BMS-986519 (KarXT/Cobenfy): A Novel Muscarinic Agonist Combination for Neuropsychiatric Disorders

1. Introduction to BMS-986519 (KarXT/Cobenfy)

1.1. Identification and Nomenclature

BMS-986519 is an investigational agent identified in the Bristol Myers Squibb (BMS) pipeline, undergoing Phase 1 development for psychiatric disorders.[1] This development code is intrinsically linked to KarXT, a fixed-dose combination of xanomeline, a muscarinic acetylcholine receptor agonist, and trospium chloride, a peripherally acting muscarinic antagonist.[1] Upon its approval by the U.S. Food and Drug Administration (FDA), KarXT has been marketed under the brand name COBENFY™.[2] Other development codes associated with this therapeutic program include BMS-986510 and KarX-EC, the latter referring to an enteric-coated formulation of xanomeline.[1] Given that BMS-986519 is an early development identifier for the KarXT/Cobenfy program, this report will focus on the comprehensive pharmacological and clinical profile of the xanomeline and trospium chloride combination as the clinically realized entity.

The development of multiple internal codes such as BMS-986519, BMS-986510, and KarX-EC [1] for what is essentially the same core combination of xanomeline and trospium chloride suggests a multifaceted early development strategy by Bristol Myers Squibb. Pharmaceutical companies often assign distinct internal codes to different formulations, dosage strengths, or specific research initiatives related to a lead compound. The explicit mention of "Xanomeline Enteric-coated" for KarX-EC [1] clearly indicates exploration of formulation modifications, potentially aimed at optimizing pharmacokinetic profiles, enhancing tolerability by altering drug release characteristics, or tailoring the product for specific patient populations or indications before consolidating under the unified KarXT/Cobenfy branding for broader clinical development and commercialization.

1.2. Novelty and Significance

The introduction of KarXT/Cobenfy marks a significant advancement in neuropsychiatric pharmacotherapy, particularly for schizophrenia. It is the first antipsychotic agent approved by the FDA in several decades that operates via a novel mechanism of action, distinct from the dopamine D2 receptor blockade that has been the cornerstone of schizophrenia treatment for over 50 years.[2] By targeting M1 and M4 muscarinic acetylcholine receptors, KarXT/Cobenfy offers a new therapeutic paradigm with the potential to address a broader range of schizophrenic symptoms, including negative and cognitive symptoms, which are often inadequately managed by existing treatments, and to provide a more favorable side-effect profile.[2]

The rapid progression of KarXT/Cobenfy through clinical development to achieve FDA approval [2], despite its first-in-class mechanism, implies the presentation of a robust and compelling preclinical and clinical data package. This package must have convincingly demonstrated a favorable benefit-risk profile, particularly highlighting its efficacy and differentiated safety (e.g., reduced propensity for extrapyramidal symptoms and metabolic disturbances) in addressing the significant unmet medical needs of individuals with schizophrenia. Such a profile would be necessary to navigate the heightened regulatory scrutiny often applied to novel therapeutic classes.

1.3. Developer and Commercialization

KarXT/Cobenfy was originally developed by Karuna Therapeutics.[3] In a landmark deal announced in December 2023 and finalized in March 2024, Bristol Myers Squibb acquired Karuna Therapeutics for $14 billion, with KarXT/Cobenfy being the principal asset driving the acquisition.[6] This acquisition underscores the immense therapeutic and commercial potential attributed to this novel antipsychotic. PureTech Health is credited with the initial invention of KarXT, which was subsequently advanced by its founded entity, Karuna Therapeutics.[12]

The substantial $14 billion investment by Bristol Myers Squibb in acquiring Karuna Therapeutics for its lead asset, KarXT/Cobenfy [6], is a strong indicator of BMS's strategic commitment to re-entering and significantly impacting the neuroscience therapeutic area. Such a valuation suggests that BMS projects KarXT/Cobenfy to achieve blockbuster status, driven by its novel mechanism of action, differentiated clinical profile, and its potential to address long-standing unmet needs in the treatment of schizophrenia and possibly other neuropsychiatric disorders. This level of investment is typically reserved for assets perceived to have the capacity to transform treatment paradigms and capture substantial market share, rather than being merely incremental improvements over existing therapies.

For the Greater China region (mainland China, Hong Kong, Macau, and Taiwan), Zai Lab Limited holds an exclusive license from Karuna Therapeutics (now a BMS company) for the development, manufacturing, and commercialization of KarXT.[8]

2. Mechanism of Action

The therapeutic effect of BMS-986519, manifested as KarXT/Cobenfy, is derived from the distinct yet complementary pharmacological actions of its two components: xanomeline and trospium chloride.

2.1. Xanomeline Pharmacology

Xanomeline is a muscarinic acetylcholine receptor agonist that exhibits functional preference for the M1 and M4 subtypes.[2] While in vitro binding studies indicate that xanomeline possesses similar high affinity for all five human muscarinic receptor subtypes (M1-M5), with reported Ki values generally in the nanomolar range (e.g., M1: 7.9–82 nM; M2: 8.1–724 nM; M3: 7.8–40 nM; M4: 11–72 nM; M5: 9.3–80 nM) [51], its functional assays demonstrate greater agonistic activity at M1 and M4 receptors. Some evidence also suggests potential antagonist or partial agonist activity at the M5 receptor.[51]

The central nervous system (CNS) effects of xanomeline are key to its therapeutic action:

• M1 Receptor Agonism: Activation of M1 receptors, which are highly expressed in brain regions critical for cognition such as the hippocampus and prefrontal cortex, is believed to enhance cholinergic transmission, facilitate learning, and improve cognitive function.[9] This pathway is also thought to modestly regulate psychosis symptom domains.[9]
• M4 Receptor Agonism: Activation of M4 receptors, also found in brain regions important for dopamine modulation (e.g., striatum), is thought to inhibit dopamine release in key circuits like the nucleus accumbens and ventral striatum. This action is primarily linked to the reduction of positive symptoms of schizophrenia and may also contribute to cognitive improvements.[9] Preclinical studies demonstrated that xanomeline selectively inhibits the firing of A10 (mesolimbic) dopamine neurons, which are implicated in psychosis, without significantly affecting A9 (nigrostriatal) dopamine neurons, which are involved in motor control.[20] This selectivity provides a neurobiological basis for its antipsychotic effects with a potentially lower risk of extrapyramidal symptoms (EPS).

Beyond direct muscarinic agonism, xanomeline indirectly modulates dopaminergic and glutamatergic neurotransmitter systems [7], which are known to be dysregulated in schizophrenia. Xanomeline also interacts with serotonin receptors, exhibiting partial agonism at 5-HT1A, agonism at 5-HT1B, and antagonism at 5-HT2A, 5-HT2B, and 5-HT2C receptors, albeit generally with lower affinity than for muscarinic receptors.[51] These serotonergic actions could subtly contribute to its overall clinical profile, potentially influencing mood, anxiety, or side effects. For instance, 5-HT2A antagonism is a feature of many atypical antipsychotics and is thought to contribute to efficacy against negative symptoms and reduce EPS liability. While its primary mechanism is M1/M4 agonism, these additional serotonergic interactions may offer a broader modulatory effect on complex neuropsychiatric symptoms.

The "M1/M4 preferring" agonism of xanomeline [2] is a critical pharmacological feature. Although binding affinities (Ki values) for M1-M5 subtypes are relatively close [51], the crucial aspect is its functional selectivity, meaning it elicits a more pronounced agonistic response through M1 and M4 receptors compared to M2, M3, and M5 receptors within the CNS. This functional preference is vital; non-selective, potent agonism across all central muscarinic subtypes could lead to a complex and potentially intolerable array of CNS effects that would not be mitigated by peripheral blockade alone. The preferential activation of M1 and M4 allows for a more targeted modulation of the specific neural circuits believed to be dysfunctional in schizophrenia, thereby optimizing therapeutic benefit while minimizing undesirable central effects from overstimulation of other muscarinic subtypes.

2.2. Trospium Chloride Pharmacology

Trospium chloride is a non-selective muscarinic receptor antagonist.[2] Its key characteristic in the KarXT/Cobenfy formulation is its peripheral restriction. As a quaternary ammonium compound, trospium chloride is highly polarized and does not readily cross the blood-brain barrier (BBB).[2] Consequently, its anticholinergic effects are largely confined to peripheral tissues.

