Is the Weight-Gain Era Over? 52-Week Data Confirms Cobenfy’s Long-Term Safety Profile in Schizophrenia treatment

Introduction

Historically, the pharmacopeia for schizophrenia has been defined by dopaminergic blockade. Standard antipsychotics—both first and second-generation—rely on binding to postsynaptic D2 receptors, effectively "muting" overactive dopamine signaling in the mesolimbic pathway.^1,2

However, this "shotgun" binding profile isn't surgical. These agents often interact with a heterogeneous array of other targets:

• Serotonergic (5-HT): Often targeted to balance mood and motor side effects.^3,4,5

• Histaminergic (H1): Frequently leading to weight gain and sedation.^6,7

• Cholinergic (mACh): Paradoxically antagonized (blocked), which can impair cognition and cause dry mouth.^8,9

A Muscarinic Breakthrough: The Xanomeline-Trospium Paradigm

The recent FDA approval of Cobenfy (xanomeline and trospium chloride) or Kar XT marks a definitive shift in the schizophrenia pharmacopeia.¹⁰ This "Cobenfy Paradigm" represents the first successful decoupling of antipsychotic efficacy from direct D2 dopamine antagonism.¹¹

Approved by the FDA in September 2024, Cobenfy represents a fundamental departure from this lineage.¹⁰ Instead of directly obstructing dopamine, it leverages the brain’s cholinergic system to restore balance.¹²

The Mechanism: Cobenfy acts as a preferential agonist at M1 and M4 muscarinic receptors.¹¹

The Result: By activating these receptors, the drug indirectly modulates dopamine circuits in the mesolimbic and mesocortical pathways.¹³

The Synergy: To avoid the "peripheral storm" (nausea/cramping) typically associated with cholinergic activation, the formula includes trospium—a shield that blocks receptors in the body but cannot cross the blood-brain barrier.¹⁴

Adapted from Azargoonjahromi A. 2024.

Beyond the 5-Week Horizon: What the EMERGENT-5 Trial Tells Us About the Cobenfy Paradigm

EMERGENT-5 trial included stable schizophrenia patients who were switched from current antipsychotic medication to KarXT and followed for 1 year. Twice daily KarXT (maximum dose 125/30 mg) reduced symptoms and was generally well tolerated in adults with schizophrenia in three, 5-week, randomized, double-blind, placebo-controlled trials and a 52-week, open-label extension trial. Nausea, vomiting, constipation, dry mouth, diarrhea, dyspepsia, dizziness, hypertension, and somnolence were the most commonly occurring adverse events. The majority were mild to moderate in intensity, did not lead to discontinuation of COBENFY, and resolved with continued treatment. KarXT improved PANSS total, PANSS positive and negative subscale, and CGI-S scores over the trial duration.¹⁵

 At week 52, 30% of participants had a ≥30% reduction from baseline in the PANSS total score, with an average reduction of -5.5-points from baseline. Treatment with COBENFY was associated with a mean change in body weight of -2.2 kg (+ 6.3 kg) from baseline at 52 weeks. Additionally, COBENFY was not associated with clinically meaningful changes in movement disorder scales or hyperprolactinemia.¹⁶

The 'Persistence' Factor: Why Weight Neutrality is more than just Aesthetics.

Antipsychotic induced weight gain (AIWG) influences medication nonadherence/discontinuation, whereby antipsychotics (APs) with higher weight gain liability are associated with nonadherence/discontinuation. Obese individuals who had reported weight gain in relation to AP use had an increased odds of AP nonadherence (OR 2.37; 95% CI 1.51–3.73; p = 0.0002). Olanzapine was associated with a 3.32times (95% CI 2.32–4.74; p < 0.00001) increased likelihood of nonadherence or discontinuation when compared to other APs with lower weight gain liabilities.¹⁷ All these factors support greater adherence to treatment with Cobenfy compared to other antipsychotics and the discontinuation rate was 18% due to treatment emergent adverse events (TEAEs).¹⁶

Reference

1. Tost H, Alam T, Meyer-Lindenberg A. Dopamine and psychosis: theory, pathomechanisms and intermediate phenotypes. Neurosci Biobehav Rev. 2010 Apr;34(5):689-700.

2. Stępnicki P, Kondej M, Kaczor AA. Current Concepts and Treatments of Schizophrenia. Molecules. 2018 Aug 20;23(8):2087.

