Emraclidine (CVL-231): A Comprehensive Report on a Novel M4 PAM from Promising Breakthrough to Pivotal Setback and Strategic Repositioning

I. Executive Summary

Emraclidine (CVL-231) is an investigational small molecule that emerged as a highly anticipated therapeutic candidate for schizophrenia and Alzheimer's disease psychosis. Its development was predicated on a novel mechanism of action as a highly selective positive allosteric modulator (PAM) of the muscarinic M4 acetylcholine receptor. This approach represented a significant departure from traditional antipsychotics, which primarily function through direct dopamine D2 receptor antagonism and are associated with a substantial burden of motor, metabolic, and endocrine side effects. By indirectly modulating striatal dopamine and cortical glutamate activity, Emraclidine was designed to achieve antipsychotic efficacy while offering a superior safety and tolerability profile, a key unmet need in the treatment of psychotic disorders.

Initial clinical development was highly promising. A Phase 1b trial in patients with schizophrenia, the results of which were published in The Lancet, demonstrated statistically significant and clinically meaningful improvements in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo. Critically, these efficacy signals were achieved without the side effects that plague current therapies, such as extrapyramidal symptoms and weight gain. This success positioned Emraclidine as a potential best-in-class asset and was a cornerstone of AbbVie's decision to acquire its developer, Cerevel Therapeutics, in a landmark $8.7 billion transaction in 2024.

However, the trajectory of Emraclidine shifted dramatically in November 2024 with the announcement that two larger, potentially registrational Phase 2 trials, EMPOWER-1 and EMPOWER-2, failed to meet their primary efficacy endpoints. Despite a consistent and favorable safety profile, the drug did not demonstrate a statistically significant improvement in PANSS scores over placebo. The failure was attributed in part to an unexpectedly high placebo response in the multi-site studies, a persistent challenge in psychiatric drug development. The clinical setback had immediate and severe financial repercussions, leading to a significant drop in AbbVie's market capitalization and a subsequent $3.5 billion impairment charge on the acquired asset.

In the wake of this failure, AbbVie has recalibrated its development strategy for Emraclidine. While the monotherapy indication for schizophrenia is now considered a high-risk endeavor, the company is pivoting to explore its potential as an adjunctive therapy in schizophrenia and as a monotherapy for psychosis associated with neurodegenerative disorders, namely Alzheimer's and Parkinson's disease. This strategic shift leverages the drug's most compelling attribute—its excellent tolerability—in patient populations that are either receiving concomitant therapies or are particularly vulnerable to the side effects of existing antipsychotics. The competitive landscape has also been reshaped, with Bristol Myers Squibb's recently approved dual M1/M4 agonist, Cobenfy (KarXT), now facing a clearer path to market dominance. The future of Emraclidine now hinges on AbbVie's ability to demonstrate its value in these new, more targeted indications, a high-risk but potentially high-reward endeavor that will be closely watched by the neuroscience community.

II. Scientific Foundation: A New Paradigm in Antipsychotic Therapy

A. Drug Profile and Chemical Properties

Emraclidine is an investigational small molecule drug being developed for the treatment of central nervous system (CNS) disorders.[1] It is identified by the developmental codes

CVL-231 and, from its time at Pfizer, PF-06852231.[1] Its Chemical Abstracts Service (CAS) registration number is

2170722-84-4.[3]

From a chemical standpoint, Emraclidine is classified as a heterocyclic compound belonging to several chemical families, including azetidines, fluorobenzenes, ketones, pyridines, and pyrroles.[1] Its molecular formula is

C20​H21​F3​N4​O, and it has a molecular weight of 390.41 g/mol.[5] The structural properties of the molecule, including a calculated XLogP of 2.24 and a Topological Polar Surface Area (TPSA) of 49.33 Ų, are consistent with a compound designed for oral administration and penetration of the blood-brain barrier, which is essential for its intended action on CNS targets.[6]

B. Mechanism of Action: Selective M4 Receptor Modulation

Emraclidine's therapeutic hypothesis is rooted in a novel mechanism of action that distinguishes it from all currently approved antipsychotics. It functions as a positive allosteric modulator (PAM) that exhibits high selectivity for the muscarinic acetylcholine receptor M4 subtype.[1]

