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

Abstract

Since the 1950s, understanding of antipsychotic activity in schizophrenia has been largely grounded in the dopamine (DA) hypothesis. Most antipsychotics approved for schizophrenia interact with D₂ DA receptors as an important part of their mechanism of action. While antipsychotics blocking D₂ DA receptors can be effective for positive symptoms of schizophrenia, none are approved by regulatory authorities for predominant negative or cognitive symptoms. Moreover, many of these agents induce a range of problematic side effects related to D₂ DA receptor blockade (eg, drug-induced parkinsonism, akathisia, tardive dyskinesia, hyperprolactinemia and related sexual side effects, sedation). This has prompted the search for novel mechanisms with improved efficacy and tolerability based on evidence supporting involvement of other neurotransmitter systems in schizophrenia pathophysiology, including acetylcholine, gamma-aminobutyric acid, and glutamate. Among these options, targeting muscarinic receptors emerged as a promising treatment strategy. In September 2024, the U.S. Food and Drug Administration approved xanomeline and trospium chloride for treatment of adults with schizophrenia based on results from three 5-week, randomized, double-blind, placebo-controlled trials and two 52-week open-label trials. In the placebo-controlled trials, xanomeline/trospium reduced symptoms of schizophrenia, was generally well tolerated, and was not associated with clinically meaningful motor symptoms, hyperprolactinemia, sexual side effects, or weight gain compared with placebo. The long-term safety of xanomeline/trospium was also confirmed in two 52-week, open-label trials. This paper reviews the preclinical and clinical rationale for muscarinic receptor activation as a treatment for schizophrenia and the efficacy, safety, and tolerability profile of xanomeline/trospium.

INTRODUCTION

Schizophrenia is a serious and heterogeneous mental health disorder affecting approximately 24 million people worldwide and associated with substantial disability, morbidity, and mortality.^1,2 The positive (eg, delusions, hallucinations, disorganized speech and behavior), negative (eg, diminished expression, alogia, anhedonia, avolition), and cognitive (eg, impaired attention, working memory, processing speed, executive function) symptoms of schizophrenia contribute to functional and psychosocial impairment. People living with schizophrenia experience substantially more disability than those with anxiety disorders, major depressive disorder, bipolar disorder, alcohol use disorder, or autism spectrum disorder,³ making it one of the top 15 causes of disability worldwide.⁴ Life expectancy of people living with schizophrenia is also reduced by almost 30 years compared with the general population.⁵ Among the contributors to the excess mortality of schizophrenia are unnatural causes (eg, suicide, accidents) and medical comorbidities (eg, cardiovascular disease and diabetes mellitus).^5-9

Since the 1950s, understanding of schizophrenia pathogenesis and antipsychotic activity has been largely grounded in various iterations of the dopamine (DA) hypothesis. The core aspects of the DA hypothesis posit that DA dysregulation in various brain regions, including the limbic and associative striatum and prefrontal cortex (PFC), contributes in part to the symptoms of schizophrenia.^10,11 The hypothesis that excessive presynaptic DA release into relevant areas of the striatum underlies the positive symptoms of schizophrenia explains the efficacy basis of most antipsychotics approved prior to 2024: positive symptoms were lessened by postsynaptic D₂ DA receptor antagonism or partial antagonism.¹² Unlike most antipsychotics, the efficacy of clozapine is likely to involve other receptors beyond D₂ DA receptors. Although clozapine has lower binding affinity for D₂ DA receptors, it can be effective for patients with inadequate response to D₂ DA receptor binding antipsychotics (ie, those with treatment-resistant schizophrenia) and this appears to be due to non-dopaminergic activities that contribute to its clinical profile.¹³

Current antipsychotics are helpful for many people living with schizophrenia but have numerous limitations. Up to 80% of people have residual positive symptoms despite adequate doses and duration of antipsychotic treatment¹⁴; moreover, no antipsychotics are approved for the treatment of predominant negative or cognitive symptoms, and D₂ DA receptor or anticholinergic activities can worsen negative and cognitive symptoms (eg, attention, memory, executive function, processing speed).^15,16 Antipsychotic side effects directly related to D₂ DA receptor antagonism include motor symptoms (drug-induced parkinsonism [DIP], akathisia, tardive dyskinesia [TD]) and hyperprolactinemia and related sexual AEs, all of which contribute to poor adherence and relapse risk.^17,18 Atypical antipsychotics are also associated with metabolic AEs including dyslipidemia, glucose intolerance, and weight gain.¹⁹ Early use of reserpine and tetrabenazine in the 1950s and 1960s, both of which deplete catecholamines from presynaptic vesicles by vesicular monoamine transporter type 2 (VMAT2) inhibition²⁰ generated long-standing interest in modulating presynaptic DA release in schizophrenia rather than managing its sequelae by blocking postsynaptic D₂ DA receptors. Unfortunately, VMAT2-induced presynaptic DA depletion was nonselective, impacting striatal regions associated with positive symptoms and motor areas alike and resulting in substantial rates of DIP and akathisia at doses that controlled psychotic symptoms.^21,22

