Drugs (2025) 85:103–109

[Link]

ADISINSIGHT REPORT

Xanomeline/Trospium Chloride: First Approval

Yahiya Y. Syed1

Accepted: 13 November 2024 / Published online: 24 December 2024

© Springer Nature Switzerland AG 2024

Abstract
Xanomeline/trospium chloride (COBENFY™), formerly KarXT, is a first-in-class, oral, fixed-dose muscarinic agonist/
antagonist combination being developed for use in schizophrenia and Alzheimer's disease psychosis. Xanomeline is thought
to confer efficacy by acting as an agonist at M
­ 1 and ­M4 muscarinic acetylcholine receptors in the brain, and trospium chloride
reduces the peripheral cholinergic adverse events associated with xanomeline. Xanomeline/trospium chloride received its
first approval on 26 September 2024 in the USA for the treatment of schizophrenia in adults. This article summarizes the
milestones in the development of xanomeline/trospium chloride leading to this first approval for schizophrenia.

Digital Features for this AdisInsight Report can be found at receptors, addressing primarily positive symptoms [1, 2].
[Link] This approach is also associated with adverse events (AEs)
such as extrapyramidal symptoms, hyperprolactinaemia,
sedation, weight gain and metabolic syndrome [2, 3]. Target-
Xanomeline/trospium chloride (COBENFY™): Key ing the muscarinic cholinergic system is a promising novel
Points strategy that may not only address a broader spectrum of
symptoms but could also reduce the AEs associated with
A muscarinic agonist/antagonist combination is being dopamine receptor blockade [4, 5].
developed by Bristol-Myers Squibb for the treatment of Xanomeline/trospium chloride (COBENFY™), formerly
schizophrenia and Alzheimer's disease psychosis KarXT, is a first-in-class, oral, fixed-dose combination of a
muscarinic agonist (xanomeline) and a muscarinic antago-
Received its first approval on 26 September 2024 in the nist (trospium chloride) being developed by Bristol-Myers
USA Squibb for the treatment of schizophrenia and psychosis
Approved for use in schizophrenia in adults associated with Alzheimer's disease. Xanomeline, a prefer-
ential agonist of ­M1 and ­M4 muscarinic acetylcholine recep-
tors with no direct D­ 2 dopamine receptor effects, improved
psychotic symptoms and cognition in schizophrenia and
1 Introduction
Alzheimer's disease in clinical trials [2, 6]. However, it was
associated with gastrointestinal AEs due to the activation
Schizophrenia is characterized by positive, negative
of peripheral muscarinic receptors. Trospium chloride is a
and cognitive symptoms [1]. Most current antipsychot-
nonselective muscarinic receptor antagonist that does not
ics confer efficacy by blocking dopamine and serotonin
significantly cross the blood-brain barrier, limiting its effects
to peripheral tissues. Combining trospium chloride with
xanomeline reduces the peripheral cholinergic AEs associ-
This profile has been extracted and modified from the AdisInsight ated with xanomeline [2, 6].
database. AdisInsight tracks drug development worldwide through Xanomeline/trospium chloride received its first approval
the entire development process, from discovery, through pre-clinical on 26 September 2024 in the USA for the treatment of
and clinical studies to market launch and beyond. schizophrenia in adults [7, 8]. The recommended dos-
* Yahiya Y. Syed
age starts at 50 mg/20 mg twice daily (BID) for ≥ 2 days,
dru@[Link] increasing to 100 mg/20 mg BID for ≥ 5 days [7]. The
dosage may be increased to 125 mg/30 mg BID (maximum
1
Springer Nature, Private Bag 65901, Mairangi Bay, recommended) based on patient tolerability and response.
Auckland 0754, New Zealand

Vol.:(0123456789)
104 Y. Y. Syed

NDA submitted in the USA (Sep)

NDA accepted in the USA (Nov)

Approved in the USA for

schizophrenia (Sep)

Preclinical trials initiated US PDUFA goal date

(Aug 2015) (Sep)

2018 2019 2020 2021 2022 2023 2024 2025

EMERGENT-1
EMERGENT-2
Phase II trial EMERGENT-3 Est. Feb 2027
ARISE
Phase III trials