Allosteric modulators represent a sophisticated pharmacological approach. Instead of binding to the primary (orthosteric) site where the endogenous neurotransmitter acetylcholine binds, Emraclidine binds to a distinct, secondary (allosteric) site on the M4 receptor.[9] This binding event does not activate the receptor on its own but rather enhances the receptor's response to acetylcholine. This potentiation of the natural signaling process allows for a more nuanced modulation of neuronal activity compared to direct, full agonism.[11]

The M4 receptor is a G protein-coupled receptor (GPCR) that is highly expressed in the striatum, a brain region critically involved in the regulation of dopamine signaling.[2] The prevailing hypothesis for schizophrenia implicates hyperdopaminergia, or excessive dopamine activity, in the striatum as a key driver of positive psychotic symptoms.[12] The M4 receptor functions as a presynaptic autoreceptor on cholinergic neurons, and its activation leads to an inhibition of acetylcholine release. This reduction in acetylcholine, in turn, indirectly modulates and reduces the downstream release of dopamine in the striatum.[2] By selectively potentiating M4 receptor activity, Emraclidine is designed to normalize this striatal hyperdopaminergia and thereby produce an antipsychotic effect.[2]

Furthermore, M4 receptor activation is also thought to have beneficial effects on cortical glutamatergic hyperactivity, another neurotransmitter system implicated in the pathophysiology of schizophrenia, particularly in its early stages.[2]

A crucial element of Emraclidine's design is its high selectivity for the M4 receptor subtype. The five muscarinic receptor subtypes (M1-M5) have highly conserved orthosteric binding sites, making it difficult for traditional agonists to target just one subtype. This lack of selectivity is a primary reason why earlier pan-muscarinic agonists, such as xanomeline, were associated with significant peripheral cholinergic side effects, including gastrointestinal distress.[18] By targeting a unique allosteric site that differs more significantly between subtypes, Emraclidine achieves its M4 selectivity, a feature intended to harness the antipsychotic benefits of M4 activation while avoiding the tolerability issues associated with broad muscarinic agonism.[2]

C. Rationale for Development and Unmet Needs

The development of Emraclidine was driven by a significant and persistent unmet need for better-tolerated antipsychotic medications. For over 70 years, the pharmacological treatment of schizophrenia has been dominated by drugs that function as direct antagonists of the dopamine D2 receptor.[18] While this mechanism is effective in controlling the positive symptoms of psychosis (e.g., hallucinations, delusions), it comes at a substantial cost.

Blocking dopamine receptors throughout the brain disrupts pathways essential for motor control, motivation, and hormonal regulation, leading to a wide array of burdensome side effects. These include extrapyramidal symptoms (EPS) such as parkinsonism and dystonia, tardive dyskinesia (a potentially irreversible movement disorder), significant weight gain, and metabolic syndrome (e.g., diabetes, hyperlipidemia).[2] These adverse events severely impact patients' quality of life and are a primary driver of treatment nonadherence.[10] Discontinuation rates for current antipsychotics are alarmingly high, with some studies showing that nearly 75% of patients stop their medication within 18 months, leading to high rates of relapse.[10]

Emraclidine was conceived as a solution to this long-standing therapeutic dilemma. Its therapeutic hypothesis was that by indirectly modulating dopamine levels through a non-dopaminergic target (the M4 receptor), it could achieve antipsychotic efficacy comparable to existing agents but without the liabilities of direct D2, serotonin, or histamine receptor blockade.[9] The goal was to create a once-daily oral medication that would be effective, safe, and well-tolerated, thereby improving patient compliance, reducing relapse rates, and ultimately offering a better long-term prognosis for individuals living with schizophrenia.[10]

III. Clinical Development and Efficacy Analysis

The clinical development of Emraclidine has been a tale of two distinct chapters: an initial phase of remarkable promise that generated significant excitement, followed by a pivotal setback that necessitated a complete strategic re-evaluation.

A. Early Promise: The Phase 1b Trial (NCT04136873)

The foundation for the initial optimism surrounding Emraclidine was laid by a well-designed Phase 1b clinical trial (NCT04136873), the results of which were published in the prestigious journal The Lancet.[10] This study provided the first robust clinical evidence supporting the M4 PAM mechanism for treating schizophrenia.