The primary role of trospium in the combination is to mitigate the peripheral cholinergic side effects induced by xanomeline, such as nausea, vomiting, diarrhea, excessive salivation, and other gastrointestinal disturbances.[2] These side effects were dose-limiting when xanomeline was investigated as a monotherapy. Trospium achieves this by competitively blocking muscarinic receptors (notably M3 receptors in smooth muscle and glands) in the periphery, thereby preventing xanomeline from activating these sites.[35]

2.3. KarXT/Cobenfy - Combined Mechanism of Action

The therapeutic strategy of KarXT/Cobenfy hinges on the synergistic interplay between its two components. Xanomeline provides the desired central M1/M4 muscarinic agonism for antipsychotic and potential pro-cognitive effects, while trospium chloride acts as a peripheral shield, selectively antagonizing muscarinic receptors outside the CNS to improve tolerability.[2] This co-formulation is a critical pharmaceutical innovation, as it "unlocked" the therapeutic potential of xanomeline by making it tolerable at effective CNS doses. This "peripheral blockade for central gain" approach could serve as a model for other CNS-active compounds that are limited by peripheral adverse events.

This mechanism is fundamentally different from that of all previously approved antipsychotics, which primarily target dopamine D2 receptors.[2] By avoiding direct D2 receptor antagonism, KarXT/Cobenfy is hypothesized to offer a distinct efficacy profile, potentially with greater effects on negative and cognitive symptoms of schizophrenia, and a more favorable side-effect profile, particularly concerning EPS, hyperprolactinemia, weight gain, and sedation.[5] The absence of direct D2 receptor antagonism also implies a significantly reduced risk of long-term neurological complications such as tardive dyskinesia, a major concern with traditional antipsychotics.[33] This is because TD is believed to result from chronic D2 receptor blockade leading to receptor hypersensitivity, a mechanism not engaged by KarXT/Cobenfy.

3. Preclinical Development

The preclinical development of xanomeline, and subsequently the KarXT combination, provided the foundational evidence for its progression into human trials.

3.1. Xanomeline In Vitro Receptor Binding and Functional Profile

Xanomeline's interaction with various neurotransmitter receptors has been characterized extensively. The following table summarizes its binding affinities (Ki values, primarily for human receptors) for key targets:

Table 1: Xanomeline In Vitro Receptor Binding Profile

Receptor Subtype	Binding Affinity (Ki, nM) - Human (Range or Specific Value)	Source(s)
Muscarinic M1	7.9 – 82 (or 10)	20
Muscarinic M2	8.1 – 724 (or 12)	20
Muscarinic M3	7.8 – 40 (or 17)	20
Muscarinic M4	11 – 72 (or 7)	20
Muscarinic M5	9.3 – 80 (or 22)	20
Serotonin 5-HT1A	63	20
Serotonin 5-HT1B	50	20
Serotonin 5-HT1D	6.3	20
Serotonin 5-HT2A	126	20
Serotonin 5-HT2B	20	20
Serotonin 5-HT2C	40	20
Dopamine D2	1000	20
Dopamine D3	398	20
Adrenergic α1 (Rat)	2020	20
Adrenergic α2 (Rat)	1000	20
Histamine H1 (Rat)	398	20
nACh (neuronal)	>10,000	20
nACh (muscle)	>10,000	20

This table quantitatively outlines xanomeline's binding affinities, underscoring its primary engagement with muscarinic receptors while also detailing its interactions with other CNS targets like serotonin receptors. This profile is crucial for understanding its specific M1/M4 functional preference in the context of broader receptor interactions and for predicting potential secondary pharmacological effects or side effects, thereby guiding safety assessments and differentiating it from other psychotropic agents.

Functionally, xanomeline acts as a partial agonist with preference for M1 and M4 receptors, exhibiting more modest partial agonism at M2, M3, and M5 subtypes.[51] This functional selectivity is critical, as it is believed to target the specific muscarinic pathways involved in psychosis and cognition while potentially minimizing broader, less desirable CNS muscarinic effects.

3.2. Xanomeline In Vivo Preclinical Efficacy

Animal models provided strong evidence for xanomeline's antipsychotic-like and cognitive-enhancing potential:

• Antipsychotic-like Activity: Xanomeline demonstrated efficacy in several established animal models predictive of antipsychotic action. It selectively inhibited the firing of A10 (mesolimbic) dopamine neurons over A9 (nigrostriatal) neurons in rats, a profile consistent with antipsychotic effects without inducing extrapyramidal motor side effects.[20] This A10 versus A9 selectivity provides a compelling neurobiological rationale for its antipsychotic action with a reduced risk of motor adverse events. Furthermore, xanomeline blocked dopamine agonist-induced behaviors (turning in 6-OHDA lesioned rats, apomorphine-induced climbing in mice) and, critically, inhibited conditioned avoidance responding (CAR) in rats.[20] The CAR model is a robust predictor of clinical antipsychotic efficacy, and the observation that xanomeline's effect in this model was reversible by the muscarinic antagonist scopolamine strongly implicated central muscarinic agonism as the primary driver of its antipsychotic-like effects, distinct from D2 receptor blockade.
• Motor Safety Profile: A key preclinical finding was xanomeline's lack of catalepsy induction in rats, even at doses showing antipsychotic-like activity.[20] Catalepsy is a widely accepted preclinical marker for EPS liability in humans. This observation, combined with the A10/A9 selectivity, provided early and strong support for a differentiated motor safety profile compared to traditional D2-blocking antipsychotics.
• Cognitive Effects: The M1 and M4 agonistic properties of xanomeline suggested potential for cognitive enhancement, supported by preclinical models where muscarinic activation is linked to improved learning and memory.[23] Early human data from Alzheimer's disease trials with xanomeline monotherapy also pointed towards pro-cognitive effects.[9]

3.3. Rationale and Preclinical Support for the Xanomeline-Trospium Combination (KarXT)

The clinical development of xanomeline as a monotherapy was initially hampered by dose-limiting peripheral cholinergic side effects, primarily gastrointestinal (nausea, vomiting) and cardiovascular, despite promising CNS activity observed in early trials for Alzheimer's disease and schizophrenia.[7] This translational barrier led to the innovative strategy of combining xanomeline with trospium chloride.

The decision to add trospium was a pharmacologically astute approach to a common drug development challenge: a centrally active compound with problematic peripheral effects. Trospium is a well-characterized, peripherally restricted muscarinic antagonist, already approved for overactive bladder, which does not readily cross the BBB.[7] The hypothesis was that trospium would counteract xanomeline's effects on peripheral muscarinic receptors, thereby improving tolerability and allowing xanomeline to achieve therapeutic concentrations in the CNS. This "protect-the-periphery" strategy was supported by early studies in healthy volunteers, where the combination reportedly reduced cholinergic side effects by approximately 50% compared to xanomeline alone [9], validating the approach before large-scale efficacy trials. The use of an existing drug like trospium, with a known safety profile, likely streamlined the early development of the KarXT combination.

4. Pharmacokinetics and Pharmacodynamics (PK/PD)

The pharmacokinetic (PK) and pharmacodynamic (PD) properties of both xanomeline and trospium chloride, when administered as the combination product Cobenfy/KarXT, have been characterized in human studies.

Table 2: Key Pharmacokinetic Parameters of Xanomeline and Trospium Chloride (from Cobenfy/KarXT Administration)

Parameter	Xanomeline	Trospium Chloride	Source(s)
Bioavailability	~1%	~15%	58
Tmax (Time to Peak Conc.)	~2 hours	~1 hour	58
Effect of Food on Absorption	Minimal (low or high-fat meals)	Significantly reduced bioavailability (low or high-fat meals)	7
Volume of Distribution (Vd)	~10,800 L	~531 L	58
Plasma Protein Binding	~95%	~80%	50
Key Metabolic Pathways	Extensive gut/liver CYP (2D6, 2B6, 1A2, 2C9, 2C19) & FMO (FMO1, FMO3)	Ester hydrolysis, glucuronidation (non-CYP mediated)	58
Active Metabolites	No (inactive circulating metabolites)	Not specified as active	58
Primary Excretion Route	Urine (~78%), Feces (~12%) (as metabolites)	Feces (~85%), Urine (~6%, of which ~60% is unchanged trospium)	58
Half-life (t1/2)	~5 hours	~6 hours (immediate release)	57
CNS Penetration	Yes	No (limited due to polarity)	9
Approved Titration Dosing (BID)	Starting: 50mg xanomeline / 20mg trospium; Max: 125mg xanomeline / 30mg trospium	As above	4

This table provides a comparative summary of the essential PK parameters for xanomeline and trospium chloride when administered as Cobenfy/KarXT. It highlights critical differences, such as their respective bioavailabilities, food effects, and metabolic pathways, which are fundamental to understanding the dosing regimen, potential for interactions, and overall clinical pharmacology of the combination therapy.

