Highlights
Karuna Therapeutics has developed Cobenfy (xanomeline + trospium), a new drug for the treatment of schizophrenia.
Karuna’s goal in developing Cobenfy was to make the treatment of schizophrenia more effective in terms of more complete relief of the symptoms of this endogenous polymorphic psychiatric disorder, while maximizing freedom from the side effects associated with all existing neuroleptics (antipsychotics) currently used in the treatment of schizophrenia.
Unlike existing drugs, Cobenfy acts indirectly on dopamine neurotransmission, making it the first fundamentally new pharmacotherapy for schizophrenia in over 50 years if it receives regulatory approval.
Oral Cobenfy, known by the codename KarXT, is a dual agonist of the muscarinic acetylcholine receptors M1 and M4 in the central nervous system, which are thought to mediate the positive, negative, and cognitive symptoms of schizophrenia.
A decision from the U.S. Food and Drug Administration (FDA), to which Karuna submitted a New Drug Application (NDA) for Cobenfy at the end of September 2023, is expected by the end of September 2024. It is possible that the agency will convene an advisory committee of independent experts to fully evaluate investigational drug’s safety and efficacy profiles [1].
Industry observers predict that peak annual sales of Cobenfy could reach $1.2 billion.
In parallel, Cobenfy is being studied for the treatment of psychosis in Alzheimer’s disease.
Cobenfy will enter the market in 2024.
According to experts at the Institute of Clinical and Economic Review (ICER), the annual cost of treating schizophrenia with Cobenfy will be acceptable if it falls within the range of $16,000 to $20,000 for American patients [2].
In mid-March 2024, Bristol-Myers Squibb (BMS) completed the $14 billion ($12.7 billion in cash) acquisition of Karuna, which was initially announced at the end of December 2023 [3] [4].
Clinical Details
The efficacy and safety of KarXT were evaluated as part of the large-scale EMERGENT clinical program, which consisted of three completed placebo-controlled trials: EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123). Furthermore, long-term safety studies are ongoing, including EMERGENT-4 (NCT04659174) and EMERGENT-5 (NCT04820309).
All three placebo-controlled clinical trials successfully demonstrated the statistically significant (p<0,0001) superiority of KarXT over the control groups, as measured by the change in the Positive and Negative Syndrome Scale (PANSS) total score.
Thus, in EMERGENT-1, EMERGENT-2, and EMERGENT-3, administration of KarXT twice daily for 5 weeks resulted in a decrease the PANSS total score by an average of absolute 17.4, 21.2, and 20.6 points and relative to placebo by 11.6, 9.6, and 8.4 points [1] [2] [3] [4] [5] [6] [7] [8].
The administration of KarXT resulted in a reduction in both positive and negative symptoms of schizophrenia as assessed by the PANSS positive and negative subscales and the Marder factor.
Among the most common adverse events (AEs) reported during KarXT therapy for schizophrenia: nausea, dyspepsia, vomiting, constipation, headache, hypertension, diarrhea, and insomnia — were all characterized by mild to moderate severity.
The frequencies of AEs typical for existing neuroleptics, including weight gain, sedation, parkinsonism, dystonia, akathisia, and prolactin level rise, while taking KarXT were similar to those of placebo. This indicates that a more than acceptable safety profile was demonstrated.
The long-term results of KarXT administration over one year of therapy for schizophrenia demonstrated that treatment with EMERGENT-4 resulted in an average reduction of 33.3 total points on the PANSS. Furthermore, three-quarters of patients (over 75%) demonstrated greater than 30% improvement in symptoms. The subjects’ schizophrenia severity status changed from “markedly ill” to “moderately” or “mildly” according to the change in Clinical Global Impression-Severity (CGI-S) score [9].
The one-year administration of KarXT, as studied during EMERGENT-4 and EMERGENT-5, confirmed an acceptable safety profile. There were no AEs common to therapy with any of the existing neuroleptics, such as weight gain, increased prolactin levels, neuromotor impairment, sexual dysfunction, and sedation. In contrast, 65% of patients showed an average decrease in body weight by 2.6 kg [10].
Among the most common AEs during KarXT administration were nausea (in 20% of patients), vomiting (18%), constipation (17%), and hypertension (10%). All AEs were mild to moderate in severity. Treatment due to AEs (mainly due to nausea or vomiting) was discontinued by 15% of subjects.