Study Design

The trial was a two-part, randomized, double-blind, placebo-controlled study conducted in the United States.[24]

• Part A was a multiple ascending-dose (MAD) portion involving 49 participants with stable schizophrenia. Its purpose was to evaluate the safety, tolerability, and pharmacokinetics of oral doses ranging from 5 mg to 40 mg, thereby establishing the appropriate doses for further testing.[24]
• Part B was the proof-of-concept portion. It enrolled 81 adults experiencing an acute exacerbation of psychosis. These participants were randomized in a 1:1:1 ratio to one of three groups for a 6-week treatment period: Emraclidine 30 mg once-daily (QD), Emraclidine 20 mg twice-daily (BID), or placebo.[24] The primary endpoint was safety and tolerability, with efficacy assessed as a key secondary outcome.[24]

Efficacy Results

The efficacy results from Part B were highly encouraging and statistically significant. At the end of the 6-week treatment period, both Emraclidine arms demonstrated a clinically meaningful improvement in schizophrenia symptoms as measured by the PANSS total score.[2]

• The 30 mg QD group (n=27) showed a least squares (LS) mean reduction of 12.7 points versus placebo (p=0.023), corresponding to a robust effect size (Cohen's d) of 0.68.[2]
• The 20 mg BID group (n=27) showed an LS mean reduction of 11.1 points versus placebo (p=0.047), with an effect size of 0.59.[2]

Safety and Tolerability

The safety profile was a key highlight of the study and supported the drug's therapeutic hypothesis. Emraclidine was generally well-tolerated, with an overall incidence of adverse events (AEs) that was similar to the placebo group (52-56% for Emraclidine vs. 52% for placebo).[24] Most importantly, the data confirmed the absence of the burdensome side effects associated with traditional antipsychotics. There were no meaningful differences observed in extrapyramidal symptoms or weight gain compared to placebo.[2] Furthermore, due to the drug's M4 selectivity, gastrointestinal side effects were infrequent and comparable to placebo, a key differentiator from less selective muscarinic agents.[2] The most common AE was headache, which occurred at similar rates in both the Emraclidine and placebo groups (28% vs. 26%).[24]

These compelling results from the Phase 1b trial provided strong validation for the M4 PAM mechanism and positioned Emraclidine as a potential breakthrough therapy, justifying its advancement into a larger, comprehensive Phase 2 program.[2]

B. The EMPOWER Program Failure (NCT05227690 & NCT05227703)

Building on the success of the Phase 1b study, Cerevel Therapeutics, and later AbbVie, initiated the EMPOWER program, a pair of parallel Phase 2 trials designed to be registration-enabling. The program aimed to confirm the efficacy and safety of Emraclidine across a broader dose range in a larger patient population. However, in a surprising and significant setback, both trials failed to meet their primary efficacy endpoint.

Study Design

The EMPOWER program consisted of two multicenter, randomized, double-blind, placebo-controlled, 6-week trials in adults with schizophrenia experiencing an acute exacerbation of psychosis.[2]

• EMPOWER-1 (NCT05227690) evaluated two fixed doses: 10 mg QD and 30 mg QD of Emraclidine versus placebo.[29]
• EMPOWER-2 (NCT05227703) evaluated two different fixed doses: 15 mg QD and 30 mg QD of Emraclidine versus placebo.[29]

The primary endpoint for both studies was the change from baseline in the PANSS total score at Week 6.[17] This robust design, involving multiple doses and two separate trials, was intended to fully characterize the therapeutic dose range and provide the necessary evidence for regulatory submission.[16]

Efficacy Results

On November 11, 2024, AbbVie announced that both EMPOWER-1 and EMPOWER-2 had failed to achieve their primary endpoint.[2] While Emraclidine demonstrated numerical improvements in PANSS scores, the differences compared to the placebo group were not statistically significant. A detailed summary of the efficacy results is presented in Table 1.

Table 1: Summary of Efficacy Results from EMPOWER-1 and EMPOWER-2 Trials

Trial	Treatment Arm	N	Baseline PANSS (Mean, SD)	LS Mean Change from Baseline (95% CI)
EMPOWER-1	Placebo	127	98.3 (8.16)	-13.5 (-17.0, -10.0)
(NCT05227690)	Emraclidine 10 mg QD	125	97.6 (7.65)	-14.7 (-18.1, -11.2)
	Emraclidine 30 mg QD	127	97.9 (7.89)	-16.5 (-20.0, -13.1)
EMPOWER-2	Placebo	128	97.4 (8.22)	-16.1 (-19.4, -12.8)
(NCT05227703)	Emraclidine 15 mg QD	122	98.0 (8.49)	-18.5 (-22.0, -15.0)
	Emraclidine 30 mg QD	123	97.2 (7.75)	-14.2 (-17.6, -10.8)