The search for presynaptic mechanisms was not entirely abandoned, especially when advances in neuroimaging techniques supported that positive symptoms were indeed a presynaptic problem in most individuals with schizophrenia, and arose from excess release of DA in the human associative striatum (and adjacent portions of the sensorimotor striatum). These findings parallel the presynaptic DA dysfunction found in the mesolimbic pathway in animal models (Figure 1).²³ While DA dysfunction remains central to the pathophysiology of schizophrenia, evidence supporting involvement of additional neurotransmitter systems, including acetylcholine (ACh),^25-28 gamma-aminobutyric acid (GABA),^29,30 serotonin,³¹ and glutamate,^31-34 provided the stimulus to explore a range of strategies that might address schizophrenia symptoms without D₂ DA receptor binding.²³ Presynaptic DA depletion was largely abandoned in the early 1960s due to the significant complaints of motor adverse effects and depression seen with reserpine and tetrabenazine³⁵; however, another approach to modulating presynaptic DA release that was also selective for striatal pathways related to positive symptoms was discovered in the form of muscarinic receptor agonism. The potential for this approach is highlighted by the recent approval of xanomeline and trospium chloride by the U.S. Food and Drug Administration (FDA) in September 2024. Here, we review the rationale for targeting muscarinic receptors in schizophrenia and key evidence from xanomeline/trospium clinical trials that supports the validity and feasibility of this approach (see Paul²⁶ and Dean³⁶ for review of other approaches for targeting muscarinic receptors).

RATIONALE FOR TARGETING MUSCARINIC RECEPTORS IN SCHIZOPHRENIA

The unexpected realization in the late 1990s that muscarinic receptor activation was another method for regulating presynaptic DA release revived a hypothesized connection that remained unexplored and incompletely understood for decades.^26,27 In 1957, data were published indicating that the nonselective pan muscarinic receptor agonist arecoline possessed antipsychotic activity in preclinical models of psychosis and in clinical studies.³⁷ Unfortunately, these early arecoline studies in schizophrenia were largely forgotten or ignored in the wake of chlorpromazine’s discovery and the subsequent hyperfocus on the DA hypothesis of psychosis.²⁸ In the 1980s, muscarinic receptor agonists, including xanomeline, a potent synthetic muscarinic receptor agonist derived from arecoline, were developed as potential procognitive drugs in neurocognitive disorders such as dementia.^25,27 At the time of its synthesis, xanomeline was initially characterized as an M₁ muscarinic receptor agonist.³⁸ Subsequent work demonstrated that xanomeline binds to and has functional activity at all 5 muscarinic receptor subtypes but with the highest degree of intrinsic activity at M₁ and M₄ muscarinic receptors.^39,40

The revived interest in muscarinic receptor agonists as a potential antipsychotic strategy stems from a serendipitous finding seen in a clinical trial of xanomeline for people with Alzheimer’s disease (AD). In a 6-month, double-blind, placebo-controlled phase 2 clinical trial enrolling 343 participants, xanomeline improved cognition (measured by the cognitive subscale of the Alzheimer’s Disease Assessment Scale) and was also associated with dose-dependent and rapid improvements in psychotic symptoms (measured by the Alzheimer’s Disease Symptomatology Scale) in people with these symptoms at trial baseline, and also mitigated new onset positive symptoms.⁴¹ In 2008, xanomeline was subsequently evaluated in a 4-week, double-blind, placebo-controlled schizophrenia trial (N = 20). Despite the small sample size and limited statistical power, xanomeline was associated with significant improvements in psychotic symptoms (measured by the Positive and Negative Syndrome Scale [PANSS] and the Brief Psychiatric Rating Scale) and also demonstrated procognitive effects in several subtests of the neuropsychological test battery.⁴² However, in both the dementia and schizophrenia trials, xanomeline was associated with substantial peripheral procholinergic side effects (eg, nausea, vomiting) that stymied further clinical development.^41-43

Prior to the 2008 schizophrenia trial, xanomeline’s pharmacology was explored extensively in preclinical models to further understand the basis of its antipsychotic activity.^44-47 In vitro studies noted that xanomeline did not bind to D₂ DA receptors, so antipsychotic activity was necessarily unrelated to any direct DA receptor interaction. In vivo work noted that xanomeline inhibited amphetamine-induced activity in a mouse model of psychosis; however, xanomeline’s activity was substantially attenuated in M₄ muscarinic receptor knockout mice and was attenuated in M₁ muscarinic receptor knockout mice, demonstrating that its effects at reducing hyperdopaminergic behaviors required activation of these receptor subtypes.⁴⁸ The antipsychotic effects of xanomeline were also blocked by central muscarinic receptor antagonists such as scopolamine.⁴⁴ Conversely, xanomeline reversed scopolamine-induced disruptions in latent inhibition in a rat model of schizophrenia.⁴⁹ Taken together, these findings support that the antipsychotic effects of xanomeline are mediated by stimulation of muscarinic receptors.

MUSCARINIC RECEPTOR PHARMACOLOGY

Spurred by the fortuitous discovery of xanomeline’s antipsychotic activity, research accelerated greatly over the next 30 years focusing on muscarinic receptor biology and its potential connection to schizophrenia symptoms. Muscarinic receptors belong to the superfamily of G protein–coupled receptors and include 5 distinct subtypes (M₁-M₅) grouped into 2 classes based on their cognate G proteins and location within the synapse. The M₁, M₃, and M₅ subtypes primarily mediate excitatory postsynaptic currents via coupling to G_q proteins, while the M₂ and M₄ subtypes are predominantly presynaptic and inhibit depolarization through activation of G_i/o proteins.²⁷ Muscarinic receptors play a role in neuronal excitability and neurotransmitter regulation, learning and memory, cardiac function, smooth muscle contraction, and exocrine gland secretion (eg, saliva, gastric acid)²⁷ and are widely expressed throughout the central and peripheral nervous system.^27,50