Key milestones in the development of xanomeline/trospium chloride for schizophrenia. NDA New Drug Application, PDUFA Prescription Drug User
Fee Act

In geriatric patients, the recommended starting dosage is 1.1 Company Agreements

50 mg/20 mg BID, with slower titration up to a maximum of
100 mg/20 mg BID. Xanomeline/trospium chloride should In March 2011, Karuna Therapeutics entered into an agreement
be taken at least 1 h before or 2 h after a meal. Contraindica- with PureTech Health, obtaining an exclusive license to patent
tions to xanomeline/trospium chloride include urinary reten- rights for combinations of a muscarinic activator and a mus-
tion, moderate or severe hepatic impairment (Child-Pugh carinic inhibitor for treating CNS disorders [9]. In May 2012,
Class B or C), gastric retention, untreated narrow-angle Karuna Therapeutics entered into an exclusive license agreement
glaucoma and a history of hypersensitivity to the active with Eli Lilly, securing exclusive rights to certain now-expired
ingredients. Liver enzymes, bilirubin and heart rate should patents, regulatory documentation, data records and materials
be tested/monitored before starting treatment and as clini- related to xanomeline. In November 2021, Karuna Therapeu-
cally indicated during treatment [7]. Xanomeline/trospium tics entered into an exclusive license agreement with Zai Lab
chloride is undergoing phase 3 development for schizophre- for the development, manufacturing and commercialization of
nia and Alzheimer’s disease psychosis in multiple countries. xanomeline/trospium chloride in Greater China, encompassing
mainland China, Hong Kong, Macau and Taiwan [9]. In March
2024, Bristol-Myers Squibb acquired Karuna Therapeutics [10].

Cl– N+ O N

O HO S
H
O N

Trospium chloride Xanomeline

Chemical structure
Xanomeline/Trospium Chloride: First Approval 105

2 Scientific Summary of 2 h, a central volume of distribution ­(Vd) of 10,800 L,

a plasma protein binding of ≈ 95%, an elimination half-
2.1 Pharmacodynamics life ­(t1/2) of 5 h, an apparent clearance (CL) of 1950 L/h
and a renal clearance (­ CLR) of 0.085 L/h. It is primarily
Xanomeline’s mechanism of action in treating schizophrenia metabolized by CYP450 enzymes (2D6, 2B6, 1A2, 2C9 and
is unclear but is thought to involve its agonistic activity at M₁ 2C19) and flavin monooxygenases, with 78% excreted in
and M₄ muscarinic receptors in the CNS [7]. It has a high urine (< 0.01% unchanged) and 12% in faeces. Trospium
affinity for ­M1 and M­ 4 receptors (Ki = 10 and 7, respectively), has a ­Tmax of 1 h, a ­Vd of 531 L, a plasma protein binding of
compared to M ­ 2, ­M3, and M­ 5 receptors (Ki = 12, 17 and 22). ≈ 80%, a t­1/2 of 6 h, a CL of 796 L/h and a C ­ LR of 21 L/h.
At the maximum recommended dosage (125 mg/30 mg BID), It is mostly excreted unchanged in the urine (85–90%), with
xanomeline/trospium chloride does not prolong the QT inter- metabolism involving ester hydrolysis and glucuronic acid
val to any clinically significant extent [7]. conjugation [7].
In a phase 1 trial (NCT02831231) in healthy volunteers, A high-fat meal increases xanomeline's exposure, while
adding trospium to xanomeline resulted in a 46% reduc- both high- and low-fat meals decrease trospium's expo-
tion in five prespecified cholinergic AEs (nausea, vomiting, sure. In geriatric patients, xanomeline’s exposure remains
diarrhoea, excessive sweating and salivary hypersecretion), unchanged, while trospium’s exposure is higher [7]. Both
compared to xanomeline alone [11]. xanomeline and trospium exposure increase with worsen-
ing kidney function. Mild to moderate hepatic impairment
2.2 Pharmacokinetics raises xanomeline exposure but does not significantly affect
trospium exposure; the impact of severe hepatic impairment
Xanomeline exhibits greater than dose-proportional phar- on both drugs has not been evaluated [7].
macokinetics, while trospium shows dose-proportional phar- Clinically significant drug interactions may occur if
macokinetics [7]. Both drugs reach steady state in 3–5 days, xanomeline/trospium chloride is used concomitantly with
with a 2–3-fold accumulation at steady state. Xanomeline strong CYP2D6 inhibitors, drugs eliminated by active tubu-
has a T
­ max (time to maximum plasma concentration, C ­ max) lar secretion, or oral drugs that are sensitive substrates of
CYP3A4 or substrates of P-glycoprotein [7].