Source: Data compiled from [2]

The data reveals a critical issue: an unusually high placebo response. In EMPOWER-1, the placebo group improved by 13.5 points, and in EMPOWER-2, the improvement was even greater at 16.1 points. This is more than double the placebo response observed in the Phase 1b trial and effectively masked the modest therapeutic effect of Emraclidine, rendering the results statistically insignificant. AbbVie's subsequent analysis suggested that this high placebo response was site-specific, indicating that variability in trial execution across different clinical sites may have been a major confounding factor.[38]

Safety Profile

Despite the efficacy failure, Emraclidine's favorable safety and tolerability profile remained consistent. The drug was well-tolerated across all doses tested in the EMPOWER program, with an adverse event profile comparable to that seen in the Phase 1b trial.[16] The most commonly reported adverse events were headache, dry mouth, and dyspepsia, with incidence rates similar to placebo.[2] The absence of significant motor or metabolic side effects was reaffirmed, preserving one of the drug's key potential advantages.

C. Ancillary and Ongoing Studies

Beyond the core schizophrenia program, the clinical development of Emraclidine includes several other studies designed to characterize its profile and explore its potential in other populations.

• EMPOWER-3 (NCT05443724): This is a 52-week, open-label extension study for participants who completed either EMPOWER-1 or EMPOWER-2. Its primary purpose is to assess the long-term safety and tolerability of Emraclidine in a stable patient population.[17]
• Alzheimer's Disease Psychosis Program: Emraclidine is also in Phase 1 development for the treatment of psychosis associated with Alzheimer's disease.[1] A key supporting study, NCT05644977, was a multiple-dose trial evaluating the safety, tolerability, and pharmacokinetics of Emraclidine in healthy elderly volunteers and in participants with dementia due to Alzheimer's disease. This trial is complete and provides the foundational data for advancing into Phase 2 for this indication.[46]
• Pharmacokinetic Studies: Several other Phase 1 trials have been conducted to fully characterize the drug's behavior. These include a study on the effect of renal impairment (NCT05940402), a drug-drug interaction study (NCT05965219), and a trial assessing the impact of food and gastric pH-altering agents on its absorption (NCT06366243).[8]

IV. Strategic and Competitive Landscape

The clinical journey of Emraclidine is inextricably linked to a high-stakes corporate strategy, culminating in one of the largest biopharma acquisitions of recent years. The subsequent trial failure and strategic pivot have reshaped the competitive landscape for novel antipsychotics.

A. The AbbVie-Cerevel Transaction: A High-Stakes Neuroscience Bet

In a move that underscored the immense perceived value of novel neuroscience assets, AbbVie announced a definitive agreement to acquire Cerevel Therapeutics in December 2023 for approximately $8.7 billion in cash ($45.00 per share).[48] The transaction, which closed on August 1, 2024, was framed as a transformative step to strengthen AbbVie's neuroscience pipeline, which is a key growth area for the company.[52]

At the center of this acquisition was Emraclidine. It was consistently highlighted as the "crown jewel" and a "potential best-in-class, next-generation antipsychotic" with the ability to "transform the standard of care in schizophrenia".[48] AbbVie intended to leverage its extensive global commercial, regulatory, and clinical infrastructure to maximize the asset's potential, which was projected to generate multibillion-dollar sales.[50]

The failure of the EMPOWER trials just months after the deal closed had immediate and severe financial consequences. On the day of the announcement, AbbVie's stock price fell by over 12%, erasing approximately $40 billion in market capitalization.[36] Subsequently, in its fourth-quarter 2024 financial reporting, AbbVie recorded a

$3.5 billion non-cash intangible asset impairment charge specifically related to the diminished future cash flow estimates for Emraclidine.[57]

While the impairment charge is substantial, the overall strategic value of the Cerevel acquisition is supported by the other assets in its pipeline. Notably, tavapadon, a D1/D5 partial agonist for Parkinson's disease, has since reported positive Phase 3 data, providing a significant near-term asset that helps to offset the Emraclidine setback.[38]

B. Competitive Analysis: Emraclidine vs. Cobenfy (KarXT)

The development of Emraclidine occurred in parallel with that of KarXT (xanomeline-trospium), now marketed as Cobenfy by Bristol Myers Squibb. Both drugs represent the first wave of muscarinic-targeted therapies for schizophrenia, but they possess key differences in their mechanism, dosing, and clinical profile, which are detailed in Table 2.