4.1. Xanomeline Pharmacokinetics

Xanomeline, when administered as part of Cobenfy/KarXT, exhibits low oral bioavailability, estimated at approximately 1%, with time to maximum plasma concentration (Tmax) occurring around 2 hours post-dose.[58] Its absorption appears minimally affected by food intake.[58] Xanomeline has a large apparent volume of distribution (Vd ≈ 10,800 L) and is highly bound to plasma proteins (≈95%).[50] It undergoes extensive first-pass and systemic metabolism, primarily in the gut and liver, involving multiple cytochrome P450 (CYP) isoenzymes (CYP2D6, CYP2B6, CYP1A2, CYP2C9, CYP2C19) and flavin-containing monooxygenases (FMO1, FMO3), resulting in several pharmacologically inactive circulating metabolites.[58] Less than 1% of the administered dose is excreted as unchanged xanomeline, with metabolites primarily eliminated in urine (≈78%) and feces (≈12%).[58] The terminal elimination half-life of xanomeline is approximately 5 hours.[58]

4.2. Trospium Chloride Pharmacokinetics

Trospium chloride, the peripherally acting antagonist in Cobenfy/KarXT, has an oral bioavailability of about 15%, with Tmax occurring approximately 1 hour after administration.[58] Unlike xanomeline, the absorption of trospium is significantly reduced by food (both low-fat and high-fat meals).[7] This differential food effect is a notable aspect of the combination's PK; consistent administration relative to meals is important for predictable trospium exposure and, consequently, reliable mitigation of xanomeline's peripheral cholinergic effects. Trospium has a Vd of approximately 531 L and is about 80% bound to plasma proteins.[58] It is a substrate for the P-glycoprotein (P-gp) transporter [58], which may influence its disposition. Metabolism of trospium occurs mainly via ester hydrolysis to form benzylic acid and azoniaspironortropanol, followed by glucuronic acid conjugation; CYP enzymes are not expected to play a significant role in its biotransformation.[58] Excretion is predominantly via feces (≈85%), with a smaller portion in urine (≈6%), of which about 60% is unchanged trospium.[58] Its elimination half-life from the immediate-release formulation used in KarXT is approximately 6 hours.[57]

4.3. KarXT/Cobenfy Dosing

In pivotal clinical trials, KarXT/Cobenfy was administered orally twice daily (BID). The dosing regimen typically involved a titration schedule, starting at 50 mg xanomeline / 20 mg trospium BID for the initial days, then increasing to 100 mg xanomeline / 20 mg trospium BID. Based on tolerability and clinical response, the dose could be further increased to a maximum of 125 mg xanomeline / 30 mg trospium BID.[4] The FDA-approved labeling for Cobenfy reflects this flexible, titrated BID dosing strategy.[4]

4.4. Pharmacodynamics (Human)

The primary pharmacodynamic effect of KarXT/Cobenfy relevant to its antipsychotic efficacy is attributed to xanomeline's agonist activity at central M1 and M4 muscarinic acetylcholine receptors.[2] This central action is complemented by trospium chloride's peripheral muscarinic receptor antagonism, which serves to reduce treatment-emergent cholinergic side effects.[15] Clinical efficacy, demonstrated by significant reductions in the Positive and Negative Syndrome Scale (PANSS) total scores in schizophrenia trials, provides evidence of the net pharmacodynamic benefit of this combination.[4] Functional magnetic resonance imaging (fMRI) studies have suggested that xanomeline enhances neuronal network connectivity within the prefrontal cortex, potentially correlating with its cognitive and antipsychotic effects.[35]

4.5. Drug-Drug Interactions

Xanomeline does not appear to cause significant systemic inhibition or induction of major CYP enzymes. However, it has the potential to inhibit CYP3A4 and P-gp at the gut level, which could affect the oral bioavailability of co-administered drugs that are sensitive substrates of these pathways and undergo substantial intestinal first-pass metabolism.[50] Trospium chloride does not inhibit or induce major CYP enzymes.[58] Co-administration of KarXT/Cobenfy with other anticholinergic medications may lead to additive peripheral anticholinergic effects (e.g., constipation, dry mouth, urinary retention) and potentially unpredictable central effects, thus warranting caution.[7]

4.6. Specific Populations

• Renal Impairment: Cobenfy/KarXT is not recommended for use in patients with moderate (estimated glomerular filtration rate 30 to <60 mL/min/1.73 m2) or severe (eGFR <30 mL/min/1.73 m2) renal impairment.[3] This is primarily due to the renal excretion pathway of trospium.
• Hepatic Impairment: Cobenfy/KarXT is contraindicated in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment and is not recommended in mild (Child-Pugh Class A) hepatic impairment, owing to increased systemic exposure of xanomeline in such patients.[2]
• Age: After accounting for differences in renal function, age (17 to 75 years) did not show a clinically significant effect on the pharmacokinetics of xanomeline or trospium. However, trospium exposure may be higher in individuals aged 65 years and older.[58]
• Race: No clinically significant differences in the pharmacokinetics of xanomeline and trospium were observed between non-Black and Black participants.[58]
• CYP2D6 Metabolizer Status: The systemic exposure of xanomeline can be influenced by CYP2D6 genetic polymorphisms. Individuals who are CYP2D6 poor metabolizers may experience increased xanomeline exposure, while ultrarapid metabolizers may have decreased exposure.[58] This inherent variability underscores the importance of the flexible dosing regimen to allow for individual tolerability.

The extensive metabolism of xanomeline by multiple CYP enzymes, particularly the polymorphic CYP2D6 [58], introduces a potential source of inter-individual variability in drug exposure and clinical response. While reliance on multiple pathways can offer metabolic redundancy, pronounced differences in CYP2D6 activity (poor versus ultrarapid metabolizers) could lead to significantly different xanomeline concentrations. This could manifest as either increased risk of adverse effects in poor metabolizers or potentially suboptimal efficacy in ultrarapid metabolizers at standard doses, reinforcing the clinical utility of the flexible, titrated dosing schedule employed in trials.

5. Clinical Development Program: KarXT/Cobenfy

The clinical development of KarXT/Cobenfy has been extensive, primarily focusing on establishing its efficacy and safety in schizophrenia, with subsequent explorations into Alzheimer's disease psychosis (ADP), Bipolar I disorder, and adolescent psychiatric disorders.

