M5 antagonist

● M4 agonist – possible shared mechanism with xanomeline

➤ Norclozapine (metabolite): M1 and M4 agonist

● M1 agonism enhances cognition in schizophrenia

● M4 agonism may contribute to antipsychotic efficacy

● However, norclozapine is more associated with side effects than

therapeutic benefit

➤ Unlike with xanomeline/trospium, the muscarinic/antimuscarinic effects

of clozapine/norclozapine are unbalanced, resulting in:

● Severe constipation (clozapine/antimuscarinic)

● Hypersalivation (norclozapine/muscarinic)

➤ In addition to M4 receptor agonism, mechanisms that may contribute to

clozapine's unique efficacy include indirect NMDA receptor agonism

(glycine binding site) and GABA-A receptor antagonism.

❖ Olanzapine (Zyprexa): Superior antipsychotic efficacy

● M1 and M3 antagonist

● M4 agonist (less potent that clozapine)

❖ Pimavanserin (Nuplazid) has antipsychotic effects in Parkinson's disease

without blocking D2 receptors

➤ 5-HT2A inverse agonist without M1/M4 agonist effects

➤ Highlights alternative approaches to antipsychotic action

❖ Emraclidine (Phase 2 trial developmental status)

➤ Potential best-in-class next-generation antipsychotic

➤ M4 receptor positive allosteric modulator (PAM)

➤ Provisional mascot: "M(4) Raccoon"

Zorn, S. H., Jones, S. B., Ward, K. M., & Liston, D. R. (1994). Clozapine is a potent and selective muscarinic M4 receptor agonist. European Journal of Pharmacology: Molecular Pharmacology, 269(3), R1-R2.

Zeng, X. P., Le, F., & Richelson, E. (1997). Muscarinic M4 receptor activation by some atypical antipsychotic drugs. European journal of pharmacology, 321(3), 349-354.

Clozapine + Metabolite is also an M1 & M4 agonist

Orthostatic hypotension with clozapine and norclozapine mnemonics jason cafer MD

Clozapine is the gold standard for treatment-resistant schizophrenia. Several potential explanations have been proposed for clozapine's unique efficacy.

Clozapine has a complex pharmacological profile, interacting with multiple neurotransmitter systems including dopamine, serotonin, norepinephrine, and acetylcholine receptors. Its relatively weak D2 receptor antagonism combined with strong affinity for other receptors may contribute to its superior efficacy and reduced extrapyramidal side effects.

Clozapine has anti-inflammatory properties and may promote neuroplasticity and neurogenesis.

Clozapine influences glutamate signaling via modulation of NMDA receptors at the glycine binding site.

Increasing glycinergic activity through agonists or glycine reuptake inhibitors improves efficacy of non-clozapine antipsychotics, but not clozapine. Glycine at doses of 30–60 g/day has been shown to worsen the positive symptoms of schizophrenia when coadministered with clozapine.

All of the possible mechanisms of action for clozapine with Stahl-style visualization by Jason Cafer MD

Norclozapine (N-desmethylclozapine) is the primary active metabolite of clozapine. Although trials of norclozapine itself as an antipsychotic were unsuccessful, its contribution to clozapine's antipsychotic efficacy remains unclear.

As an M1 agonist, norclozapine likely benefits cognition; indeed, higher clozapine-to-norclozapine ratios have been associated with poorer cognitive function. Norclozapine is associated with more metabolic dysfunction than clozapine, which is not fully explained by known receptor binding affinities.