Of particular relevance to this review, both M₁ and M₄ muscarinic receptors are highly expressed in brain regions implicated in cognitive function and the positive symptoms of psychosis, particularly those regions containing key DA circuitry (eg, PFC, limbic striatum, associative striatum).^28,51 In rodents, expression of D₂ DA and M₁/M₄ muscarinic receptors overlaps in the nucleus accumbens, the terminal end of the mesolimbic tract that originates in the ventral tegmental area (VTA). Overactivation of these DA afferents promotes excessive presynaptic DA release and subsequent postsynaptic D₂ DA receptor activation associated with positive psychotic symptoms.²⁷ M₁ muscarinic receptors are expressed at high levels in the cortex and hippocampus, but not so for M₄ muscarinic receptors or D₂ DA receptors.^27,52 Data suggest that M₄ muscarinic receptor expression is decreased in the hippocampus among people with schizophrenia.^53,54 Notably, M₁ and M₄ muscarinic receptors are not highly expressed in brain regions related to D₂ DA blockade-mediated AEs (eg, tuberoinfundibular system, sensorimotor striatum).²⁷ See Scarr^55,56 and Perry⁵⁷ for additional information on the cholinergic system in the human central nervous system (CNS).

Preclinical research confirmed that knockout mice lacking either the M₁ or M₄ muscarinic receptor exhibit psychosis-like phenotypes.^58-60 In wild-type mice, increasing ACh signaling with M₁ or M₄ muscarinic receptor orthosteric agonists or positive allosteric modulators (PAMs) blocked the psychotomimetic effects of N-methyl D-aspartate (NMDA) antagonists (eg, phenylcyclohexyl piperidine [PCP], MK-801).^28,50 Consistent with these findings, polymorphisms in both M₁ and M₄ muscarinic receptors have been found in people with schizophrenia and are associated with clinical manifestations including dysregulated error processing and reduced gray matter volume.^61-63 Studies have also noted that individuals with schizophrenia have lower M₁ muscarinic receptor levels and expression than peers without schizophrenia.^64,65 Moreover, approximately 25% of those with schizophrenia have 75% lower M₁ muscarinic receptor expression than expected, a finding described as the muscarinic receptor deficit syndrome (MRDS)^66,67 (Figure 2). Low M₁ muscarinic receptor expression by itself may not always correlate with cognitive impairment but this remains a potential target to improve cognition in schizophrenia.

RATIONALE FOR TARGETING MUSCARINIC RECEPTORS FOR POSITIVE SYMPTOMS OF PSYCHOSIS IN SCHIZOPHRENIA

M₄ Muscarinic Receptors

As previously noted, animal models of positive symptoms of psychosis note increased activity of VTA DA neurons resulting in heightened terminal DA release in the nucleus accumbens, while in humans, the increased DA activity occurs in an analogous pathway that connects the dorsomedial substantia nigra to the associative striatum (Figure 3A).^27,68,74 The clinical finding of xanomeline’s antipsychotic properties propelled research with animal models to identify the role of cholinergic pathways that relate to positive symptoms. This research uncovered the existence of brainstem afferent cholinergic neurons that originate in the laterodorsal tegmentum (LDT) and project to the VTA. Release of ACh from the LDT activates M₅ muscarinic receptors on the VTA cell body, thereby stimulating striatal DA release.^27,68

Neurophysiology studies later discovered that ACh release from LDT afferents was regulated by inhibitory M₄ autoreceptors on axonal terminals; therefore, activation of these inhibitory autoreceptors by M₄ muscarinic receptor agonists or PAMs reduces LDT ACh release, resulting in less cholinergic stimulation of VTA DA neurons.⁶⁸ Taken together, the net biological effect of M₄ muscarinic receptor activation is decreased VTA-mediated release of DA in the striatum and a reduction in positive/psychosis symptoms. The absence of motor effects from M₄ muscarinic receptor activation is explained by the fact that in dorsal striatal motor areas, presynaptic DA release is regulated by another cholinergic pathway, the pedunculopontine nucleus (PPN). On cholinergic PPN neurons, activation of muscarinic M₂ inhibitory autoreceptors is necessary to reduce cholinergic output.⁷⁵ The finding of distinct muscarinic autoreceptor control of brainstem cholinergic inputs to striatal DA circuits provides the intriguing option of reducing positive psychosis symptoms by selective actions on relevant DA neurons while sparing off-target effects on motoric DA pathways.

M₁ Muscarinic Receptors

The mechanism by which M₁ muscarinic receptor activation might modulate neural circuits implicated in the positive symptoms of psychosis is hypothesized to be the product of cortical M₁ muscarinic heteroreceptors mediating “top-down” glutamatergic modulation of VTA DA release (Figure 3B).²⁷ Parvalbumin-positive GABAergic interneurons in the PFC regulate the activity of glutamatergic pyramidal neurons, and these inhibitory interneurons express M₁ muscarinic receptors.^27,71,72 These descending glutamate pathways terminate in the VTA, where glutamate signals stimulate presynaptic VTA striatal DA release. Activation of excitatory M₁ muscarinic receptors on GABAergic interneurons facilitates GABA release and, in turn, downregulates glutamate signaling.²⁷ The net effect is diminished glutamate release onto the VTA, decreased VTA activation, and less DA release in the striatum.²⁷ M₁ muscarinic receptor activation thus provides another presynaptic mechanism by which positive symptoms of psychosis can be reduced. M₁ muscarinic receptors in the human cortex are primarily found on pyramidal cell bodies.⁷⁶ Compared with controls, diminished cortical levels of M₁-expressing neurons are seen in people with schizophrenia. These observations suggest that changes in cortical M₁ muscarinic receptor levels among individuals with schizophrenia may affect glutamate homeostasis (see Dean⁶⁶ for review).

