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

Bristol Myers Squibb Announces Continuation of ADEPT-2 Phase 3 Study in Psychosis Associated with Alzheimer's Disease (Bristol-Myers Squibb Press Release) - "Following consultation and agreement with the U.S. Food and Drug Administration (FDA), an interim data analysis for efficacy and safety was conducted by an independent party and reviewed by the Data Monitoring Committee (DMC)...Following this analysis, the DMC recommended the study continue by enrolling additional patients to the original target study population. Based on this recommendation, BMS will continue patient enrollment and advance the program as advised by the DMC. BMS remains blinded to study data....Additional trial results from the ADEPT program in psychosis associated with Alzheimer's Disease, including ADEPT-2, ADEPT-1 and ADEPT-4, are expected to read out by the end of 2026."

Clinical data • DSMB • Trial status • Alzheimer's Disease • Psychiatry

KarXT Concentrations in the Breast Milk and Plasma of Lactating Females (clinicaltrials.gov) - P4 | N=8 | Not yet recruiting | Sponsor: Karuna Therapeutics

New P4 trial

Cholinergic Enhancement of Theta (clinicaltrials.gov) - P1 | N=50 | Not yet recruiting | Sponsor: University of Texas Southwestern Medical Center

New P1 trial • CNS Disorders • Cognitive Disorders • Epilepsy

Efficacy and Safety of Cariprazine, Asenapine, Xanomeline-Trospium, and Lumateperone for Acute Exacerbations of Schizophrenia in Adults: A Network Meta-Analysis. (PubMed, Schizophr Bull Open) - "However, further head-to-head comparisons with standard treatments are needed to guide a more evidence-based selection. Future trials with longer durations and more diverse populations are warranted to confirm and extend these findings."

Journal • Retrospective data • CNS Disorders • Psychiatry • Schizophrenia

Estimating the relative efficacy of xanomeline/trospium from placebo-controlled trials. (PubMed, Schizophr Res) - No abstract available

Journal

Profile of a new muscarinic M4 receptor (M4R) positive allosteric modulator (PAM) with antipsychotic-like efficacy (Neuroscience 2025) - "In 2024, approval of KarXT/Cobenfy™ marked a breakthrough with muscarinic M4 receptor activation, offering a new validated avenue for efficacious treatments of schizophrenia2...NTX-A is a potent and highly selective M4 PAM, metabolically stable, bioavailable and brain penetrant. NTX-A demonstrated potent and long-lasting in vivo efficacy in rodent models."

Clinical • CNS Disorders • Psychiatry • Schizophrenia

A Study to Evaluate the Effects of CYP2D6 Phenotypes on the Pharmacokinetics of Xanomeline Following KarXT Administration in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=56 | Recruiting | Sponsor: Karuna Therapeutics | Not yet recruiting ➔ Recruiting

Enrollment open

What's in a name? What shall we call xanomeline-trospium combination? (PubMed, Expert Opin Drug Saf) - No abstract available

Journal • CNS Disorders

Anticipated Major Milestones in the Fourth Quarter of 2025 and Full Year 2026 (Businesswire) - "(i) Upcoming Potential NMPA Submissions:...Efgartigimod (FcRn) for prefilled syringe in generalized myasthenia gravis (gMG) and chronic inflammatory demyelinating polyneuropathy (CIDP) in the fourth quarter of 2025; (ii) Upcoming Potential NMPA Approvals: Xanomeline-Trospium (or KarXT) (M1/M4-agonist) in schizophrenia."

China approval • China filing • Myasthenia Gravis • Schizophrenia

Real-World Implementation of Xanomeline-Trospium in Schizophrenia: A Consensus Panel Report. (PubMed, J Clin Psychiatry) - "Cross-titration experience suggests that XT can be dose-sparing when combined with dopamine blockers, reducing the burden of metabolic and motor side effects. These real-world insights highlight XT as a versatile treatment option that expands the therapeutic possibilities for schizophrenia."

Journal • Real-world evidence • CNS Disorders • Psychiatry • Schizophrenia

Managing treatment-resistant schizophrenia following clozapine cessation: a case report of xanomeline-trospium and olanzapine combination therapy. (PubMed, Front Psychiatry) - "Aripiprazole, titrated to 15 mg/day, and subsequent augmentation with olanzapine failed to restore stability. Clozapine-related VTE/PE represents a serious clinical dilemma. This case illustrates the potential of muscarinic-dopaminergic strategies to restore stability in TRS when clozapine is no longer an option."