Features and properties of xanomeline/trospium chloride

Alternative names BMS-986510; COBENFY; KarXT; trospium chloride/LY-246708; trospium chloride/xanomeline tartrate; xanomeline
tartrate/trospium chloride
Class Analgesics; antidementias; antipsychotics; antispasmodics; benzhydryl compounds; benzilates; esters; nortropanes;
pyridines; small molecules; spiro compounds; thiadiazoles; urologics
Mechanism of action Muscarinic ­M1 and ­M4 receptor agonists; Muscarinic receptor antagonists
Route of administration Oral
Pharmacodynamics Xanomeline provides antipsychotic effects attributed to its preferential agonist activity at M₁ and M₄ muscarinic recep-
tors in the brain. Trospium chloride antagonizes muscarinic receptors in peripheral tissues, reducing the peripheral
cholinergic adverse events associated with xanomeline.
Pharmacokinetics Xanomeline: greater than dose-proportional pharmacokinetics; ­Tmax 2; ­t1/2 5 h; 78% excreted in urine (< 0.01%
unchanged)
Trospium: dose-proportional pharmacokinetics; ­Tmax 1 h; ­t1/2 6 h; 85%–90% excreted in urine as unchanged compound
Most frequent adverse Nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhoea, tachycardia, dizziness and gastro-
reactions intestinal reflux disease
ATC codes
WHO ATC code G04B-D09 (Trospium); N05A-X (Other antipsychotics)
EphMRA ATC code N5A (Antipsychotics)
Chemical name [(1S,5R)-spiro[8-azoniabicyclo[3.2.1]octane-8,1'-azolidin-1-ium]-3-yl] 2-hydroxy-2,2-diphenylacetate;chloride /
3-hexoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)-1,2,5-thiadiazole;(2R,3R)-2,3-dihydroxybutanedioic acid
106 Y. Y. Syed