RATIONALE FOR TARGETING MUSCARINIC RECEPTORS FOR COGNITIVE IMPAIRMENT IN SCHIZOPHRENIA

One basis for cognitive impairment in schizophrenia relates to an altered balance of excitatory (glutamate) and inhibitory (GABA) neurotransmission leading to disinhibition and discoordination of interacting neural networks.^51,77 Converging lines of evidence from in vitro and in vivo studies suggest that M₁ and M₄ muscarinic receptors may be important therapeutic targets for the treatment of cognitive impairment in schizophrenia in part due to their interactions with glutamatergic circuits.^27,51 Abnormal cholinergic neurotransmission also contributes to cognitive dysfunction based on the findings noted previously: schizophrenia is associated with low M₁ receptor expression, with 25% of patients having MRDS (ie, M₁ muscarinic receptor expression more than 75% below mean levels in the general population).^66,67

M₄ Muscarinic Receptors

The appropriate balance between excitatory and inhibitory signaling in the hippocampus is critical to learning and memory processes, and disruption of this balance can lead to cognitive impairment.^78,79 M₄ muscarinic receptors are expressed on excitatory pyramidal cells in the CA3 area of the hippocampus and may have a role in modulating this balance.⁸⁰ These pyramidal cells control excitatory drive to CA1 by releasing glutamate at the CA3-CA1 synapse. Activation of M₄ muscarinic receptors in CA3 lowers excitatory drive and is required for cholinergic suppression of neurotransmission at this synapse (Figure 4B).^80,84

Disruptions in this pathway are associated with cognitive deficits in preclinical models. M₄ muscarinic receptor knockout mice have deficits in the acquisition of both contextual and cue-dependent fear conditioning but not spatial memory, suggesting that M₄ muscarinic receptors may have a role in certain types of memory.^60,85 Conversely, M₄ muscarinic receptor agonists have shown procognitive benefits in rodent models^85-88 and in nonhuman primates.⁸⁹ In rodent imaging studies, administration of an M₄ muscarinic receptor PAM can normalize amphetamine-induced changes in hippocampal activity⁹⁰ and enhance the rate of acquisition,⁸⁷ suggesting modulation of M₄ muscarinic receptors can enhance cognition.⁵¹

M₁ Muscarinic Receptors

M₁ muscarinic receptors are highly expressed in the cortex and hippocampus²⁷ and are hypothesized to play a central role in learning, memory, and executive functions.⁵¹ In addition to direct stimulation of cholinergic neurotransmission, activation of M₁ heteroreceptors expressed on PFC GABAergic interneurons increases inhibitory GABA signaling, as described previously.^27,71,72 Increased GABA release onto glutamate pathways not only can moderate subcortical processes (eg, glutamate stimulation of VTA DA release), but activation of parvalbumin-positive GABAergic interneurons is also hypothesized to normalize the excitatory/inhibitory balance in cortical areas associated with cognition (Figure 4A).^27,77

The proposed models described above are supported by multiple preclinical and human studies. Loss of cholinergic neurons, particularly in the nucleus basalis of Meynert, is implicated in the pathophysiology of cognitive impairment in neurodegenerative disorders such as Parkinson’s Disease and AD.⁹¹ In rodent models, pharmacological blockade or genetic deletion of M₁ muscarinic receptors results in significant learning and memory disturbances.^92-95 Conversely, in vivo studies found that activation of M₁ muscarinic receptors enhances synaptic plasticity in prefrontal and hippocampal circuits,^80,96 increases neuronal excitability,⁹⁷ facilitates learning, and improves cognitive deficits induced by NMDA antagonists⁵⁰ or genetic mutations in the NMDA receptor.⁹⁸ Furthermore, M₁ muscarinic receptor activation has been shown to enhance memory consolidation and retrieval in various tasks (eg, object recognition, spatial learning, fear conditioning), executive function and attention,⁹⁹ and cognitive flexibility.¹⁰⁰

OVERVIEW OF XANOMELINE/TROSPIUM CLINICAL DEVELOPMENT PROGRAM

In September 2024, the U.S. FDA approved xanomeline/trospium, making it the first approved muscarinic receptor agonist for the treatment of schizophrenia. This medication combines the dual M₁/M₄ muscarinic receptor agonist xanomeline and the peripherally restricted muscarinic receptor antagonist trospium chloride. Xanomeline is responsible for efficacy, while the role of trospium is to reduce side effects associated with peripheral receptor activation by xanomeline without interfering with xanomeline’s mechanism in the CNS. The basis for the choice of trospium rests in the fact that it possesses a highly polar quaternary amine structure that limits passive diffusion into the CNS while also having high affinity for the P-glycoprotein efflux transporter present at the blood-brain barrier, which leads to its rapid extrusion from the CNS.^101,102 The strategy of pairing xanomeline with trospium was subsequently evaluated in a double-blind, randomized, placebo-controlled trial; xanomeline paired with trospium demonstrated a clinically meaningful improvement in tolerability compared with xanomeline paired with placebo.¹⁰³ A global clinical development program was then undertaken to evaluate the potential of xanomeline/trospium in schizophrenia as monotherapy or adjunctive therapy to other antipsychotics, and as monotherapy for psychosis in AD (Table 1).

