Cobenfy (xanomeline/trospium) / ZAI Lab, BMS, Royalty, PureTech - LARVOL DELTA

Study to Assess Safety and Tolerability of KarXT With Administration of Antiemetics in Healthy Volunteers (clinicaltrials.gov) - P4 | N=225 | Recruiting | Sponsor: Karuna Therapeutics, Inc., a Bristol Myers Squibb company | Not yet recruiting ➔ Recruiting

Enrollment open

A Prospective, Observational, Single-Arm, Multicenter Real-World Study Evaluating the Treatment Pattern, Safety and Effectiveness of Xanomeline and Trospium Chloride Capsules (KarXT) in the Treatment of Chinese Adult Participants with Schizophrenia (ChiCTR) - P=N/A | N=250 | Not yet recruiting | Sponsor: Peking University Sixth Hospital ( Institute of Mental Health ); Peking University Sixth Hospital ( Institute of Mental Health )

New trial • Real-world evidence • CNS Disorders • Psychiatry • Schizophrenia

Cobenfy (xanomeline-trospium chloride) for schizophrenia: A clinical update. (PubMed, Australas Psychiatry) - "As of March 2026, no Therapeutic Goods Administration (TGA) registration application has been submitted. However, Australian doctors working in psychiatry should familiarise themselves with the evidence base and anticipated prescribing challenges in advance of TGA review."

Journal • CNS Disorders • Psychiatry • Schizophrenia

Relapse Prevention Trial Evaluating KarXT Treatment in Schizophrenia (clinicaltrials.gov) - P3 | N=472 | Recruiting | Sponsor: Karuna Therapeutics, Inc., a Bristol Myers Squibb company | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Psychiatry • Schizophrenia

Xanomeline and Trospium Chloride: Mechanism of Action, Clinical, and Translational Science. (PubMed, Clin Transl Sci) - "Treatment-emergent adverse events were primarily mild to moderate in severity and were mainly transient nausea (19%), constipation (17%), dyspepsia (15%), and vomiting (14%). Discontinuation rates due to adverse events were low (6.2% vs. 5.2% for placebo), and Cobenfy was not associated with weight gain, extrapyramidal symptoms, or cardiometabolic risks seen in conventional antipsychotics."

Journal • Review • CNS Disorders • Constipation • Dyspepsia • Gastroenterology • Gastrointestinal Disorder • Psychiatry • Schizophrenia • DRD2

Treatment-resistant Parkinson's disease psychosis responding to xanomeline-trospium: A case report. (PubMed, Clin Park Relat Disord) - "He was referred specifically for a trial of clozapine therapy, which the patient and caregiver declined due to its risk profile. The patient's psychosis proved refractory to three pharmacologically distinct therapies-quetiapine, a low-affinity, rapidly dissociating dopamine D2 receptor antagonist; brexpiprazole, a dopamine D2 partial agonist; and pimavanserin, a selective 5-HT2A receptor inverse agonist-before improving with xanomeline-trospium, whose antipsychotic effects are mediated through central M1/M4 muscarinic receptor agonism. This case supports the further investigation of muscarinic receptor agonism as a therapeutic strategy for Parkinson's disease psychosis."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • Psychiatry • DRD2

A Prospective, Observational, Single-Arm, Multicenter Real-World Study Evaluating the Treatment Pattern, Safety and Effectiveness of Xanomeline and Trospium Chloride Capsules (KarXT) in the Treatment of Chinese Adult Participants With Schizophrenia (clinicaltrials.gov) - P=N/A | N=250 | Not yet recruiting | Sponsor: Zai Lab (Shanghai) Co., Ltd.

New trial • Real-world evidence • CNS Disorders • Psychiatry • Schizophrenia

Comment on "Safety profile and potential clinical risks of xanomeline and trospium chloride" - Confirmatory findings from an independent FAERS analysis. (PubMed, Neurotherapeutics) - No abstract available

Journal • CNS Disorders • Psychiatry • Schizophrenia

Long-Term Real-World Safety of Cobenfy in Adults With Schizophrenia (clinicaltrials.gov) - P=N/A | N=3000 | Active, not recruiting | Sponsor: Bristol-Myers Squibb

New trial • Real-world evidence • CNS Disorders • Psychiatry • Schizophrenia

The mechanism of action and clinical efficacy of xanomeline-trospium in schizophrenia: A comprehensive review. (PubMed, Ther Adv Psychopharmacol) - "Future research should focus on identifying risk factors for early discontinuation and developing both pharmacological and non-pharmacological strategies to improve long-term adherence. Overall, as a novel non-dopaminergic antipsychotic strategy, xanomeline-trospium offers an important therapeutic option for patients who are intolerant to the metabolic or motor adverse effects of traditional antipsychotics, although challenges related to long-term adherence remain to be addressed."