Table 3: Summary of Key Clinical Trials for KarXT/Cobenfy

Trial Identifier / Name	Phase	Target Indication(s)	Patient Population Summary	N (Approx.)	Basic Design	Primary Endpoint(s)	Key Efficacy Outcome Summary	Key Safety Outcome Summary	Status (as of latest snippet)	Source(s)
EMERGENT-1 (NCT03697252)	2	Schizophrenia (acute psychosis)	Adults 18-60 yrs, PANSS ≥80, CGI-S ≥4	182	5-wk, R, DB, PC, inpatient, flexible dose	Change in PANSS total score at Wk 5	Sig. reduction vs placebo (LSMD -11.6)	Generally well-tolerated, transient GI AEs	Completed	15
EMERGENT-2 (NCT04659161)	3	Schizophrenia (acute psychosis)	Adults 18-65 yrs, PANSS ≥80, CGI-S ≥4	252	5-wk, R, DB, PC, flexible dose, inpatient	Change in PANSS total score at Wk 5	Sig. reduction vs placebo (LSMD -9.6)	Consistent with prior trials; common AEs: constipation, dyspepsia, nausea	Completed	4
EMERGENT-3 (NCT04738123)	3	Schizophrenia (acute psychosis)	Adults 18-65 yrs, PANSS ≥80, CGI-S ≥4	256	5-wk, R, DB, PC, flexible dose, inpatient	Change in PANSS total score at Wk 5	Sig. reduction vs placebo (LSMD -8.4)	Consistent with prior trials; common AEs: nausea, dyspepsia, vomiting	Completed	4
Zai Lab Bridging Trial (China)	3	Schizophrenia (acute psychosis)	Adults, acutely psychotic, hospitalized	202	5-wk R, DB, PC + 12-wk OLE	Change in PANSS total score at Wk 5	Sig. reduction vs placebo (LSMD -9.2)	Tolerable, common AEs: vomiting, tachycardia, nausea	Completed	8
ARISE (NCT05599242 / KAR-012 / CN012-0008 / NCT05145413)	3	Schizophrenia (adjunctive, inadequate response to atypical APD)	Adults 18-65 yrs, on stable atypical APD, PANSS ≥70	~386	6-wk, R, DB, PC, outpatient	Change in PANSS total score at Wk 6	Not met (LSMD -2.0, p=0.11)	Tolerability consistent with monotherapy	Completed	3
EMERGENT-4 (NCT04659174 / NCT04659176)	3	Schizophrenia (long-term)	Rollover from acute trials	156 (initial)	52/53-wk, OL extension	Long-term safety & tolerability	Sustained/improved PANSS, favorable metabolic profile (weight loss)	Generally well-tolerated, transient GI AEs	Completed	31
EMERGENT-5 (NCT04738136 / NCT04820309)	3	Schizophrenia (long-term)	De novo or rollover from acute trials	566 (pooled with EMERGENT-4 for some analyses)	52/56-wk, OL study	Long-term safety & tolerability	Sustained/improved PANSS, favorable metabolic profile	Generally well-tolerated, transient GI AEs	Completed	31
ADEPT-1 (NCT05511363)	3	Alzheimer's Disease Psychosis (ADP)	Adults 55-90 yrs, mild-severe AD, mod-severe psychosis	~380	Up to 44-wk, R, DB, PC, relapse prevention	Safety, efficacy (relapse prevention)	N/A (ongoing)	N/A (ongoing)	Recruiting	41
ADEPT-2 (NCT05532805 / CN012-0027)	3	Alzheimer's Disease Psychosis (ADP)	Adults 55-90 yrs, mild-severe AD, mod-severe psychosis	Not specified	R, DB, PC, parallel group	Efficacy on NPI-C H+D score	N/A (ongoing)	N/A (ongoing)	Active, Not Recruiting (Mar 2025)	43
ADEPT-4 (NCT06585787 / CN012-0056)	3	Alzheimer's Disease Psychosis (ADP)	Adults 55-90 yrs, mild-severe AD, mod-severe psychosis	406	R, DB, PC	Relapse prevention	N/A (ongoing)	N/A (ongoing)	Active, Recruiting (Apr 2025)	45
BALSAM-3 (NCT06929273 / CN012-0038)	3	Bipolar I Disorder (manic/mixed episodes)	Adults 18-65 yrs, rollover or de novo	62	OL extension	Long-term safety	N/A (planned)	N/A (planned)	Not Yet Recruiting (May 2025)	47
Adolescent PK/PD (NCT06853171 / CN012-0022)	1	Psychiatric Disorders (Schizophrenia, Bipolar, ADHD, Tourette's)	Adolescents	Not specified	OL, safety, tolerability, PK	Safety, PK	N/A (ongoing)	N/A (ongoing)	Recruiting	1

Abbreviations: R: Randomized, DB: Double-Blind, PC: Placebo-Controlled, OL: Open-Label, APD: Antipsychotic Drug, PANSS: Positive and Negative Syndrome Scale, CGI-S: Clinical Global Impression-Severity, NPI-C H+D: Neuropsychiatric Inventory-Clinician Hallucinations and Delusions, LSMD: Least Squares Mean Difference, AE: Adverse Event, GI: Gastrointestinal, PK: Pharmacokinetics. Status reflects latest available information from snippets.

This table provides a consolidated, high-level overview of the extensive clinical trial program for KarXT/Cobenfy. It allows for rapid identification of key studies across different indications (schizophrenia, Alzheimer's psychosis, bipolar disorder) and trial phases, summarizing their design, primary goals, and general outcomes. This structured format is essential for understanding the breadth and depth of evidence supporting the drug's development and regulatory approvals.

5.1. Schizophrenia Program

The cornerstone of KarXT/Cobenfy's development has been its evaluation in adults with schizophrenia.

Monotherapy - Pivotal EMERGENT Trials: The EMERGENT program, comprising Phase 2 (EMERGENT-1, NCT03697252) and Phase 3 (EMERGENT-2, NCT04659161; EMERGENT-3, NCT04738123) trials, consistently demonstrated the efficacy and tolerability of KarXT as monotherapy for acute psychosis in hospitalized adults with schizophrenia.4 These 5-week, randomized, double-blind, placebo-controlled, flexible-dose inpatient studies enrolled adults (typically 18-65 years) with PANSS total scores ≥80 and CGI-S scores ≥4.

• In EMERGENT-1 (N=182), KarXT showed a statistically significant reduction in PANSS total score at Week 5 compared to placebo (Least Squares Mean Difference -11.6 points, p<0.001).[15]
• EMERGENT-2 (N=252) confirmed these findings, with KarXT achieving an LSMD of -9.6 points in PANSS total score versus placebo at Week 5 (p<0.0001, Cohen's d effect size=0.61).[4]
• EMERGENT-3 (N=256) further replicated these results, demonstrating an LSMD of -8.4 points in PANSS total score versus placebo at Week 5 (p<0.001, Cohen's d effect size=0.60).[4] Across these trials, KarXT also met key secondary endpoints, including improvements in PANSS positive and negative subscales and CGI-S scores. The consistency of these positive results across three well-controlled trials, particularly for a novel mechanism of action, was a significant factor in its regulatory approval and underscored the robustness of the M1/M4 agonism approach for treating schizophrenia.

Adjunctive Therapy - ARISE Trial (NCT05599242 and other identifiers): The Phase 3 ARISE trial evaluated KarXT as an adjunctive treatment to existing atypical antipsychotics in outpatients with schizophrenia who had an inadequate response to their current therapy.3 This 6-week, randomized, double-blind, placebo-controlled study did not meet its primary endpoint. Adjunctive KarXT demonstrated a numerical improvement with a 2.0-point reduction in PANSS total score compared to placebo plus antipsychotic at Week 6, but this difference was not statistically significant (LSMD -2.0, p=0.11).3 Key secondary endpoints were also not met.

Interestingly, a post-hoc subgroup analysis suggested a differential response based on the background antipsychotic: patients on non-risperidone antipsychotics (paliperidone, aripiprazole, ziprasidone, lurasidone, cariprazine) showed a statistically significant benefit with adjunctive KarXT (LSMD -3.4, nominal p=0.03), whereas those on risperidone did not.3 The failure of the ARISE trial to meet its primary endpoint indicates that the benefits of KarXT's M1/M4 agonism may be less pronounced or more complex when added to existing D2-modulating antipsychotics. The differing responses based on background therapy are hypothesis-generating and may point to specific pharmacodynamic interactions or patient population characteristics that warrant further, prospective investigation. This outcome has tempered some initial expectations for broad adjunctive use without more targeted studies.

Long-Term Open-Label Extension (OLE) Studies (EMERGENT-4, EMERGENT-5): Participants from the acute EMERGENT trials, as well as de novo patients, had the option to enroll in 52-week OLE studies (EMERGENT-4: NCT04659174/NCT04659176; EMERGENT-5: NCT04738136/NCT04820309) where all received KarXT.[31] These studies demonstrated that long-term treatment with KarXT was generally well-tolerated, with a safety profile consistent with the acute trials. Importantly, efficacy, as measured by PANSS scores, was maintained or continued to improve over the 52-week period. A particularly notable finding from these OLEs was KarXT's favorable long-term metabolic profile: most patients experienced stability or improvements in key metabolic parameters, and a majority (65%) experienced an overall reduction in weight over one year, with an average reduction of 2.6 kg in completers, and a larger mean reduction of 4.1 kg in clinically obese patients (BMI > 30 kg/m2).[31] Total cholesterol, triglyceride, and HbA1c levels did not meaningfully change. This long-term metabolic benefit is a crucial differentiating factor from many traditional antipsychotics, which are often associated with significant weight gain and metabolic syndrome, thereby addressing a major concern in the chronic management of schizophrenia.