The clinical development program for xanomeline/trospium included 3 pivotal, 5-week, randomized, double-blind, placebo-controlled trials in adults with schizophrenia experiencing an acute exacerbation of psychosis: EMERGENT-1 (NCT03697252; phase 2),¹⁰⁴ EMERGENT-2 (NCT04659161; phase 3),¹⁰⁵ and EMERGENT-3 (NCT04738123; phase 3).¹⁰⁶ The 5-week EMERGENT trials were of similar design and enrolled adults with a primary diagnosis of schizophrenia based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, a PANSS total score of 80-120, a Clinical Global Impression-Severity (CGI-S) score ≥4, and recent worsening of psychosis warranting hospitalization. Participants were randomized 1:1 to twice-daily oral xanomeline/trospium or matched placebo for 5 weeks. Dosing started at xanomeline 50 mg/trospium chloride 20 mg and was titrated to a maximum dose of xanomeline 125 mg/trospium chloride 30 mg over 7 days. The primary endpoint in each trial was the change from baseline to week 5 in PANSS total score. Other outcome measures included change from baseline to week 5 in PANSS positive subscale, PANSS negative subscale, PANSS Marder negative factor, and CGI-S scale scores, as well as the proportion of participants achieving ≥30% reduction in PANSS total score. The long-term safety of xanomeline/trospium in schizophrenia was evaluated in the 52-week, open-label EMERGENT-4 (NCT04659174) and EMERGENT-5 (NCT04820309) trials. EMERGENT-4 was an extension trial enrolling participants who rolled over from EMERGENT-2 and EMERGENT-3, while EMERGENT-5 enrolled de novo participants who were not previously exposed to xanomeline/trospium. As previously discussed, xanomeline alone improved both psychotic symptoms and cognition in an early trial in people with AD.⁴¹ The ongoing ADEPT clinical development program is evaluating the potential of xanomeline/trospium for psychosis in AD, and the early trial supports further exploration of the potential of xanomeline/trospium for cognitive deficits in AD and related dementias, as well as potentially in other disorders with prominent cognitive deficits.

As xanomeline/trospium lacks D₂ DA receptor activity and worked presynaptically to selectively decrease DA release in striatal regions outside of motor areas, there was great interest in the potential to augment antipsychotic response without incurring greater risk for D₂-related motor or endocrine adverse effects. Preclinical data confirmed that xanomeline produced synergistic benefits in models of psychosis when coadministered with risperidone or the DA partial agonist aripiprazole.¹⁰⁷ Given this rationale, the ongoing 5-week ARISE (NCT05145413) and 52-week ARISE open-label extension (NCT05304767) trials were designed to evaluate the efficacy, safety, and tolerability of xanomeline/trospium as adjunctive treatment in people whose symptoms of schizophrenia are inadequately controlled with current antipsychotic treatment.¹⁰⁸

Finally, as discussed, in a phase 2 trial, xanomeline showed promise for its procognitive and antipsychotic effects in people with AD.⁴¹ The ongoing ADEPT clinical development program (ADEPT-1, NCT05511363; ADEPT-2, NCT06126224; ADEPT-3, NCT05980949; ADEPT-4, NCT06585787) is evaluating the efficacy, safety, and tolerability of xanomeline/trospium in the treatment of psychosis in people with AD in both acute and long-term trials.

EFFICACY OF XANOMELINE/TROSPIUM IN SCHIZOPHRENIA

In each of the acute EMERGENT trials, xanomeline/trospium significantly improved symptoms compared with placebo as demonstrated by the primary endpoint, the change from baseline to week 5 in PANSS total score. In pooled analyses of the acute EMERGENT trials, xanomeline/trospium was associated with a significantly greater 9.9-point reduction from baseline to week 5 in PANSS total score compared with placebo (Figure 5A; P < .0001; pooled Cohen’s d effect size, 0.65).¹⁰⁹ Improvement in PANSS total score was significantly greater in the xanomeline/trospium vs placebo group starting at week 2, the earliest time point measured, and continuing through the end of the 5-week trials in each trial individually and in the pooled analysis.

Improvements in PANSS total score with xanomeline/trospium were significant vs placebo across most participant subgroups assessed based on baseline demographics and characteristics, including age, race, gender, body mass index (BMI), and disease severity.¹¹⁰

Xanomeline/trospium was also associated with statistically significant and clinically meaningful reductions in PANSS positive and negative subscale scores. In pooled analyses of the acute EMERGENT trials, xanomeline/trospium was associated with significantly greater reductions compared with placebo at week 5 in PANSS positive subscale score (Figure 5C; −3.2 points; P < .0001; Cohen’s d effect size, 0.67), PANSS negative subscale score (Figure 5D; −1.7 points; P < .0001; Cohen’s d effect size, 0.40), and PANSS Marder negative factor score (−2.0 points P < .0001; Cohen’s d effect size, 0.42).¹⁰⁹ These improvements were significantly greater with xanomeline/trospium vs placebo starting at week 2 for the PANSS positive subscale and at week 3 in PANSS negative subscale and PANSS Marder negative factor scores. In the pooled analyses, significance was maintained from the time of initial observation through week 5 across all primary and secondary efficacy measures.