Journal • Review • CNS Disorders • Constipation • Gastroenterology • Gastrointestinal Disorder • Psychiatry • Schizophrenia

A Study to Evaluate Novel KarX and KarT Prototypes Versus the KarXT and KarX-EC Reference Following Single Doses, Explore the Effect of Food After Multiple Doses of Selected Prototypes, and Evaluate Alternative Formulations of KarX and KarXT Following Single and Multiple Ascending Doses (clinicaltrials.gov) - P1 | N=236 | Recruiting | Sponsor: Bristol-Myers Squibb | N=72 ➔ 236

Enrollment change

Combining Clozapine and Xanomeline/Trospium Chloride: Mechanisms of Action and the Genesis of Catatonia. (PubMed, Prim Care Companion CNS Disord) - "Prim Care Companion CNS Disord 2026;28(4):26f04194. Author affiliations are listed at the end of this article."

Journal • Psychiatry

Muscarinic agonists for schizophrenia: Bridging preclinical evidence and clinical enthusiasm. (PubMed, Br J Pharmacol) - "The recent approval of KarXT, the first muscarinic-targeting antipsychotic drug, marks a potentially important shift in therapeutic strategy...We consider mechanistic overlap with clozapine, and the evidence that 5-HT1A receptor partial agonist actions and 5-HT7 receptor modulation may contribute to xanomeline's broader profile. We propose that combining muscarinic actions with activity at 5-HT receptors may enhance efficacy by restoring disrupted circuits and networks relevant to the full spectrum of symptoms, while reducing dopamine-mediated and metabolic side effects. In conclusion, muscarinic modulation is a promising direction not only for schizophrenia but potentially trans-diagnostically in psychiatry."

Journal • Preclinical • Review • CNS Disorders • Psychiatry • Schizophrenia

Methodological Concerns in a Recently Published Systematic Review and Meta-Analysis of Xanomeline-Trospium in Schizophrenia : Re: Azargoonjahromi A, Nasiri H. Efficacy and Safety of KarXT (Xanomeline-Trospium; Cobenfy™) in Schizophrenia: A Systematic and Meta-Analysis Review of Randomized Controlled Trials. Psychiatric Quarterly. 2025. https://doi.org/10.1007/s11126-025-10226-7. (PubMed, Psychiatr Q) - "Additionally, the review lacks registered protocol details, structured risk-of-bias reporting, and safety outcome pooling. Readers and clinicians are cautioned against interpreting the pooled conclusions in isolation."

Journal • Retrospective data • Review • CNS Disorders • Psychiatry • Schizophrenia

Bristol Myers delays Cobenfy Alzheimer’s psychosis readout again amid another quarterly beat (Fierce Pharma) - "Rather than readouts in 2026, BMS now expects data from the three Adept trials to arrive beginning in early 2027 and be 'spread across the year,'The delay was attributed to slower enrollment in the Adept-2 and Adept-4 studies and slower relapse event accrual in Adept-1, Boerner explained. Adept-1 could undergo an interim analysis as early as later this year, and BMS also plans to share safety and efficacy data this year from the trial’s open-label lead-in portion..."

P3 data • Trial status • Alzheimer's Disease • Psychiatry

An Extension Study to Assess Long-Term Safety and Tolerability of Adjunctive KarXT in Subjects With Inadequately Controlled Symptoms of Schizophrenia (clinicaltrials.gov) - P3 | N=290 | Completed | Sponsor: Karuna Therapeutics, Inc., a Bristol Myers Squibb company | Recruiting ➔ Completed

Trial completion • CNS Disorders • Psychiatry • Schizophrenia

Systematic review and network meta-analysis of the efficacy, safety and tolerability of xanomeline plus trospium chloride compared with eight oral antipsychotics for the acute treatment of schizophrenia. (PubMed, J Comp Eff Res) - "KarXT was associated with greater odds of clinical response (≥30% improvement in PANSS total score) than aripiprazole (odds ratio [OR]: 1.85; 95% credible interval [CrI]: 1.11, 3.11), brexpiprazole (OR: 2.23; 95% CrI: 1.34, 3.83) and cariprazine (OR: 2.05; 95% CrI: 1.19, 3.57); improved change from baseline (CFB) PANSS positive symptoms score versus brexpiprazole; improved CFB CGI-S score against aripiprazole, brexpiprazole, cariprazine and olanzapine; reduced odds of clinically significant (≥7%) weight gain over all comparators except clozapine (no data); improved CFB weight against brexpiprazole, clozapine, olanzapine, quetiapine and risperidone; and greater odds of all-cause discontinuation than aripiprazole, brexpiprazole, clozapine, lumateperone, olanzapine, quetiapine and risperidone. In this NMA, for patients receiving acute treatment for schizophrenia, KarXT compared favorably with second-generation antipsychotics on key efficacy endpoints and in terms of..."