Zai Lab Phase 3 Bridging Trial in China: To support registration in Greater China, Zai Lab conducted a Phase 3 multicenter, randomized, placebo-controlled bridging trial in 202 acutely psychotic hospitalized adult patients with schizophrenia in China.[8] This 5-week trial met its primary endpoint, with KarXT demonstrating a statistically significant 9.2-point reduction in PANSS total score compared to placebo (p=0.0014). All key secondary efficacy endpoints were also met. The safety profile was consistent with global studies, with common TEAEs including vomiting, tachycardia, nausea, hypertension, dizziness, and diarrhea. These positive results paved the way for Zai Lab's NDA submission to the NMPA.

5.2. Alzheimer's Disease Psychosis (ADP) Program

Recognizing the role of cholinergic dysfunction in Alzheimer's disease and the antipsychotic effects of xanomeline, an extensive clinical program (ADEPT trials) is underway to evaluate KarXT for the treatment of psychosis in patients with AD.[10] Data from these registrational trials are anticipated in 2026.[38] Key trials include:

• ADEPT-1 (NCT05511363): A Phase 3 relapse prevention study in ~380 adults (55-90 years) with mild-to-severe AD and moderate-to-severe psychosis, ongoing and recruiting.[41]
• ADEPT-2 (NCT05532805): A Phase 3 study evaluating efficacy on NPI-C Hallucinations and Delusions (H+D) score in adults (55-90 years) with AD psychosis; status reported as active, not recruiting as of March 2025.[43]
• ADEPT-4 (NCT06585787): A Phase 3 relapse prevention study in 406 adults (55-90 years) with AD psychosis; currently recruiting.[45]

5.3. Other Investigated Indications

The therapeutic potential of KarXT is also being explored in other neuropsychiatric conditions:

• Bipolar I Disorder (Manic/Mixed Episodes): The BALSAM-3 trial (NCT06929273) is a Phase 3 open-label extension study designed to assess the long-term safety of KarXT in adults (18-65 years) with manic or mixed episodes associated with Bipolar I disorder. This trial is planned for participants rolling over from preceding double-blind studies or for de novo enrollment and was not yet recruiting as of May 2025.[38]
• Psychiatric Disorders in Adolescents (NCT06853171): A Phase 1 study is evaluating the safety, tolerability, and pharmacokinetics of KarXT and a dual-burst release formulation of xanomeline with immediate-release trospium (KarX-EC) in adolescents with various psychiatric disorders, including schizophrenia, bipolar disorder, ADHD, and Tourette's disorder.[1] This study is currently recruiting.

The expansion of KarXT/Cobenfy's clinical program into ADP, Bipolar I disorder, and adolescent psychiatric conditions reflects a "pipeline-in-a-product" strategy by BMS. This approach aims to leverage the novel M1/M4 muscarinic agonist mechanism across multiple neuropsychiatric conditions where cholinergic system dysfunction and symptoms like psychosis or cognitive impairment are implicated. Success in these additional indications, which also represent areas of high unmet medical need, would significantly broaden the drug's market and clinical utility, thereby maximizing the return on the substantial investment made in acquiring Karuna Therapeutics.

6. Regulatory Status and Market Context

6.1. FDA Approval and Regulatory Submissions

Cobenfy (xanomeline and trospium chloride) received approval from the U.S. Food and Drug Administration (FDA) on September 26, 2024, for the treatment of schizophrenia in adults.[2] This approval was based on the positive outcomes of the EMERGENT clinical trial program. The FDA considers Cobenfy to be a first-in-class medication, representing the first new pharmacological approach for schizophrenia in several decades.[2] Significantly, Cobenfy's label does not include atypical antipsychotic class warnings or a boxed warning, which is often present for other antipsychotics.[8] This distinction by the FDA is noteworthy, suggesting a perceived safety profile that differs favorably in certain critical aspects (e.g., risk of EPS, metabolic disturbances) from existing D2-blocking agents, likely due to its novel mechanism of action.

In Greater China, Zai Lab Limited announced in January 2025 that China's National Medical Products Administration (NMPA) had accepted its New Drug Application (NDA) for KarXT for the treatment of schizophrenia in adults, following positive results from a Phase 3 bridging trial in China.[8]

6.2. Special Regulatory Designations

The provided research materials do not contain explicit statements confirming that KarXT/Cobenfy received FDA Fast Track designation or Orphan Drug Designation for schizophrenia or Alzheimer's disease psychosis. While related programs or other drugs from associated companies might have received such designations for different indications (e.g., LYT-200 for AML [17], SPG302 for FXS [11]), this information is not directly applicable to KarXT/Cobenfy based on the supplied snippets.

6.3. Market Context and Commercial Outlook

KarXT/Cobenfy was developed by Karuna Therapeutics, which was subsequently acquired by Bristol Myers Squibb (BMS) in a deal valued at $14 billion, primarily driven by the potential of KarXT.[6] BMS anticipates KarXT to be a significant revenue contributor.[38] Initial market uptake following the US launch was reported as strong, with good formulary access.[6]

However, analyst expectations and sales forecasts have seen some adjustments. The failure of the Phase 3 ARISE trial to meet its primary endpoint for adjunctive therapy in schizophrenia led some analysts to lower their long-term sales projections for Cobenfy, with peak estimates for schizophrenia ranging from approximately $3 billion to $3.7 billion.[6] This highlights the market's sensitivity to clinical trial outcomes, especially for label expansions that could significantly broaden a drug's patient base. While monotherapy approval is a substantial achievement, the adjunctive market represents a considerable additional opportunity, and the uncertainty following the ARISE trial results impacts the overall valuation and perceived market penetration.

Zai Lab's exclusive rights to develop, manufacture, and commercialize KarXT in Greater China [8] represent a key component of the global commercialization strategy. The positive results from Zai Lab's Phase 3 bridging study in a Chinese population [37] are crucial for NMPA approval and suggest that the drug's efficacy and safety profile is consistent across different ethnic groups, an important factor for successful global market access and adoption.

7. Comprehensive Safety and Tolerability Profile

The safety and tolerability of KarXT/Cobenfy have been extensively evaluated throughout its clinical development program. A key differentiator from traditional antipsychotics is its distinct side-effect profile, attributed to its novel mechanism of action that avoids direct dopamine D2 receptor blockade.

Table 4: Common Treatment-Emergent Adverse Events (TEAEs) for KarXT/Cobenfy vs. Placebo in Pivotal Schizophrenia Monotherapy Trials (Representative Data from EMERGENT-2 [22] and FDA Approval Summary [4])

Adverse Event	KarXT/Cobenfy (%) (N ≈ 126 per trial)	Placebo (%) (N ≈ 126 per trial)
Nausea	19	1-6
Dyspepsia (Indigestion)	18-19	5-8
Constipation	17-21	7-10
Vomiting	14-15	1
Hypertension	10-11	1-2
Headache	14	12-15
Dizziness	5-9	2-3
Abdominal Pain	8	4
Diarrhea	6	2-3
Tachycardia (Increased Heart Rate)	5	2
Dry Mouth	Not consistently high in pivotal, but noted	Not consistently high in pivotal
Somnolence/Sedation	5 (similar to placebo)	4 (similar to placebo)
Extrapyramidal Symptoms (EPS)	≤1 (similar to placebo)	≤1 (similar to placebo)
Akathisia	≤1 (similar to placebo)	≤1 (similar to placebo)
Weight Gain (Clinically Significant)	Low / Similar to placebo	Low / Similar to placebo

Note: Percentages are approximate, based on data from individual trials (EMERGENT-2) or pooled FDA summaries. Specific rates can vary slightly between trials. This table highlights the most frequently reported TEAEs and those of particular clinical interest when comparing to traditional antipsychotics.

This table summarizes the common adverse events observed with KarXT/Cobenfy in its pivotal schizophrenia trials, compared to placebo. It is valuable for clinicians and researchers to quickly understand the typical side effect profile, particularly noting the prevalence of gastrointestinal and cardiovascular AEs, and the relative absence of common D2-blocker-associated AEs like significant EPS or weight gain, which is a key differentiating feature.