To further evaluate the potential of benefits specifically on negative symptoms, a post hoc analysis¹¹¹ was conducted to evaluate the effect of xanomeline/trospium on negative symptoms in a subgroup of the acute trial participants with moderate/severe negative symptoms and no predominance of positive symptoms at baseline based on the following previously published criteria¹¹²: (1) PANSS Marder negative factor score ≥ 24¹¹³; (2) PANSS Mohr positive score ≤ 19¹¹⁴; and (3) scores ≥ 4 on at least 2 of 3 PANSS blunted affect, passive/apathetic social withdrawal, or lack of spontaneity/flow of conversation items.¹¹⁵ Ten percent of the acute trial population (64/640) met these criteria. In this subgroup, xanomeline (n = 29) was associated with a significantly greater reduction from baseline to week 5 in PANSS Marder negative factor score compared with placebo (n = 35) (least squares mean difference = -4.71, P < .0001; Cohen’s d = 1.18). In addition, in both the full population and the subgroup with prominent negative symptoms, xanomeline/trospium was associated with significantly greater improvements from baseline to week 5 in the negative symptoms of both diminished emotional experience (Cohen’s d = 0.52 vs 1.08) and emotional expression (Cohen’s d = 0.22 vs 0.84). In the subgroup with prominent negative symptoms, the effect of xanomeline on negative symptoms remained significant after covarying for all types of symptoms, suggesting this treatment effect was not pseudospecific or secondary to improvement in other symptoms.

In the acute trials, responder analyses based on PANSS total and CGI-S score also favored xanomeline/trospium vs placebo.¹⁰⁹ In the pooled analyses, a significantly greater proportion of participants achieved a ≥30% reduction in PANSS total score from baseline to week 5 in the xanomeline/trospium (41.4%) vs placebo (20.9%) groups. Similarly, 62.7% of participants in the xanomeline/trospium group experienced a ≥1-point improvement in CGI-S score at week 5 compared with 40.8% of participants in the placebo group.

The effect of xanomeline/trospium on cognitive impairment was evaluated as an exploratory endpoint in the 3 acute EMERGENT trials. EMERGENT-1 used the Cogstate Brief Battery,¹¹⁶ while EMERGENT-2 and EMERGENT-3 used the Cambridge Neuropsychological Test Automated Battery to assess cognitive function (Figure 6).¹¹⁷ The effect of xanomeline/trospium on cognitive performance was significant for those with baseline cognitive performance ≥1 SD below age-matched normative performance. In EMERGENT-1¹¹⁶ and pooled analyses for EMERGENT-2 and EMERGENT-3,¹¹⁷ the effect of xanomeline/trospium on cognitive performance was significant for those with baseline cognitive performance ≥1 SD below age-matched normative performance, which represented about 40% of participants across the 3 trials. Of note, this impact on cognition was not seen in the subgroup with milder baseline levels of cognitive dysfunction. Improvements in pooled analyses of EMERGENT-2/EMERGENT-3 were minimally correlated with changes in PANSS total, PANSS positive subscale, or PANSS negative subscale scores in both xanomeline/trospium and placebo treatment groups, suggesting any effect of xanomeline/trospium on cognition may not be pseudospecific and may be independent of changes in psychosis symptoms, although further research is needed.¹¹⁷

The 52-week, open-label EMERGENT-4 and EMERGENT-5 trials were designed to provide long-term safety and tolerability data, while also examining changes in symptom response, bearing in mind the uncontrolled nature of the trial design. EMERGENT-4 was an open-label extension trial enrolling participants who completed the randomized, double-blind, placebo-controlled EMERGENT-2 or EMERGENT-3 trials and EMERGENT-5 enrolled participants with no prior exposure to xanomeline/trospium. An interim analysis of the EMERGENT-4 study (N = 110) noted that xanomeline/trospium treatment was associated with continuing improvement in PANSS total, PANSS positive and negative subscales, and PANSS Marder negative factor scores throughout the 52-week trial¹¹⁸ regardless of whether participants were previously treated with xanomeline/trospium or placebo during the acute trials.

SAFETY AND TOLERABILITY OF XANOMELINE/TROSPIUM IN SCHIZOPHRENIA

Overall Summary of Safety and Tolerability

In the 5-week, acute EMERGENT clinical trials, the majority of AEs with xanomeline/trospium related to muscarinic effects and were either procholinergic (eg, nausea, vomiting) or anticholinergic in nature (eg, dry mouth, constipation). Overall, these AEs were typically mild or moderate in intensity, tended to resolve with continued treatment, and were not associated with treatment discontinuation. There was no single AE leading to discontinuation that occurred at a rate ≥ 2% in participants treated with xanomeline/trospium and greater than the rate of placebo. Pooled data from the acute EMERGENT trials found the most common treatment-related AEs with an incidence of ≥2% in the xanomeline/trospium group and at a rate more than twice those in the placebo group were nausea (17% vs 3%), constipation (15% vs 5%), dyspepsia (12% vs 2%), vomiting (11% vs 1%), systemic hypertension (6% vs 1%), dry mouth (5% vs 2%), abdominal pain (5% vs 2%), tachycardia (5% vs 2%), dizziness (4% vs 2%), diarrhea (3% vs 2%), gastroesophageal reflux (3% vs <1%), and blurred vision (2% vs <1%) (Table 2).¹¹⁹ The discontinuation rates due to AEs were low and similar for the xanomeline/trospium and placebo groups (5.9% vs 4.4%).