Journal • Retrospective data • Anesthesia • CNS Disorders • Psychiatry • Schizophrenia

Emerging non-D2 receptor-based therapies for schizophrenia: a focus on muscarinic and glutamatergic pathways. (PubMed, Front Psychiatry) - "A paradigm shift occurred in 2024 with the FDA approval of KarXT, a first-in-class muscarinic acetylcholine receptor agonist selectively targeting M1 and M4 subtypes, marking the first non-D2 receptor-based antipsychotic approved in over 70 years...Collectively, muscarinic agonism constitutes the first clinically validated non-D2 receptor-based mechanism in schizophrenia treatment. Advancing precision psychiatry will require rigorous head-to-head comparative trials and biomarker-informed patient stratification to extend therapeutic benefits beyond psychosis control to functional and cognitive recovery."

Journal • Review • CNS Disorders • Cognitive Disorders • Mental Retardation • Psychiatry • Schizophrenia • DRD2

Human Cognition During Surgery: Stimulation-based and Cholinergic Modulation (clinicaltrials.gov) - P1 | N=30 | Not yet recruiting | Sponsor: University of Texas Southwestern Medical Center

New P1 trial • CNS Disorders • Cognitive Disorders • Epilepsy • Essential Tremor • Movement Disorders

A Study to Evaluate the Effects of KarXT on the Drug Levels of Midazolam, Fexofenadine, and Digoxin (clinicaltrials.gov) - P1 | N=62 | Completed | Sponsor: Karuna Therapeutics, Inc., a Bristol Myers Squibb company | Recruiting ➔ Completed

Trial completion

Xanomeline-Trospium Validates Muscarinic Agonism as an Effective Non-Dopaminergic Treatment for Schizophrenia. (PubMed, Int J Mol Sci) - "Furthermore, we contrast this success with the recent failures of other novel mechanisms and explore the potential for precision medicine through the identification of muscarinic receptor deficit biotypes. We conclude that M1/M4 muscarinic receptor agonism represents an important advance toward circuit-based therapeutics that may help overcome some of the limitations inherent to dopamine-centered pharmacotherapy."

Journal • Review • CNS Disorders • Cognitive Disorders • Movement Disorders • Psychiatry • Schizophrenia

A PET/MRI Study of Cobenfy on Dopamine Transmission in Schizophrenia (clinicaltrials.gov) - P1/2 | N=12 | Recruiting | Sponsor: New York State Psychiatric Institute | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Psychiatry • Schizophrenia

A Study to Evaluate Novel KarX and KarT Prototypes Versus the KarXT and KarX-EC Reference Following Single Doses, and to Explore the Effect of Food After Multiple Doses of Selected Prototypes in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=72 | Recruiting | Sponsor: Bristol-Myers Squibb | Trial completion date: Aug 2026 ➔ Mar 2027 | Trial primary completion date: Aug 2026 ➔ Mar 2027

Trial completion date • Trial primary completion date

Toward a Pluralistic Model for the Schizophrenia Spectrum-Dopamine and Beyond. (PubMed, JAMA Psychiatry) - "The efficacy of the muscarinic M1/M4-preferring agonist xanomeline-trospium, which lacks direct D2 receptor antagonism, suggests that nondopaminergic mechanisms can reduce psychotic symptoms...A pluralistic model-recognizing multiple interacting neurochemical and cellular processes-may better account for heterogeneity and translational failures. Future development of novel treatments may depend on biomarker-informed stratification, mechanism-based clinical trials, and integration of molecular, circuit-level, and clinical phenotypes."

Journal • Addiction (Opioid and Alcohol) • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • Metabolic Disorders • Psychiatry • Schizophrenia

Relapse Prevention Trial Evaluating KarXT Treatment in Schizophrenia (clinicaltrials.gov) - P3 | N=472 | Not yet recruiting | Sponsor: Karuna Therapeutics, Inc., a Bristol Myers Squibb company

New P3 trial • CNS Disorders • Psychiatry • Schizophrenia