7.1. Common Adverse Events

The most frequently reported TEAEs with KarXT/Cobenfy are primarily cholinergic in nature and include nausea, dyspepsia, constipation, and vomiting.[2] Cardiovascular effects such as hypertension and tachycardia have also been observed.[4] Other reported AEs include dizziness, headache, abdominal pain, diarrhea, and gastroesophageal reflux disease.[4] Most of these AEs were rated as mild to moderate in severity and were often transient, occurring early in treatment or during dose titration.[15]

7.2. Comparison with Traditional Antipsychotics

A significant aspect of KarXT/Cobenfy's safety profile is the low incidence of adverse events commonly associated with traditional D2-receptor blocking antipsychotics. Clinical trial data consistently show that KarXT/Cobenfy is not associated with clinically meaningful extrapyramidal symptoms (EPS), akathisia, or drug-induced parkinsonism at rates different from placebo.[5] Furthermore, unlike many atypical antipsychotics, KarXT/Cobenfy has demonstrated a favorable impact on weight and long-term metabolic parameters. Long-term OLE studies showed that most patients experienced stability or even reductions in weight, and there were no meaningful adverse changes in cholesterol, triglycerides, or HbA1c levels over 52 weeks of treatment.[21] Rates of somnolence/sedation were also similar to placebo.[15] This differentiated safety profile, particularly the avoidance of burdensome motor and metabolic side effects, is a primary driver of its clinical value and potential to improve long-term treatment adherence and quality of life for individuals with schizophrenia.

7.3. Contraindications, Warnings, and Precautions

The FDA-approved labeling for Cobenfy includes specific contraindications and warnings [2]:

• Contraindications: History of hypersensitivity to xanomeline or trospium chloride, urinary retention, gastric retention, untreated narrow-angle glaucoma, and moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.[2]
• Warnings and Precautions:
• Urinary Retention: Monitor for symptoms; not recommended in patients with moderate or severe renal impairment.[2]
• Increased Heart Rate (Tachycardia) and Blood Pressure (Hypertension): Assess heart rate and blood pressure at baseline and periodically during treatment.[4]
• Decreased Gastric Movement/Gastric Retention: Use with caution in patients with conditions that may be exacerbated by decreased gastric motility.[2]
• Angioedema: Has been reported with Cobenfy and trospium chloride.[2]
• Risk of Use in Patients with Biliary Disease: Transient increases in liver enzymes consistent with transient biliary obstruction due to biliary contraction and possible gallstone passage have occurred. Assess liver enzymes and bilirubin prior to initiating and as clinically indicated.[2]
• Cognitive and Motor Impairment: May cause anticholinergic adverse reactions that could impair mental or physical abilities.

The need for dose titration, typically starting at 50mg xanomeline/20mg trospium BID and gradually increasing [4], is likely designed to improve tolerability, particularly for the initial cholinergic and anticholinergic effects. While KarXT/Cobenfy offers a novel and generally well-tolerated profile, these specific warnings and contraindications emphasize that careful patient selection, appropriate baseline assessments (e.g., renal function, hepatic function, cardiovascular status), and ongoing monitoring are essential for its safe and effective use.

8. Conclusion and Future Perspectives

BMS-986519, clinically developed and marketed as KarXT/Cobenfy (xanomeline and trospium chloride), represents a landmark achievement in neuropsychiatric drug development. Its approval as the first antipsychotic with a novel mechanism of action targeting M1/M4 muscarinic receptors in several decades signifies a paradigm shift in the pharmacological approach to schizophrenia.[2] The extensive EMERGENT clinical trial program consistently demonstrated KarXT/Cobenfy's efficacy in reducing both positive and negative symptoms of schizophrenia in adults experiencing acute psychosis, with a safety and tolerability profile notably distinct from traditional D2 dopamine receptor antagonists.[4] Specifically, the low incidence of extrapyramidal symptoms, weight gain, and adverse metabolic changes observed in both acute and long-term studies addresses some of the most burdensome side effects that limit adherence and long-term outcomes with existing antipsychotics.[7]

The innovative combination of the centrally acting M1/M4 agonist xanomeline with the peripherally restricted muscarinic antagonist trospium chloride was key to unlocking xanomeline's therapeutic potential by mitigating its dose-limiting peripheral cholinergic side effects.[7] This rational drug design approach has yielded a therapy that offers a new hope for many individuals living with schizophrenia.

While the ARISE trial did not meet its primary endpoint for adjunctive therapy in schizophrenia [3], the monotherapy data remains robust. The ongoing development of KarXT/Cobenfy for Alzheimer's disease psychosis (ADEPT program) and Bipolar I disorder (BALSAM program), along with early investigations in adolescent psychiatric disorders, underscores Bristol Myers Squibb's "pipeline-in-a-product" strategy.[10] Success in these additional indications would further solidify the importance of this M1/M4-targeted therapeutic approach across a range of neuropsychiatric conditions characterized by cholinergic dysregulation, psychosis, and cognitive impairment.

Future perspectives include the potential development of a long-acting injectable (LAI) formulation of xanomeline/trospium, such as TerXT by Terran Biosciences.[9] Given that adherence to oral antipsychotics is a significant challenge in schizophrenia management, a successful LAI based on this novel mechanism could greatly enhance its clinical utility and market impact by ensuring consistent medication delivery and improving long-term patient outcomes. Further research will also be needed to fully elucidate the nuances of its interaction with other psychotropic medications, optimize its use in specific patient subpopulations (e.g., based on CYP2D6 metabolizer status), and confirm its long-term benefits on functional outcomes and quality of life.

In conclusion, BMS-986519 (KarXT/Cobenfy) has emerged as a transformative therapy in schizophrenia, offering a novel and effective treatment with a differentiated safety profile. Its continued development and exploration in other neuropsychiatric disorders hold considerable promise for addressing significant unmet medical needs.