In the 52-week, long-term, open-label trials, the tolerability and safety profile of xanomeline/trospium was consistent with that observed in the 5-week acute trials, with no new safety signals identified. In an interim pooled analysis from the open-label EMERGENT-4 and EMERGENT-5 trials, xanomeline/trospium was generally well tolerated in the outpatient setting across 52 weeks.¹²⁰ The most common treatment-related AEs with an incidence of ≥2% in the xanomeline/trospium group were nausea (17%), vomiting (15%), constipation (14%), dry mouth (9%), dyspepsia (6%), dizziness (6%), hypertension (6%), diarrhea (5%), headache (4%), somnolence (4%), hyperhidrosis (3%), gastroesophageal reflux (2%), upper abdominal pain (2%), salivary hypersecretion (2%), and blurred vision (2%).

In both the acute and long-term trials, the AEs associated with xanomeline/trospium were consistent with the known side effects associated with muscarinic receptors, particularly in peripheral tissues. Importantly, across the EMERGENT clinical trial program, the rates of AEs commonly associated with D₂ DA-binding antipsychotics (ie, motor symptoms, weight and metabolic changes, somnolence/sedation, hyperprolactinemia and related sexual AEs) were low and/or similar to placebo.

Motor Adverse Effects

In pooled analyses of the acute EMERGENT trials, few people treated with xanomeline/trospium (2%) or placebo (<1%) experienced treatment-related motor symptoms based on the preferred FDA terminology of “extrapyramidal adverse effects (EPS).” All EPS treatment-emergent adverse events (TEAEs) occurred at extremely low rates, were mild or moderate, and most resolved during the treatment period without dosage changes to trial medication. The most common treatment-related adverse motor symptom was akathisia, reported by 2 (<1%) and 1 (<1%) participants in the xanomeline/trospium and placebo groups, respectively. Treatment-related dystonia, dyskinesia, and extrapyramidal disorder were each reported only in a single participant in the xanomeline/trospium group and none in the placebo group. There were no reports of TD in the acute EMERGENT trials. Consistent with the lack of treatment-related motor AEs, there was no effect seen on the movement disorder scale scores in the 3 acute trials (Simpson-Angus Scale score: −0.1; Barnes Akathisia Rating Scale score: −0.1; Abnormal Involuntary Movement Scale score: 0)¹¹⁹ or the long-term trials (Simpson-Angus Scale score: −0.2; Barnes Akathisia Rating Scale score: 0; Abnormal Involuntary Movement Scale score: −0.1).¹²⁰ Together, these results suggest that xanomeline/trospium is not associated with clinically meaningful motor symptoms as predicted by its pharmacology.

Weight Gain and Metabolic Effects

In both the acute and long-term EMERGENT trials, xanomeline/trospium was not generally associated with clinically meaningful weight gain or changes in metabolic parameters,¹¹⁹ both of which are common antipsychotic-associated AEs.¹²¹ It is worth noting that it is common for participants on placebo to experience weight gain in acute schizophrenia trials when such trials are conducted in inpatient settings. In pooled analyses across all 3 acute trials, exposure to xanomeline/trospium was associated with a 1.41 kg increase in body weight compared with a 1.94 kg increase in the placebo group. Approximately half as many people in the xanomeline/trospium group (5.3%) experienced clinically meaningful weight gain (defined as an increase of ≥7%) compared with placebo (11.4%), and approximately twice as many people in the xanomeline/trospium group (1.5%) lost ≥7% weight compared with placebo (0.7%). Similar results were observed for other weight-related factors such as BMI and waist circumference. In the 52-week open-label trials, there was a mean body weight change with xanomeline/trospium of −2.6 ± 0.5 kg over 52 weeks. After 52 weeks of treatment, the proportion of people with potentially clinically significant weight gain (≥7% increase; 4.6%) was lower than the proportion with potentially clinically significant weight loss (≥7% decrease; 17.6%). Similarly, the proportion of people with a TEAE of weight loss (3.9%) was higher than increased weight (1.8%). Xanomeline/trospium was not associated with clinically meaningful adverse changes in metabolic parameters (including HbA_1c and lipid levels) when looking at either mean changes or threshold analysis.¹⁰⁹ These data highlight the limited weight and metabolic impact of xanomeline/trospium, consistent with its muscarinic pharmacology and in contrast to that seen with many atypical antipsychotics.

Heart Rate and Blood Pressure

In addition to the EMERGENT trials, a dedicated 24-hour, open-label, inpatient ambulatory blood pressure (BP) monitoring trial in people living with schizophrenia was designed to definitively assess potential BP changes associated with xanomeline/trospium and to provide heart rate (HR) data. The trial was statistically powered to determine whether there was a clinically meaningful change in systolic BP, consistent with U.S. FDA guidance, and collected vital sign data 48 times per day to provide a 24-hour average change in vital sign parameters. In that trial, xanomeline/trospium was associated with a −0.6 mmHg change in systolic BP and was successful on the primary endpoint by determining statistically (P < .05) that xanomeline/trospium was not associated with a clinically meaningful increase in systolic BP (3 mmHg threshold established per U.S. FDA guidance). Xanomeline/trospium was associated with a small, non-significant increase in diastolic BP (+ 1.9 mmHg) and an increase in HR (+ 9.8 beats per minute [bpm]), which is consistent with the pooled data from both the acute and long-term trials.