3. Romeo B, Willaime L, Rari E, Benyamina A, Martelli C. Efficacy of 5-HT2A antagonists on negative symptoms in patients with schizophrenia: A meta-analysis. Psychiatry Res. 2023 Mar;321:115104. 

4. Li P, Snyder GL, Vanover KE. Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future. Curr Top Med Chem. 2016;16(29):3385-3403.

5. Moran PM, Granger KT. IUPHAR review: Moving beyond dopamine-based therapeutic strategies for schizophrenia. Pharmacol Res. 2025 Jun;216:107727.

6. Carli M, Kolachalam S, Longoni B, Pintaudi A, Baldini M, Aringhieri S, Fasciani I, Annibale P, Maggio R, Scarselli M. Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences. Pharmaceuticals (Basel). 2021 Mar 8;14(3):238.

7. Kondej M, Stępnicki P, Kaczor AA. Multi-Target Approach for Drug Discovery against Schizophrenia. Int J Mol Sci. 2018 Oct 10;19(10):3105. 

8. Rehse M, Bartolovic M, Baum K, Richter D, Weisbrod M, Roesch-Ely D. Influence of Antipsychotic and Anticholinergic Loads on Cognitive Functions in Patients with Schizophrenia. Schizophr Res Treatment. 2016;2016:8213165. 

9. Bishara D. Anticholinergic action is rarely a good thing. Ther Adv Psychopharmacol. 2023 Sep 8;13:20451253231195264.

10. Żełabowski K, Pichowicz W, Dembowska J, Szwajkowski M, Mykhailova D, Wurm G, Biedka K, Błaszczyk K, Piotrowski P. From dopamine to muscarine: xanomeline-trospium (KarXT) as a novel direction in the psychopharmacotherapy of schizophrenia. Front Pharmacol. 2026 Feb 11;17:1774437.

11. Kaul I, Sawchak S, Walling DP, Tamminga CA, Breier A, Zhu H, Miller AC, Paul SM, Brannan SK. Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry. 2024 Aug 1;81(8):749-756. 

12. Bukhari SMR, Btool S, Abbas J, Hussain A, Mehdi H, Raza M. Cobenfy (xanomeline-trospium): a breakthrough FDA-approved therapy redefining schizophrenia treatment. Ann Med Surg (Lond). 2025 Apr 22;87(6):3065-3067.

13. Vasiliu O, Budeanu B, Cătănescu MȘ. The New Horizon of Antipsychotics beyond the Classic Dopaminergic Hypothesis-The Case of the Xanomeline-Trospium Combination: A Systematic Review. Pharmaceuticals (Basel). 2024 May 9;17(5):610.

14. Azargoonjahromi A. Current Findings and Potential Mechanisms of KarXT (Xanomeline-Trospium) in Schizophrenia Treatment. Clin Drug Investig. 2024 Jul;44(7):471-493.

15. Kaul I, Claxton A, Chaturvedi S, Patel T, Wu H, Sawchak S, Sauder C. Long-term efficacy, safety, and tolerability of xanomeline and trospium chloride in schizophrenia: A 52-week, open-label trial (EMERGENT-5). Schizophr Res. 2026 Feb;288:86-94.

16. Bristol Myers Squibb. Bristol Myers Squibb presents new long-term data from the EMERGENT program evaluating COBENFY (xanomeline and trospium chloride) in adults with schizophrenia at Psych Congress 2024. Published October 31, 2024. Accessed March 20, 2026. Available at: https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Presents-New-Long-term-Data-from-the-EMERGENT-Program-Evaluating-COBENFY-xanomeline-and-trospium-chloride-in-Adults-with-Schizophrenia-at-Psych-Congress-2024/default.aspx

17. De R, Smith ECC, Navagnanavel J, Au E, Maksyutynska K, Papoulias M, Singh R, Panganiban KJ, Humber B, Mohr GH, Nielsen MØ, Ebdrup BH, Remington G, Agarwal SM, Hahn MK. The impact of weight gain on antipsychotic nonadherence or discontinuation: A systematic review and meta-analysis. Acta Psychiatr Scand. 2025 Feb;151(2):109-126.

    
    

Written by Vidya Kallorath

Assessed and Endorsed by the MedReport Medical Review Board