Works cited

1. Online Trial Tracker - Larvol Sigma, accessed May 16, 2025, https://sigma.larvol.com/ott.php?e1=582029&phase=1&sourcepg=TZ
2. U.S. Food and Drug Administration Approves Bristol Myers Squibb's COBENFY™ (xanomeline and trospium chloride), a First-In-Class Muscarinic Agonist for the Treatment of Schizophrenia in Adults, accessed May 16, 2025, https://news.bms.com/news/details/2024/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibbs-COBENFY-xanomeline-and-trospium-chloride-a-First-In-Class-Muscarinic-Agonist-for-the-Treatment-of-Schizophrenia-in-Adults/default.aspx
3. Bristol Myers Squibb Announces Topline Results from Phase 3 ARISE Trial Evaluating Cobenfy (xanomeline and trospium chloride) as an Adjunctive Treatment to Atypical Antipsychotics in Adults with Schizophrenia, accessed May 16, 2025, https://news.bms.com/news/details/2025/Bristol-Myers-Squibb-Announces-Topline-Results-from-Phase-3-ARISE-Trial-Evaluating-Cobenfy-xanomeline-and-trospium-chloride-as-an-Adjunctive-Treatment-to-Atypical-Antipsychotics-in-Adults-with-Schizophrenia/default.aspx
4. Drug Trials Snapshot: COBENFY | FDA, accessed May 16, 2025, https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-cobenfy
5. BMS wins approval for schizophrenia drug acquired from Karuna, accessed May 16, 2025, https://www.pharmaceutical-technology.com/news/bms-wins-approval-for-schizophrenia-drug-acquired-from-karuna/
6. 'Strike 2?' BMS Stumbles Again as Cobenfy Disappoints in Schizophrenia - BioSpace, accessed May 16, 2025, https://www.biospace.com/drug-development/strike-2-bms-stumbles-again-as-cobenfy-disappoints-in-schizophrenia
7. Understanding the Tolerability Profile of Xanomeline-Trospium ..., accessed May 16, 2025, https://www.psychiatrist.com/jcp/xanomeline-trospium-combination-tolerability-commentary/
8. Zai Lab Announces Acceptance of New Drug Application for KarXT for the Treatment of Schizophrenia - Investor Overview, accessed May 16, 2025, https://zailab.gcs-web.com/news-releases/news-release-details/zai-lab-announces-acceptance-new-drug-application-karxt/
9. Xanomeline/trospium chloride - Wikipedia, accessed May 16, 2025, https://en.wikipedia.org/wiki/Xanomeline/trospium_chloride
10. Zai Lab Announces Acceptance of New Drug Application for KarXT for the Treatment of Schizophrenia, accessed May 16, 2025, https://ir.zailaboratory.com/news-releases/news-release-details/zai-lab-announces-acceptance-new-drug-application-karxt/
11. Spinogenix Announces Open Enrollment for Phase 2 US Trial Following FDA Clearance of IND Application for SPG302, the First Synaptic Regenerative Therapy for Schizophrenia, accessed May 16, 2025, https://www.spinogenix.com/spinogenix-announces-open-enrollment-for-phase-2-us-trial-following-fda-clearance-of-ind-application-for-spg302-the-first-synaptic-regenerative-therapy-for-schizophrenia/
12. FDA approves first drug in 50 years for treatment of schizophrenia in adults - Pharmafocus, accessed May 16, 2025, https://www.pharmafocus.com/articles/fda-approves-first-drug-in-50-years-for-treatment-of-schizophren
13. September 30, 2024 - [nGram] Today's Neurology Scoop: KarXT & COBENFY FDA Approvals, BlueRock's Parkinson's Data, accessed May 16, 2025, https://www.ngram.com/newsalerts/neurology/2024-09-30
14. The FDA approves a new type of schizophrenia drug - NPR, accessed May 16, 2025, https://www.npr.org/2024/09/26/nx-s1-5123694/for-the-first-time-in-decades-the-fda-has-approved-a-new-type-of-schizophrenia-drug
15. SAFETY AND EFFICACY OF KARXT IN PATIENTS WITH SCHIZOPHRENIA IN THE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED EMERGENT TRIALS - PubMed Central, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11814830/
16. Zai Lab Announces Acceptance of New Drug Application for KarXT for the Treatment of Schizophrenia - Business Wire, accessed May 16, 2025, https://www.businesswire.com/news/home/20250117029564/en/Zai-Lab-Announces-Acceptance-of-New-Drug-Application-for-KarXT-for-the-Treatment-of-Schizophrenia
17. PureTech Announces Annual Results for Year Ended December 31, 2024, accessed May 16, 2025, https://firstwordpharma.com/story/5955431
18. PureTech Announces Annual Results for Year Ended December 31, 2024 - BioSpace, accessed May 16, 2025, https://www.biospace.com/press-releases/puretech-announces-annual-results-for-year-ended-december-31-2024
19. What information is available regarding the new antipsychotic ..., accessed May 16, 2025, https://dig.pharmacy.uic.edu/faqs/2025-2/january-2025-faqs/what-information-is-available-regarding-the-new-antipsychotic-xanomeline-trospium/
20. Xanomeline, an M1/M4 preferring muscarinic cholinergic receptor ..., accessed May 16, 2025, https://www.researchgate.net/publication/12530939_Xanomeline_an_M1M4_preferring_muscarinic_cholinergic_receptor_agonist_produces_antipsychotic-like_activity_in_rats_and_mice
21. From theory to therapy: unlocking the potential of muscarinic receptor activation in schizophrenia with the dual M1/M4 muscarinic receptor agonist xanomeline and trospium chloride and insights from clinical trials, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11997306/
22. 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 - PubMed, accessed May 16, 2025, https://pubmed.ncbi.nlm.nih.gov/38104575/
23. Xanomeline-trospium (Cobenfy[TM]) for Schizophrenia: A Review of the Literature - Clinical Psychopharmacology and Neuroscience, accessed May 16, 2025, https://www.cpn.or.kr/view.html?uid=1726&vmd=Full
24. Xanomeline-Trospium as a Novel Agent for Treatment of Psychosis in Schizophrenia, accessed May 16, 2025, https://www.psychiatrictimes.com/view/xanomeline-trospium-as-a-novel-agent-for-treatment-of-psychosis-in-schizophrenia
25. From theory to therapy: unlocking the potential of muscarinic receptor activation in schizophrenia with the dual M1/M4 muscarinic receptor agonist xanomeline and trospium chloride and insights from clinical trials - Oxford Academic, accessed May 16, 2025, https://academic.oup.com/ijnp/advance-article/doi/10.1093/ijnp/pyaf015/8063932
26. Does KarXT (xanomeline-trospium) represent a novel approach to ..., accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11959844/
27. Antipsychotic Efficacy of KarXT (Xanomeline−Trospium): - IU Indianapolis ScholarWorks, accessed May 16, 2025, https://scholarworks.indianapolis.iu.edu/server/api/core/bitstreams/b22d08d4-9eb0-4882-af2d-2be8e0f303df/content
28. Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial - PubMed Central, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11063924/
29. KarXT for schizophrenia–effectiveness and value: A summary from the Institute for Clinical and Economic Review's New England Comparative Effectiveness Public Advisory Council, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11144989/
30. Efficacy of KarXT (Xanomeline Trospium) in Schizophrenia: Pooled Results From the Randomized, Double-Blind, Placebo-Controlled EMERGENT Trials | CNS Spectrums | Cambridge Core, accessed May 16, 2025, https://www.cambridge.org/core/journals/cns-spectrums/article/efficacy-of-karxt-xanomeline-trospium-in-schizophrenia-pooled-results-from-the-randomized-doubleblind-placebocontrolled-emergent-trials/0F6F99833D286ABBD379A5DFDAD839DB
31. New Data Demonstrates KarXT's Positive Long-Term Metabolic Profile - Psychiatric Times, accessed May 16, 2025, https://www.psychiatrictimes.com/view/new-data-demonstrates-karxt-positive-long-term-metabolic-profile
32. Efficacy of xanomeline and trospium chloride in schizophrenia: pooled results from three 5-week, randomized, double-blind, placebo-controlled, EMERGENT trials, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11531488/
33. Xanomeline-Trospium in schizophrenia: A detailed review and comparison with the Institute for Clinical and Economic Review's analysis, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11144999/
34. Posters Share Positive Data on Long-Term Treatment with Xanomeline/Trospium, accessed May 16, 2025, https://www.psychiatrictimes.com/view/posters-share-positive-data-on-long-term-treatment-with-xanomeline-trospium
35. What is the mechanism of action of Xanomeline Tartrate/Trospium ..., accessed May 16, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-action-of-xanomeline-tartratetrospium-chloride
36. Bristol Myers' prized schizophrenia drug stumbles in testing | BioPharma Dive, accessed May 16, 2025, https://www.biopharmadive.com/news/cobenfy-bristol-myers-trial-failure-schizophrenia-adjuvant-wall-street/746073/
37. Zai Lab Reports Positive Topline Data from Phase 3 Bridging Trial Evaluating KarXT for the Treatment of Schizophrenia in China, accessed May 16, 2025, https://ir.zailaboratory.com/news-releases/news-release-details/zai-lab-reports-positive-topline-data-phase-3-bridging-trial/