2.3 Therapeutic Trials (age 18–65 years) with schizophrenia hospitalized for acute
psychosis was subsequently evaluated in two 5-week, ran-
2.3.1 Phase 2 Trial domized, double-blind, placebo-controlled phase 3 trials
(EMERGENT-2 [15] and EMERGENT-3 [16]). These trials
Xanomeline/trospium chloride treatment over 5 weeks utilized a similar design as EMERGENT-1, including trial
reduced positive and negative symptoms in adults with duration, eligibility criteria, study treatment regimen and
schizophrenia hospitalized for acute psychosis, as demon- the primary endpoint. Both phase 3 trials met their primary
strated in a randomized, double-blind, placebo-controlled endpoints [15, 16].
phase 2 trial (EMERGENT-1) [12]. Key eligibility criteria The mITT population in EMERGENT-2 included 117
included: age 18–60 years; a primary diagnosis of schizo- patients in the xanomeline/trospium chloride group and
phrenia per the Diagnostic and Statistical Manual of Men- 119 in the placebo group [15]. The LSM change from
tal Disorders, 5th edition; acute exacerbation or relapse of baseline in PANSS total score at week 5 in the respective
psychosis requiring hospitalization within 2 months prior group was – 21.2 versus – 11.6 (difference – 9.6; 95% CI
to screening; a Positive and Negative Syndrome Scale – 13.9 to – 5.2; p < 0.0001) [primary endpoint]. Significant
(PANSS) total score ≥ 80 (range 30–210; higher scores (p ≤ 0.0055) between-group differences were also observed
indicate more severe symptoms), with a score of ≥ 5 on for PANSS positive (– 6.8 vs – 3.9) and negative (– 3.4 vs
one positive symptom item or ≥ 4 on two positive symptom – 1.6) subscale scores, PANSS Marder negative factor score
items; a Clinical Global Impression–Severity (CGI-S) score (– 4.2 vs – 2.0), CGI-S scale score (– 1.2 vs – 0.7) and
of ≥ 4 (range 1–7; higher scores reflect greater severity); and PANSS response rate, defined as the percentage of patients
no antipsychotic use for ≥ 2 weeks at baseline. Patients with with ≥ 30% reduction from baseline in PANSS total score
a history of antipsychotic resistance or suicidal ideation were (55% vs 28%) [15].
among those excluded. Participants received xanomeline/ The mITT population in EMERGENT-3 included 114
trospium chloride (n = 90) or placebo (n = 92) BID for patients in the xanomeline/trospium chloride group and
5 weeks. Xanomeline/trospium chloride dosing was flexible, 120 in the placebo group [16]. The LSM change from
starting at 50 mg/20 mg and increasing to a maximum of baseline in PANSS total score at week 5 in the respective
125 mg/30 mg, with the option to reduce to 100 mg/20 mg group was – 20.6 versus – 12.2 (difference – 8.4; 95% CI
in case of AEs [12]. – 12.4 to – 4.3; p < 0.0001) [primary endpoint]. Significant
In the modified intent-to-treat population (mITT), the (p < 0.0001) between-group differences were observed for
least-squares mean (LSM) change from baseline in PANSS PANSS positive subscale score (– 7.1 vs – 3.6) and CGI-S
total score at week 5 was – 17.4 in the xanomeline/trospium scale score (– 1.1 vs – 0.6) and PANSS response rate (50.6%
chloride group and – 5.9 in the placebo group (difference vs 25.3%). However, there was no significant between-group
– 11.6; 95% CI – 16.1 to – 7.1; p < 0.001) [primary end- difference for PANSS negative subscale score (– 2.7 vs
point] [12]. Significant (p < 0.001) between-group differ- – 1.8) and PANSS Marder negative factor score (– 3.5 vs
ences were also observed for PANSS positive and negative – 2.7) [16].
subscale scores, and PANSS Marder negative symptom In a 5-week, randomized, double-blind, phase 3 pivotal
subscale scores. However, the proportion of patents with a bridging trial (UNITE-001), xanomeline/trospium chloride
CGI-S score of 1 or 2 (normal or borderline ill) at week 5 did was effective for treating Chinese patients with schizo-
not differ between the groups [12]. In additional analyses, phrenia hospitalized for acute psychosis [17]. Consistent
xanomeline/trospium chloride produced clinically meaning- with results from the global EMERGENT-2 and -3 trials,
ful responder rates on the PANSS total score, with responses UNITE-001 met its primary endpoint (PANSS total score)
observed as early as 2 weeks and improvements across all and all key secondary endpoints (PANSS positive subscale
five PANSS symptom domains: positive symptoms, nega- score, PANSS negative subscale score, PANSS negative
tive symptoms, disorganized thought, uncontrolled hostil- Marder factor score, CGI-S score and PANSS responder
ity and anxiety/depression [13]. Xanomeline/trospium may rate) at week 5. Mean changes from baseline at week 5 for
also improve cognition, particularly in patients with baseline xanomeline/trospium chloride versus placebo were as fol-
cognitive impairment [14]. lows: PANSS total score, – 16.9 versus – 7.7 (difference
– 9.2; p = 0.0014); PANSS positive subscale score, – 6.5
versus – 4.6 (difference –1.9; p = 0.0474); and PANSS neg-
2.3.2 Phase 3 Trials ative subscale score, – 3.2 versus – 0.7 (difference – 2.5;
p = 0.0062) [17].
Based on the positive results of EMERGENT-1 [12], the
use of xanomeline/trospium chloride for treating adults
Xanomeline/Trospium Chloride: First Approval 107