In 2025, the results of the ARISE (NCT05145413) phase 3 clinical trial will be available, which investigated the prescribing of KarXT as an add-on to the treatment of schizophrenia with neuroleptics, including risperidone, paliperidone, aripiprazole, ziprasidone, lurasidone, or cariprazine.
The ADEPT-1 (NCT05511363) and ADEPT-2 (NCT06126224) phase 3 clinical trials of the safety and efficacy of KarXT in the treatment of psychosis in Alzheimer’s disease are anticipated to be concluded in 2026.
Mechanism of Action
Antipsychotic medications are associated with a number of adverse events (AEs), including extrapyramidal symptoms, sedation, weight gain, metabolic disturbances, and hyperprolactinemia. These AEs contribute to poor treatment adherence and psychosis relapses [1] [2]. Furthermore, approximately 20%–33% of patients fail to achieve a response to standard treatment, and others have residual psychotic symptoms [3]. Consequently, a significant proportion of patients with schizophrenia exhibit poor functional status and quality of life, despite long-term treatment with modern neuroleptics [4] [5].
Antipsychotics approved for the treatment of schizophrenia act primarily by modulating dopamine and serotonin activity. Two generations of such drugs have been proposed, differing in their affinity ratio for dopamine D2 receptors and serotonin 5-HT2A receptors. The former is characterized by a high D2/5-HT2A ratio, whereas the latter is characterized by a low ratio [6]. Nevertheless, there are reasons to believe that the muscarinic cholinergic system is also involved in the pathophysiology of schizophrenia [7] [8] [9] [10] [11].
Xanomeline, an oral muscarinic cholinergic receptor agonist synthesized by Eli Lilly and Novo Nordisk in the early 1990s, has no direct effect on dopamine receptors [12] and predominantly stimulates muscarinic cholinergic receptors of the central M1 and M4 subtypes [13]. This modulation leads to the regulation of key dopaminergic and glutamatergic circuits in the brain, which are considered to be dysregulated in patients suffering from neuropsychiatric diseases such as schizophrenia and Alzheimer’s disease [14].
In studies among patients with Alzheimer’s disease or schizophrenia, xanomeline provided greater relief of some psychotic symptoms than the placebo [15] [16]. However, dose-dependent cholinergic AEs in the form of nausea, vomiting, diarrhea, sweating, and hypersalivation mediated by stimulation of peripheral muscarinic cholinergic receptors were observed.
Trospium chloride is an oral panmuscarinic receptor antagonist that has been approved for the treatment of overactive bladder [17]. The highly polar structure of this tertiary amine prevents it from reaching the level of detection in cerebrospinal fluid, which excludes AEs from the central nervous system [18].
Studies have demonstrated that the incidence of cholinergic AEs was approximately half lower when trospium was added to xanomeline than when xanomeline was used alone [19]. This suggests that therapeutic antipsychotic doses of xanomeline stimulate brain muscarinic receptors, while the addition of trospium limits the associated peripheral cholinergic AEs [20].
Extras
Corporate
Karuna Therapeutics. Corporate Presentation. November, 2023. [PDF]
Schizophrenia
Schizophrenia. Fact Sheets. Karuna Therapeutics. [PDF]
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Psychosis in Alzheimer’s Disease
2024 Alzheimer’s Disease Facts and Figures. Alzheimer’s Association. [Source]
Psychosis in Alzheimer’s disease. Biol Psychiatry. 2014 Apr 1;75(7):542-52. [Source]
Medical Conferences
Further Evaluation of the Procognitive Effect of KarXT in Acutely Symptomatic Schizophrenia: Consideration of Cognitive Subdomains and Methodological Factors. ISCTM 2024. [PDF]
Long-Term Metabolic Outcomes Associated With KarXT (Xanomeline and Trospium): Interim Results From Pooled, Long-Term Safety Studies EMERGENT-4 and EMERGENT-5. SIRS 2024. [PDF]