38. Bristol Myers Squibb Strengthens Neuroscience Portfolio with ..., accessed May 16, 2025, https://news.bms.com/news/details/2023/Bristol-Myers-Squibb-Strengthens-Neuroscience-Portfolio-with-Acquisition-of-Karuna-Therapeutics/default.aspx
39. Karuna's KarXT shows promise for schizophrenia treatment - Clinical Trials Arena, accessed May 16, 2025, https://www.clinicaltrialsarena.com/analyst-comment/karxt-schizophrenia-treatment/
40. An Extension Study to Assess Long-term Safety, Tolerability, and Efficacy of KarXT in Adult Patients With Schizophrenia (EMERGENT-4) | Clinical Research Trial Listing - CenterWatch, accessed May 16, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT04659174/an-extension-study-to-assess-long-term-safety-tolerability-and-efficacy-of-karxt-in-adult-patients-with-schizophrenia-emergent-4?phase3=true&activelyRecruiting=false&page=5&id=148&slug=tourettes-syndrome
41. ADEPT-1 - NHS Health Research Authority, accessed May 16, 2025, https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/adept-1-2/
42. ADEPT-1 - Alzheimer Europe, accessed May 16, 2025, https://www.alzheimer-europe.org/research/clinical-trials/adept-1?language_content_entity=en
43. A Study to Assess Efficacy and Safety of KarXT for the Treatment of Psychosis Associated With Alzheimer's Disease (ADEPT-2) - Be Part of Research - Trial Details, accessed May 16, 2025, https://bepartofresearch.nihr.ac.uk/trial-details/trial-detail?trialId=51373&location=the%20UK&distance=
44. A Study to Assess Efficacy and Safety of KarXT for the Treatment of Psychosis Associated With Alzheimer's Disease (ADEPT-2) - BMS Clinical Trials, accessed May 16, 2025, https://www.bmsstudyconnect.com/no/en/clinical-trials/NCT06126224.html
45. A Study to Evaluate KarXT as a Treatment for Psychosis Associated With Alzheimer's Disease (ADEPT-4) | Clinical Research Trial Listing - CenterWatch, accessed May 16, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT06585787/a-study-to-evaluate-karxt-as-a-treatment-for-psychosis-associated-with-alzheimers-disease-adept-4
46. Zai Lab presents positive outcomes from KarXT Phase III trial for schizophrenia, accessed May 16, 2025, https://www.clinicaltrialsarena.com/news/zai-lab-positive-outcomes-karxt-phase-iii-trial/
47. A Study to Assess the Long-term Safety of KarXT for the Treatment of Manic Episodes in Bipolar-I Disorder (BALSAM-3) - BMS Clinical Trials, accessed May 16, 2025, https://www.bmsstudyconnect.com/se/en/clinical-trials/NCT06929273.html
48. A Phase 3, Open-label Extension Study to Assess the Long-term Safety of KarXT for the Treatment of Mania or Mania With Mixed Features in Bipolar-I Disorder (BALSAM-3) - AdisInsight, accessed May 16, 2025, https://adisinsight.springer.com/trials/700382104
49. Xanomeline tartrate | DrugBank Online, accessed May 16, 2025, https://go.drugbank.com/salts/DBSALT003557
50. Xanomeline | C14H23N3OS | CID 60809 - PubChem, accessed May 16, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Xanomeline
51. Xanomeline - Wikipedia, accessed May 16, 2025, https://en.wikipedia.org/wiki/Xanomeline
52. Accepted Manuscript - Oxford Academic, accessed May 16, 2025, https://academic.oup.com/ijnp/advance-article-pdf/doi/10.1093/ijnp/pyaf015/62343407/pyaf015.pdf
53. APPLICATION NUMBER: - 216158Orig1s000 OTHER REVIEW(S) - accessdata.fda.gov, accessed May 16, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/216158Orig1s000OtherR.pdf
54. Institute for Clinical and Economic Review Publishes Final Evidence Report on Treatment for Schizophrenia - ICER, accessed May 16, 2025, https://icer.org/news-insights/press-releases/institute-for-clinical-and-economic-review-publishes-final-evidence-report-on-treatment-for-schizophrenia/
55. The New Horizon of Antipsychotics beyond the Classic Dopaminergic Hypothesis—The Case of the Xanomeline–Trospium Combination: A Systematic Review - PubMed Central, accessed May 16, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11124398/
56. Trospium chloride | DrugBank Online, accessed May 16, 2025, https://go.drugbank.com/salts/DBSALT000883
57. Trospium: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed May 16, 2025, https://go.drugbank.com/drugs/DB00209
58. www.accessdata.fda.gov, accessed May 16, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/216158Orig1s000IntegratedR.pdf
59. CLINICAL STUDY PROTOCOL - ClinicalTrials.gov, accessed May 16, 2025, https://cdn.clinicaltrials.gov/large-docs/52/NCT03697252/Prot_000.pdf
60. Xanomeline and Trospium Chloride Versus Placebo for the Treatment of Schizophrenia: A Post Hoc Analysis of Number Needed, accessed May 16, 2025, https://www.tandfonline.com/doi/pdf/10.2147/NDT.S503494
61. Cobenfy as Add-On Treatment for Schizophrenia Fails to Meet Primary Endpoint in Phase 3 ARISE Trial - Psychiatric Times, accessed May 16, 2025, https://www.psychiatrictimes.com/view/cobenfy-as-add-on-treatment-for-schizophrenia-fails-to-meet-primary-endpoint-in-phase-3-arise-trial
62. Cobenfy Falls Short in Phase 3 ARISE Trial as Adjunctive Schizophrenia Therapy - HCPLive, accessed May 16, 2025, https://www.hcplive.com/view/cobenfy-falls-short-phase-3-arise-trial-adjunctive-schizophrenia-therapy
63. Bristol Myers Squibb Presents New Pooled Interim Long-Term Safety and Metabolic Outcomes Data from the EMERGENT Program Evaluating KarXT in Schizophrenia at the 2024 Annual Congress of the Schizophrenia International Research Society, accessed May 16, 2025, https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Presents-New-Pooled-Interim-Long-Term-Safety-and-Metabolic-Outcomes-Data-from-the-EMERGENT-Program-Evaluating-KarXT-in-Schizophrenia-at-the-2024-Annual-Congress-of-the-Schizophrenia-International-Research-Society/default.aspx
64. An Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of KarXT in Adult Patients With Schizophrenia (EMERGENT-5) | Clinical Research Trial Listing - CenterWatch, accessed May 16, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT04820309/an-open-label-study-to-assess-the-long-term-safety-tolerability-and-efficacy-of-karxt-in-adult-patients-with-schizophrenia-emergent-5?phase3=true&activelyRecruiting=false&page=5&id=148&slug=tourettes-syndrome
65. A Study to Evaluate KarXT as a Treatment for Psychosis Associated With Alzheimer's Disease (ADEPT-4) - BMS Clinical Trials, accessed May 16, 2025, https://www.bmsstudyconnect.com/pl/en/clinical-trials/NCT06585787.html
66. Trial Details - A Study to Assess Efficacy and Safety of KarXT for the Treatment of Psychosis Associated With Alzheimer's Disease (ADEPT-1), accessed May 16, 2025, https://bepartofresearch.nihr.ac.uk/trial-details/trial-detail?trialId=51361&location=the%20UK&distance=
67. Trospium Not Yet Recruiting Phase 3 Trials for Bipolar affective disorder, manic Treatment, accessed May 16, 2025, https://go.drugbank.com/drugs/DB00209/clinical_trials?conditions=DBCOND0025030&phase=3&purpose=treatment&status=not_yet_recruiting
68. Safety, Tolerability, and Pharmacokinetics of KarXT and Dual-burst Release of Xanomeline With Immediate-release Trospium Chloride in Adolescents With Psychiatric Disorders | BMS Study Connect, accessed May 16, 2025, https://www.bmsstudyconnect.com/no/en/clinical-trials/NCT06853171.html
69. A Study to Assess Efficacy and Safety of Adjunctive KarXT in Subjects With Inadequately Controlled Symptoms of Schizophrenia - BMS Clinical Trials, accessed May 16, 2025, https://www.bmsstudyconnect.com/mx/en/clinical-trials/NCT05145413.html
70. A Study to Assess Efficacy and Safety of Adjunctive KarXT in Subjects With Inadequately Controlled Symptoms of Schizophrenia (ARISE) - ClinicalTrials.Veeva, accessed May 16, 2025, https://ctv.veeva.com/study/a-study-to-assess-efficacy-and-safety-of-adjunctive-karxt-in-subjects-with-inadequately-controlled-s
71. A Study to Assess Efficacy and Safety of Adjunctive KarXT in Subjects With Inadequately Controlled Symptoms of Schizophrenia | Clinical Research Trial Listing - CenterWatch, accessed May 16, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT05145413/a-study-to-assess-efficacy-and-safety-of-adjunctive-karxt-in-subjects-with-inadequately-controlled-symptoms-of-schizophrenia
72. ADEPT-2 - Alzheimer Europe, accessed May 16, 2025, https://www.alzheimer-europe.org/research/clinical-trials/adept-2?language_content_entity=en&language=nn
73. Alzheimer's Disease Psychosis - Nova Clinical Research, accessed May 16, 2025, http://novaclinicalresearch.com/alzheimers-psychosis/
74. FDA Grants Fast Track Designation to Posdinemab for Early Alzheimer Disease, accessed May 16, 2025, https://www.psychiatrictimes.com/view/fda-grants-fast-track-designation-to-posdinemab-for-early-alzheimer-disease
75. Pharma Archives - GlobalData, accessed May 16, 2025, https://www.globaldata.com/media/pharma/
76. Aripiprazole - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 16, 2025, https://synapse.patsnap.com/drug/46db0d868a9d4dd59a1aeff95e9d5954