2.3.3 Long‑Term Studies Xanomeline/trospium chloride significantly (p < 0.0001 vs

placebo) improved agitation, as measured by the PANSS-
Patients who completed the EMERGENT-2 or EMER- Excited Component [26], and also significantly (p = 0.004
GENT-3 trials were eligible for an open-label extension vs placebo) improved cognition in a subgroup of patients
study (EMERGENT-4), where all received xanomeline/ with baseline cognitive impairment, as measured by the
trospium chloride, starting at 50 mg/20 mg BID and titrated CANTAB computerised battery [27].
up to a maximum of 125 mg/30 mg BID for 52 weeks [18].
Xanomeline/trospium chloride showed sustained efficacy 2.3.5 Network Meta‑Analysis
over 52 weeks, regardless of prior treatment with xanome-
line/trospium chloride or placebo. At week 52, the mean A network meta-analysis conducted by the Institute for
change from the parent trial baseline in PANSS total score Clinical and Economic Review found that xanomeline/
was – 33.8 for patients initially receiving xanomeline/ trospium chloride and three second-generation antipsy-
trospium chloride and – 31.3 for those receiving placebo. chotics (aripiprazole, risperidone and olanzapine) signifi-
Additionally, 68.6% of the 35 patients experienced a ≥ 30% cantly improved PANSS total scores and PANSS response
reduction in floor-adjusted PANSS total score by week 52. rates compared to placebo, with no significant differences
Similar improvements were observed in CGI-S, and PANSS between the drugs [28]. However, xanomeline/trospium
positive and negative subscale scores [18]. chloride led to significantly less body weight gain than
In a 52-week open-label study (EMERGENT-5), xanome- olanzapine [mean difference − 2.86 kg; 95% credible
line/trospium chloride was effective in de novo patients interval (Crl) − 3.97 to − 1.82] and risperidone (mean
with stable schizophrenia symptoms suitable for outpatient difference − 2.06 kg; 95% Crl − 3.29 to − 0.87), poten-
care [19]. The treatment, initiated at 50 mg/20 mg BID tially reducing the risk of metabolic syndrome over time.
and titrated to a maximum of 125 mg/30 mg BID, resulted Under this assumption, the health benefit price bench-
in the following mean changes from baseline at week 52: mark for xanomeline/trospium chloride is estimated at
PANSS total score, – 5.5; CGI-S score, – 0.4; PANSS posi- USD$16,000–20,000 per year. However, all-cause treat-
tive subscale score, – 1.9; and PANSS negative subscale ment discontinuation rates were significantly higher for
score, – 0.8. Moreover, 30.0% of 283 patients experienced xanomeline/trospium chloride compared to olanzapine
a ≥ 30% reduction in floor-adjusted PANSS total score by (relative risk 1.67; 95% Crl 1.21 to 2.29) and risperidone
week 52 [19]. In a preliminary analysis of an optional quali- (relative risk 1.58; 95% Crl 1.14 to 2.2). Overall, due to
tative sub-study (n ≤ 70), most participants reported high limited long-term data, the net health benefit of xanome-
satisfaction with xanomeline/trospium chloride compared line/trospium chloride is rated as promising but inconclu-
to their previous antipsychotic treatment, with satisfaction sive compared to olanzapine and risperidone [28].
maintained for up to 6 months [20]. Key factors contributing
to this satisfaction included improvements in schizophrenia 2.4 Adverse Events
symptoms and health-related quality of life, along with mini-
mal treatment burden [20, 21]. Xanomeline/trospium chloride was generally well tolerated
in the 5-week EMERGENT-1, EMERGENT-2 and EMER-
2.3.4 Pooled Analyses GENT-3 trials in patients with schizophrenia [12, 15, 16].
In a pooled analysis of EMERGENT-2 and -3 (n = 504),
In post hoc pooled analyses of the EMERGENT-1, EMER- adverse reactions to xanomeline/trospium chloride occurring
GENT-2 and EMERGENT-3 trials, xanomeline/trospium at ≥ 5% incidence and at least twice that of placebo were
chloride reduced PANSS total score significantly more nausea (19% vs 4% with placebo), dyspepsia (18% vs 5%),
than placebo at week 5 (– 19.4 vs – 9.6; p < 0.0001) [22], constipation (17% vs 7%), vomiting (15% vs 1%), hyperten-
with a 41.4% versus 20.9% PANSS response rate [23]. The sion (11% vs 2%), abdominal pain (8% vs 4%), diarrhoea
number needed to treat was 5 for achieving a ≥ 30% reduc- (6% vs 2%), tachycardia (5% vs 2%), dizziness (5% vs 2%)
tion in PANSS total score and 7 for a ≥ 2-point decrease and gastroesophageal reflux disease (5% vs < 1%) [7]. Other
in CGI-S score [24]. Of note, xanomeline/trospium chlo- clinically significant adverse reactions included increases
ride improved negative symptoms independently of other in heart rate, liver enzyme elevations and urinary retention.
symptom domains [25]. In patients with prominent negative Adverse reactions led to treatment discontinuation in 6% of
symptoms (n = 64), the LSM difference in PANSS Marder xanomeline/trospium chloride recipients (including nausea
negative factor scores between xanomeline/trospium chlo- in 2% and vomiting in 1%) and 4% of placebo recipients [7].
ride and placebo at week 5 was – 4.7 (95% CI – 7.03 to The safety and tolerability profiles of xanomeline/trospium
– 2.39; p < 0.001), compared to – 2.0 (95% CI – 2.77 to chloride remained consistent in the long-term, as shown in the
– 1.18; p < 0.001) in the overall population (n = 640) [25]. 52-week EMERGENT-4 [18] and EMERGENT-5 [19] trials,
108 Y. Y. Syed