The Impact of KarXT on Cognitive Impairment in Acute Schizophrenia: Replication in Pooled Data From Phase 3 Trials. SIRS 2024. [PDF]
Maintenance of Efficacy of KarXT (Xanomeline and Trospium) in Schizophrenia. SIRS 2024. [PDF]
Long-Term Safety of KarXT (Xanomeline and Trospium) in Schizophrenia. SIRS 2024. [PDF]
Blinded Remote Ratings of Site-Based PANSS Interviews Address Functional Unblinding in a Study of Acute Exacerbation of Psychosis in Schizophrenia. SIRS 2024. [PDF]
Potential Impact of KarXT on Negative Symptoms in Acute Schizophrenia: An Analysis of Pooled Data From 3 Trials. CNS 2023. [PDF]
Design of ADEPT-2, a Phase 3, Parallel-Group Study to Evaluate KarXT (Xanomeline-Trospium) as a Treatment for Psychosis Associated With Alzheimer’s Disease. AAIC 2023. [PDF]
KarXT (Xanomeline–Trospium) for the Treatment of Agitation in Schizophrenia: PANSS-EC Results From Three Randomized, Double-Blind, Placebo-Controlled Trials. ACNP 2023. [PDF]
KarXT (Xanomeline–Trospium) Demonstrates Broad Efficacy in People With Schizophrenia Across a Wide Range of Demographic Subgroups: Pooled Results From the 3 Randomized, Double-Blind, Placebo-Controlled EMERGENT Trials. ACNP 2023. [PDF]
The Muscarinic Agonist Xanomeline Demonstrates Antipsychotic Activity and Augments Clinical Antipsychotics in Rodent Behavioral Models of Psychosis. ACNP 2023. [PDF]
Categorial Response Rates, Time Course of Response, and Symptom Domains of Response With KarXT (Xanomeline-Trospium) in the Phase 3 EMERGENT-2 Trial. APA 2023. [PDF]
Safety and Efficacy of KarXT in Patients With Schizophrenia in the Randomized, Double-Blind, Placebo-Controlled EMERGENT Trials. ASCP 2023. [PDF]
Site-Independent Replication of Clinical Metrics in a Study of KarXT in Subjects With an Acute Exacerbation of Psychosis in Schizophrenia. ASCP 2023. [PDF]
Efficacy and Safety of KarXT in Schizophrenia: Post Hoc Analysis of the Phase 3, Randomized, Double-Blind, Placebo-Controlled EMERGENT-2 Trial. CINP 2023. [PDF]
Onset, Duration, and Severity of Adverse Events With KarXT (Xanomeline–Trospium) in the Randomised, Double-Blind, Placebo-Controlled Phase 3 EMERGENT-3 Trial. ECNP 2023. [PDF]
Categorical Response Rates, Time Course of Response, and Symptom Domains of Response With KarXT (Xanomeline–Trospium) in the EMERGENT-3 Trial. ECNP 2023. [PDF]
The Potential Role of the M1/M4 Muscarinic Receptor Agonist KarXT in the Treatment of Cognitive Impairment in Patients With Schizophrenia. ECNP 2023. [PDF]
Pooled Analysis of EPS-Like Symptoms in the EMERGENT Program of KarXT in Schizophrenia. NEI 2023. [PDF]
Safety and Tolerability of KarXT (Xanomeline–Trospium): Pooled Results From the Randomized, Double-Blind, Placebo-Controlled EMERGENT Trials. NEI 2023. [PDF]
Efficacy of KarXT (Xanomeline–Trospium) in Schizophrenia: Pooled Results From the Randomized, Double-Blind, Placebo-Controlled EMERGENT Trials. NEI 2023. [PDF]
Categorial Response Rates, Time Course of Response, and Symptom Domains of Response With KarXT (Xanomeline-Trospium) in the Phase 3 EMERGENT-2 Trial. PSYCH 2023. [PDF]
Safety and Efficacy of KarXT in Schizophrenia in the Randomized, Double-Blind, Placebo-Controlled, Phase 3 EMERGENT-3 Trial. PSYCH 2023. [PDF]
Safety and Efficacy of KarXT in Patients With Schizophrenia in the Randomized, Double-Blind, Placebo-Controlled, Phase 3 EMERGENT-2 and EMERGENT-3 Trials. SIRS 2023. [PDF]
The Role of M1 and M4 Muscarinic Receptors in Cognitive Performance. SIRS 2023. [PDF]
Understanding the Role of M1 and M4 Muscarinic Receptors in Cognitive Circuits: Implications for Cognitive Improvement. SOBP 2023. [PDF]
Safety and Efficacy of KarXT (Xanomeline–Trospium) in Patients With Schizophrenia: Results From a Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial (EMERGENT-2). ACNP 2022. [PDF]
The Clinical Candidate Xanomeline Displays a Binate Orthosteric and Allosteric Binding and Pharmacological Profile at the M4 mAChR. ACNP 2022. [PDF]