Journal • Cardiovascular • CNS Disorders • Epilepsy • Hematological Disorders • Psychiatry • Respiratory Diseases • Schizophrenia • Venous Thromboembolism

Impact of selected second and third generation antipsychotics on cognitive dysfunction in schizophrenia-spectrum disorders. Systematic review and network meta-analysis. (PubMed, Int Clin Psychopharmacol) - "This study aimed to: (a) systematically review randomized controlled trials (RCTs) evaluating the cognitive effects of third-generation antipsychotics (TGAs: brexpiprazole, cariprazine, lumateperone, and lurasidone) and xanomeline-trospium; and (b) perform a network meta-analysis (NMA) including additional second-generation antipsychotics with potential procognitive effects. A systematic literature search identified eligible RCTs, which were combined with trials on aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone from a previous meta-analysis...In conclusion, selected second and TGAs, including M1/M4 receptor agonists such as xanomeline, may offer promising treatment options for cognitive dysfunction. Further research should personalize pharmacological strategies based on cognitive profiles."

Journal • Retrospective data • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Targeting disrupted networks in schizophrenia: Can muscarinic drugs make a fundamental difference? (PubMed, J Psychopharmacol) - "The approval of Karuna Therapeutics (KarXT) in 2024 marked a significant milestone, as it became the first antipsychotic drug to target muscarinic acetylcholine receptors (mAChRs) rather than dopamine receptors...Next, we examine potential pharmacological overlap with clozapine, focusing on actions at 5-HT1A, 5-HT2A and 5-HT7 receptors and consider whether 5-HT receptor subtype agonism, inverse agonism or antagonism could be important for therapeutic efficacy...Taken together, these data suggest that there are neurobiological reasons for optimism for muscarinic agents to improve the classically described positive, negative and cognitive symptoms of schizophrenia, although the relative contribution of each mAChR subtype (M1-M5) remains unclear. We propose that a multi-targeted approach combining actions at 5-HT1A and 5-HT7 receptors could provide additional therapeutic benefits across a range of RDoC domains and hence be of clinical benefit trans-diagonistically beyond..."

Journal • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Evaluation of Treatment Satisfaction and KarXT Utilization Registry (RESKU) (clinicaltrials.gov) - P=N/A | N=300 | Recruiting | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Recruiting

Enrollment open • HEOR • Real-world evidence • CNS Disorders • Psychiatry • Schizophrenia

A Study to Evaluate the Effect of KarXT on Urological Safety (clinicaltrials.gov) - P4 | N=60 | Not yet recruiting | Sponsor: Bristol-Myers Squibb

New P4 trial • CNS Disorders • Psychiatry • Schizophrenia

A Study to Evaluate the Effects of KarXT on the Drug Levels of Midazolam, Fexofenadine, and Digoxin (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Karuna Therapeutics | Not yet recruiting ➔ Recruiting

Enrollment open

Glutamate modulation by evenamide produces statistically significant and clinically relevant improvement in patients with treatment-resistant schizophrenia (ECNP 2025) - "Recent examples include pimavanserin, which did not provide evidence of significant benefit as adjunctive therapy in inadequate responders [1] and Lu-AF35700 which failed to produce significant improvement as monotherapy in TRS [2]. Glycine re-uptake inhibition with bitopertin did not produce significant benefits in patients with inadequately controlled positive symptoms [3]. New results with KarXT indicate no significant benefit compared to placebo when used as add-on to second-generation antipsychotics (SGA) in inadequate responders despite having demonstrated improvement in acutely psychotic patients as monotherapy [4]...Results from the more recent, phase 3, double-blind, placebo-controlled, 4-week, add-on study demonstrated statistically significant and clinically important improvements in 291 patients with inadequate response to SGA including clozapine. Positive findings from these two studies, which will need to be confirmed in a larger phase 3 trial in patients..."

Clinical • CNS Disorders • Epilepsy • Psychiatry • Schizophrenia

A Study to Assess the Long-term Safety of KarXT for the Treatment of Manic Episodes in Bipolar-I Disorder (BALSAM-3) (clinicaltrials.gov) - P3 | N=450 | Recruiting | Sponsor: Bristol-Myers Squibb | N=300 ➔ 450

Enrollment change • Bipolar Disorder • CNS Disorders • Mood Disorders • Psychiatry

A Study to Evaluate the Efficacy and Safety of Adjunctive KarXT for the Treatment of Mania, With or Without Mixed Features, in Participants With Bipolar-I Disorder Taking Lithium, Valproate, or Lamotrigine (clinicaltrials.gov) - P3 | N=424 | Recruiting | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Recruiting

Enrollment open • Bipolar Disorder • CNS Disorders • Mood Disorders • Psychiatry

Xanomeline/trospium-induced polyuria: A patient case report. (PubMed, Ment Health Clin) - "We present a case of a 53-year-old White male who was treated with xanomeline/trospium for the management of schizophrenia who experienced polyuria after a dose titration to maximum dosing of xanomeline/trospium 125 mg/30 mg by mouth twice daily. Owing to the emergence of polyuria 3 days after the dose titration, the xanomeline/trospium was discontinued after discussion with the provider, and the polyuria resolved within 1 day."