In the acute and long-term EMERGENT trials, xanomeline/trospium was associated with small BP changes and an increase in HR, which peaked early during the first week of treatment and partially attenuated with continued treatment as assessed at 2 hours post dose, when plasma levels of xanomeline and trospium are both at peak levels.^104-106 From baseline to week 5, mean systolic BP changed by + 0.7 mmHg (xanomeline/trospium) and 0 mmHg (placebo), and mean diastolic BP increased by 1.9 mmHg (xanomeline/trospium) and 0.4 mmHg (placebo). In the short-term placebo-controlled trials, change in HR from baseline to week 5 was 5.9 bpm greater for xanomeline/trospium than for placebo. In interim pooled analyses of the long-term trials, xanomeline/trospium was associated with increases in HR with peak elevations on day 14 (+ 7.7 bpm), which were partially attenuated with continued dosing; mean HR change from baseline to week 52 was + 1.7 bpm.

Prolactin

Xanomeline/trospium was not associated with clinically meaningful hyperprolactinemia or related sexual AEs. In the pooled acute trials, prolactin levels were similar between the xanomeline/trospium and placebo groups over the 5-week treatment period; mean change from baseline to week 5 was 0.8 ng/L vs −1.4 ng/L, respectively.¹¹⁹ Similarly, in the interim analysis of the long-term trials, xanomeline/trospium was not associated with significant changes in prolactin levels consistent with its muscarinic receptor pharmacology.¹²⁰

SUMMARY

New treatments with novel mechanisms of action, broader efficacy, and better tolerability are needed to improve outcomes for people living with schizophrenia. Based on the serendipitous discovery that the dual M₁/M₄ muscarinic receptor agonist xanomeline could exhibit antipsychotic properties, a large body of preclinical and human evidence highlighted the potential for M₁ and M₄ muscarinic receptor activation as a promising potential treatment strategy for schizophrenia.^26-28 The recent approval of xanomeline/trospium by the U.S. FDA in September 2024 represents the culmination of 3 decades of research on the role of muscarinic receptors in the pathophysiology of schizophrenia. Xanomeline is a dual M₁/M₄ preferring muscarinic receptor agonist without activity at D₂ DA receptors and, as such, represents the first new class of medication for schizophrenia since antipsychotics were approved more than 70 years ago. Most chronic disorders, like schizophrenia, are heterogeneous and benefit from the availability of multiple classes of medications that can be used in place of or in conjunction with other treatment options. Due to its unique presynaptic mechanism of action and absence of D₂ DA receptor binding, xanomeline/trospium opens up new opportunities for people with inadequate response to D₂ DA receptor blockade.

In clinical trials, xanomeline/trospium significantly reduced schizophrenia symptoms vs placebo and was generally well tolerated. In addition to improvement in positive symptoms, xanomeline/trospium was associated with significantly greater improvement in negative symptoms, as well as in cognitive impairment in those participants with more severe impairment at baseline, compared with placebo. Analyses showed that improvements in negative symptoms and cognitive impairment with xanomeline/trospium were independent of psychosis symptoms reduction in all 3 short-term trials. In the context of acute psychosis trials, any improvement in negative and cognitive symptoms may be a product of pseudospecificity; however, analyses of these outcomes suggest that effects on those symptom domains were distinct and not a result of pseudospecific carryover related to overall symptom improvement. The most common AEs with xanomeline/trospium were consistent with the known activity of xanomeline and trospium at muscarinic receptors. Importantly, xanomeline/trospium was not associated with clinically significant motor symptoms, weight gain, hyperprolactinemia or related sexual side effects, or somnolence/sedation. Xanomeline/trospium is the first in a new class of non-D₂ binding muscarinic receptor stimulating medications and, therefore, has the potential to be an important new treatment option for persons living with schizophrenia.

Acknowledgments

Medical writing and editorial support were provided by Matthew Jacobson, Isaac Dripps, PhD, and Paula Stuckart of Apollo Medical Communications, part of Helios Global Group, and funded by Bristol Myers Squibb.

Author contributions

Jonathan M. Meyer (Conceptualization [equal], Visualization [equal], Writing—original draft [equal], Writing—review & editing [equal]), Ken Kramer (Conceptualization [equal], Visualization [equal], Writing—original draft [equal], Writing—review & editing [equal]), Scott Vuocolo (Conceptualization [equal], Visualization [equal], Writing—original draft [equal], Writing—review & editing [equal]), Inder Kaul (Conceptualization [equal], Data curation [lead], Formal analysis [lead], Funding acquisition [equal], Investigation [lead], Methodology [lead], Project administration [lead], Resources [supporting], Supervision [lead], Validation [lead], Visualization [equal], Writing—original draft [equal], Writing—review & editing [equal]), and Andrew C. Miller (Conceptualization [equal], Data curation [equal], Formal analysis [supporting], Funding acquisition [equal], Investigation [supporting], Methodology [supporting], Project administration [equal], Resources [lead], Software [equal], Supervision [lead], Validation [supporting], Visualization [equal], Writing—original draft [equal], Writing—review & editing [equal])

Funding

None declared.

Conflicts of interest

In the prior 24 months, J.M.M. has received advising, consulting, and/or speaker fees from AbbVie, Alkermes, Axsome, BioXcel, Bristol Myers Squibb, Cerevel, Delpor, Intra-Cellular Therapies, Neurocrine, Noven, Otsuka America, Relmada, Sumitomo, and Teva. K.K., S.V., and I.K. are employees of Bristol Myers Squibb. A.C.M. is a consultant to Bristol Myers Squibb.

Data availability

No new data were generated or analyzed in support of this research.

References