Antipsychotic Efficacy of KarXT (Xanomeline–Trospium): Analysis of Positive and Negative Syndrome Scale Categorial Response Rates, Time Course of Response, and Symptom Domains of Response in a Phase 2 Study. CPNP 2022. [PDF]
Evaluating KarXT (Xanomeline–Trospium) as a Treatment for Psychosis Associated With Alzheimer’s Disease Dementia: Design of the Phase 3, ADEPT-1, Relapse Prevention Study. CTAD 2022. [PDF]
Safety and Efficacy of KarXT (Xanomeline–Trospium) in Patients With Schizophrenia: Results From a Phase 3, Randomised, Double-Blind, Placebo-Controlled Trial (EMERGENT-2). ECNP 2022. [PDF]
Safety and Efficacy of KarXT (Xanomeline–Trospium) in Patients With Schizophrenia: Results From a Phase 3, Randomised, Double-Blind, Placebo-Controlled Trial (EMERGENT-2). ECNP 2022. [PDF]
Safety and Efficacy of KarXT (Xanomeline–Trospium) in Schizophrenia in the Phase 3, Randomized, Double-Blind, Placebo-Controlled EMERGENT-2 Trial. NEI 2022. [PDF]
Safety and Efficacy of KarXT (Xanomeline–Trospium) in Patients With Schizophrenia: Results From a Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial (EMERGENT-2). Psych Congress 2022. [PDF]
The Muscarinic Agonist Xanomeline Demonstrates Standalone Activity and Augments Clinical Antipsychotics in Rodent Behavioral Models of Psychosis. SIRS 2022. [PDF]
Acetylcholine as a Regulator of Dopamine Pathways: Rationale for Selective Muscarinic Agonists as Candidates for Antipsychotic Drug Development. SIRS 2022. [PDF]
The Potential of M1 Agonists to Treat Cognitive Impairment: Evidence From a Phase 2 Study of KarXT in Schizophrenia (EMERGENT-1). SIRS 2022. [PDF]
A Phase 3 Placebo-Controlled Study Evaluating the Safety and Efficacy of Adjunctive KarXT in Patients With Inadequately Controlled Schizophrenia Symptoms: Clinical Rationale and Design (ARISE Study). SIRS 2022. [PDF]
Xanomeline’s Activity in Rodent Models of Psychosis: Role of Central Muscarinic Receptors and Augmentation by Risperidone and Aripiprazole. ACNP 2021. [PDF]
Characterizing the Antipsychotic Activity and Safety Profile of the Novel Muscarinic Agonist KarXT (Xanomeline + Trospium): Primary and Secondary Results from a Phase 2 Placebo-Controlled Trial in Schizophrenia. ASCP 2021. [PDF]
KarXT Treatment Improves Cognitive Performance in Cognitively Impaired Patients with Schizophrenia: A Post hoc Analysis of the Phase 2 EMERGENT-1 Study. ECNP 2021. [PDF]
Methodological approaches to outliers in cognitive assessment for schizophrenia: A post hoc analysis of the EMERGENT-1 study. ISCTM 2021. [PDF]
Understanding Why Muscarinic Receptor Agonists Have Antipsychotic Properties. NEI Synapse 2021. [PDF]
The M1/M4 Agonist Xanomeline in Combination with Trospium is Effective for Acute Treatment of Schizophrenia: PANSS Responder and PANSS 5-Factor Analyses of a Phase 2 Placebo-Controlled Inpatient Trial. SIRS 2021. [PDF]
The M1/M4 agonist xanomeline, in combination with the peripheral anticholinergic trospium, is effective for acute treatment of schizophrenia: results of a Phase 2 RCT comparing KarXT vs placebo. ACNP 2020. [PDF]
Molecular Mechanism of Antipsychotic Xanomeline’s Selectivity at Muscarinic Receptors. ACNP 2020. [PDF]
KarXT (a new mechanism antipsychotic based on xanomeline), is superior to placebo in patients with schizophrenia: Phase 2 clinical trial results. ASCP 2020. [PDF]
Site ratings versus site-independent ratings of PANSS interviews in a schizophrenia study. CNS 2020. [PDF]
Phase 2 trial results of KarXT (xanomeline + trospium) in patients with schizophrenia: superior efficacy to placebo across positive and negative symptoms and a favorable safety/tolerability profile. ECNP 2020. [PDF]
Site ratings versus site-independent ratings of PANSS interviews in a schizophrenia study. ICSTM 2020. [PDF]
KarXT (xanomeline, a muscarinic agonist plus trospium, a peripheral muscarinic antagonist) is superior to placebo in patients with schizophrenia: Phase 2 clinical trial results. SIRS 2020. [PDF]