Key clinical trials of xanomeline/trospium chloride (Bristol-Myers Squibb)

Drug(s) Indication Phase Status Location(s) Identifier

KarXT, PL Schizophrenia 2 Completed USA EMERGENT-1; NCT03697252

KarXT, PL Schizophrenia 3 Completed USA EMERGENT-2; NCT04659161
KarXT, PL Schizophrenia 3 Completed Ukraine, USA EMERGENT-3; NCT04738123
KarXT Schizophrenia 3 Completed Ukraine, USA EMERGENT-4; NCT04659174
KarXT Schizophrenia 3 Completed Puerto Rico, USA EMERGENT-5; NCT04820309
KarXT (adj), PL Schizophrenia 3 Recruiting Global ARISE; NCT05145413, EudraCT2022-001665-12
KarXT (adj), PL Schizophrenia 3 Recruiting Global NCT05304767, EudraCT2022-001666-35
KarXT Schizophrenia 3 Recruiting USA NCT06572449
KarXT, PL Schizophrenia 3 Recruiting China UNITE-001; NCT05919823
KarXT, PL Alzheimer's disease psychosis 3 Recruiting Global ADEPT-1; NCT05511363,
EudraCT2022-001515-10
KarXT, PL Alzheimer's disease psychosis 3 Recruiting Global ADEPT-2; NCT06126224
KarXT Alzheimer's disease psychosis 3 Recruiting Global ADEPT-3; NCT05980949
KarXT, PL Alzheimer's disease psychosis 3 Recruiting USA ADEPT-4; NCT06585787

adj adjunctive therapy, KarXT xanomeline/trospium chloride, PL placebo

along with interim pooled analyses [29, 30]. At least one treat- Supplementary Information The online version contains supplemen-
ment-related AE was reported in 60% of 674 xanomeline/ tary material available at [Link] oi.o​ rg/1​ 0.1​ 007/s​ 40265-0​ 24-0​ 2126-0.
trospium chloride recipients, with the most common (inci-
Declarations
dence ≥ 5%) being nausea, vomiting, constipation, dry mouth,
dyspepsia, dizziness, hypertension and diarrhoea [29]. The Funding The preparation of this review was not supported by any
majority of these AEs were mild or moderate in severity [29]. external funding.
Importantly, xanomeline/trospium chloride treatment was not
Authorship and Conflict of interest During the peer review process the
associated with long-term metabolic disturbances [30]. manufacturer of the agent under review was offered an opportunity to
In the EMERGENT trials, xanomeline/trospium chloride comment on the article. Changes resulting from any comments received
was not associated with clinically meaningful extrapyrami- were made by the authors on the basis of scientific completeness and
dal motor symptoms, akathisia, body weight gain, metabolic accuracy. Yahiya Y. Syed is a salaried employee of Adis International
Ltd/Springer Nature, and declares no relevant conflicts of interest. All
changes, prolactin elevation or somnolence [12, 15, 16, 29, authors contributed to this article and are responsible for its content.
31, 32].
Ethics approval, Consent to participate, Consent to publish, Availability
2.5 Ongoing Clinical Trials of data and material, Code availability Not applicable.

The UNITE-001 trial is ongoing. A separate phase

3 trial (ARISE), along with its open-label extension References
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