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

Receptor subtype specific modulation of muscarinic pathways: a mechanistically distinct therapeutic strategy for schizophrenia (ECNP 2025) - "VU0152100, a selective M4 PAM, exhibits antipsychotic-like effects in rodent models, reducing amphetamine induced locomotor hyperactivity and reversing behavioral deficits...NBI-1117568, a selective M4 orthosteric agonist in Phase 2 trials for schizophrenia, attenuates dopaminergic hyperactivity and restores sensorimotor gating without sedative or motor impairments. Blarcamesine has shown neuroprotective and cognitive enhancing effects in multiple models... Targeting mAChRs, particularly M1 and M4, provides a receptor subtype specific strategy to address unmet needs in schizophrenia. KarXT and emraclidine represent leading agents in clinical development. Emerging modulators such as BQCA, AC-42, and the VU series highlight the diversity of mechanisms and potential for precision treatment tailored to receptor expression profiles and schizophrenia endophenotypes [3]."

CNS Disorders • Psychiatry • Schizophrenia

Pharmacological strategies targeting negative symptoms in schizophrenia (ECNP 2025) - "In a 14-week RCT versus risperidone (n = 460), it achieved a 2.6 point greater reduction on the PANSS Negative subscale (p<0.001) and improved social functioning [4]. Low-dose amisulpride and lurasidone have shown moderate benefits, particularly when negative symptoms are secondary to depression or extrapyramidal effects...Cholinergic modulation with xanomeline–trospium recently showed significant reductions in both positive and negative symptoms in a phase II trial (n = 182), suggesting a novel non-dopaminergic approach. Antidepressant augmentation (primarily SSRIs and mirtazapine) produced modest additional benefits, though heterogeneity across studies tempers confidence [5]... Emerging pharmacotherapies targeting dopamine D3 receptors, serotonergic modulation and glutamatergic pathways offer promising avenues for alleviating negative symptoms in schizophrenia. Cariprazine and roluperidone have demonstrated the most robust RCT evidence, memantine is a viable adjunct..."

CNS Disorders • Depression • Psychiatry • Schizophrenia

A network meta-analysis of the efficacy, safety, and tolerability of xanomeline and trospium chloride versus eight atypical antipsychotics in schizophrenia (ECNP 2025) - P2, P3 | "Xanomeline/trospium treatment significantly improved odds of clinical response versus 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), increased odds of all-cause discontinuation versus all comparators except cariprazine, and reduced odds of clinically significant weight gain versus aripiprazole, brexpiprazole, cariprazine, lumateperone, olanzapine, quetiapine, and risperidone. Additional favorable results for xanomeline/trospium included improvements in CFB CGI-S versus aripiprazole, brexpiprazole, cariprazine, and olanzapine, CFB PANSS positive symptoms score versus brexpiprazole, and CFB weight versus brexpiprazole, clozapine, olanzapine, quetiapine, and risperidone... The SLR identified 3664 unique references. After initial screening followed by the addition of 114 records identified from other sources, a total of 142 records from 111..."

Retrospective data • CNS Disorders • Psychiatry • Schizophrenia • DRD2

Long-term safety and tolerability of xanomeline and trospium chloride: pooled results from the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials (ECNP 2025) - P2, P3 | "Pooled analysis of data from the long-term, open-label EMERGENT-4 and EMERGENT-5 trials found that xanomeline/trospium was generally well tolerated in individuals with schizophrenia in an outpatient setting across 52 weeks. In combination with positive efficacy data from the acute and long-term EMERGENT trials, the present results provide additional support for xanomeline/trospium as a new therapeutic option for people living with schizophrenia."

Clinical • CNS Disorders • Movement Disorders • Psychiatry • Schizophrenia

Using digital phenotyping to index 12-month treatment effects of xanomeline and trospium chloride on physical activity in outpatients with schizophrenia (ECNP 2025) - P2, P3 | "Xanomeline/trospium treatment was associated with broad reductions in sedentary behaviour, indexed by decreased recumbent and seated activities and increased physical activity both at home and away. Step counts also increased, and these increases in steps aligned with shifts from inactive to more active activities. PA played a substantial role in mediating these changes, and further investigation of the origins and dynamics of the role of PA and sedentary behaviour is warranted."

Clinical • CNS Disorders • Psychiatry • Schizophrenia