Xanomeline plus trospium: A novel strategy to enhance pro-muscarinic efficacy and mitigate peripheral side effects. ASCP 2019. [PDF]
Scientific Publications
A network meta-analysis of KarXT and commonly used pharmacological interventions for schizophrenia. Schizophr Res. 2024 Sep 29:274:212-219. [Source]
Efficacy of KarXT on negative symptoms in acute schizophrenia: A post hoc analysis of pooled data from 3 trials. Schizophr Res. 2024 Sep 10:274:57-65. [Source]
Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry. 2024 Aug 1;81(8):749-756. [Source]
Current Findings and Potential Mechanisms of KarXT (Xanomeline-Trospium) in Schizophrenia Treatment. Clin Drug Investig. 2024 Jul;44(7):471-493. [Source]
Xanomeline-Trospium in schizophrenia: A detailed review and comparison with the Institute for Clinical and Economic Review’s analysis. J Manag Care Spec Pharm. 2024 Jun;30(6):629-632. [Source]
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. [Source]
Efficacy, safety, and tolerability of xanomeline for schizophrenia spectrum disorders: a systematic review. Expert Opin Pharmacother. 2024 Mar;25(4):467-476. [Source]
Muscarinic Receptor Activators as Novel Treatments for Schizophrenia. Biol Psychiatry. 2024 Mar 25:S0006-3223(24)01173-9. [Source]
Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet. 2024 Jan 13;403(10422):160-170. [Source]
Muscarinic M1 and M4 receptor agonists for schizophrenia: promising candidates for the therapeutic arsenal. Expert Opin Investig Drugs. 2023 Jul-Dec;32(12):1113-1121. [Source]
Evidence of trospium’s ability to mitigate cholinergic adverse events related to xanomeline: phase 1 study results. Psychopharmacology (Berl). 2023 May;240(5):1191-1198. [Source]
Structural basis of efficacy-driven ligand selectivity at GPCRs. Nat Chem Biol. 2023 Apr;19(4):529. [Source]
Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia. Am J Psychiatry. 2022 Sep;179(9):611-627. [Source]
Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study. Transl Psychiatry. 2022 Nov 21;12(1):491. [Source]
Muscarinic acetylcholine receptors for psychotic disorders: bench-side to clinic. Trends Pharmacol Sci. 2022 Dec;43(12):1098-1112. [Source]
Safety and tolerability of KarXT (xanomeline-trospium) in a phase 2, randomized, double-blind, placebo-controlled study in patients with schizophrenia. Schizophrenia (Heidelb). 2022 Dec 3;8(1):109. [Source]
Antipsychotic Efficacy of KarXT (Xanomeline-Trospium): Post Hoc Analysis of Positive and Negative Syndrome Scale Categorical Response Rates, Time Course of Response, and Symptom Domains of Response in a Phase 2 Study. J Clin Psychiatry. 2022 May 11;83(3):21m14316. [Source]
Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia. N Engl J Med. 2021 Feb 25;384(8):717-726. [Source]
The M1/M4 preferring muscarinic agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain. Neuropsychopharmacology. 2021 May;46(6):1194-1206. [Source]
Striatal, Hippocampal, and Cortical Networks Are Differentially Responsive to the M4- and M1-Muscarinic Acetylcholine Receptor Mediated Effects of Xanomeline. ACS Chem Neurosci. 2019 Mar 20;10(3):1753-1764. [Source]
The M1/M4 preferring agonist xanomeline reverses amphetamine-, MK801- and scopolamine-induced abnormalities of latent inhibition: putative efficacy against positive, negative and cognitive symptoms in schizophrenia. Int J Neuropsychopharmacol. 2011 Oct;14(9):1233-46. [Source]
Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008 Aug;165(8):1033-9. [Source]
Xanomeline, an M1/M4 preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. Schizophr Res. 2000 May 5;42(3):249-59. [Source]
Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol. 1997 Apr;54(4):465-73. [Source]
PET study of the M1-agonists [11C]xanomeline and [11C]butylthio-TZTP in monkey and man. Dementia. 1996 Jul-Aug;7(4):187-95. [Source]