Table 2: Comparative Profile of Emraclidine vs. Cobenfy (KarXT)

Feature	Emraclidine (CVL-231)	Cobenfy (KarXT)
Developer	AbbVie (via Cerevel/Pfizer)	Bristol Myers Squibb (via Karuna)
Target(s)	Muscarinic M4 Receptor	Muscarinic M1 and M4 Receptors
Mechanism	Selective Positive Allosteric Modulator (PAM)	Orthosteric Agonist (Xanomeline) + Peripheral Antagonist (Trospium)
Dosing Frequency	Once-Daily (QD)	Twice-Daily (BID)
Titration	Not required	Required
Key Adverse Events	Headache, Dry Mouth, Dyspepsia (rates similar to placebo)	Nausea, Vomiting, Constipation, Dyspepsia, Hypertension
FDA Status	Phase 2 (Schizophrenia), Phase 1 (ADP)	Approved (September 2024)

Source: Data compiled from [1]

The fundamental difference lies in their approach to muscarinic modulation. KarXT employs a "carpet bomb" approach with the pan-agonist xanomeline, which activates both M1 and M4 receptors centrally, and then uses the peripheral antagonist trospium to clean up the resulting cholinergic side effects outside the brain.[61] Emraclidine, in contrast, was designed as a "scalpel," selectively enhancing only M4 receptor activity to avoid the need for a second compound and to potentially achieve a better gastrointestinal tolerability profile.[64]

The FDA's approval of Cobenfy in September 2024 established it as the first-in-class muscarinic antipsychotic.[43] The subsequent failure of Emraclidine in the EMPOWER trials effectively removed its most significant and direct competitor, solidifying a "clearer win for Bristol" and removing a major market overhang for Cobenfy.[43]

C. Market Positioning and Future Outlook: AbbVie's Strategic Pivot

Faced with the definitive failure of Emraclidine as a monotherapy for schizophrenia, AbbVie has publicly outlined a revised and more targeted development strategy.[38] This strategic pivot moves away from the initial broad indication and focuses on niche areas where the drug's unique attributes may still confer a clinical advantage.

The new development plan prioritizes two main avenues:

1. Adjunctive Therapy in Schizophrenia: Emraclidine will be explored as an add-on treatment for patients who are already taking existing antipsychotics but have residual symptoms. The rationale is that its novel, non-dopaminergic mechanism could provide complementary benefits, while its excellent safety profile would make it a suitable combination partner.[38]
2. Monotherapy for Neurodegenerative Psychosis: The company is advancing programs for psychosis associated with Alzheimer's disease (ADP) and Parkinson's disease. This strategy leverages Emraclidine's favorable tolerability, a critical factor in these older, more fragile patient populations who are particularly susceptible to the adverse effects of traditional antipsychotics.[38]

To support this pivot, AbbVie plans to conduct a multiple ascending dose study in 2025 to investigate higher doses of Emraclidine, with data anticipated in early 2026. This will be followed by the initiation of Phase 2 trials in the neurodegenerative psychosis indications in 2026.[38] The monotherapy path in schizophrenia is now considered a "heavily risk adjusted opportunity," contingent on the results of these future studies.[38]

V. Expert Insights and Recommendations

A. Synthesis of Findings

Emraclidine's journey from a promising "best-in-class" asset to a high-profile Phase 2 failure encapsulates the profound challenges and risks inherent in CNS drug development. The initial scientific premise—that selective M4 PAMs could decouple antipsychotic efficacy from D2-mediated side effects—was elegant and supported by strong preclinical and Phase 1b data. This promise was sufficient to command an $8.7 billion acquisition price, signaling intense industry interest in novel mechanisms for neuropsychiatric disorders.

However, the failure of the EMPOWER trials serves as a stark reminder that efficacy signals from small, early-phase studies do not always translate to larger, more heterogeneous registrational trials. The unexpectedly high placebo response observed in the Phase 2 program overwhelmed the drug's modest therapeutic effect, leading to a negative outcome despite a consistently favorable safety profile. This has forced AbbVie into a strategic repositioning, shifting focus from a broad monotherapy indication in schizophrenia to more niche applications as an adjunctive therapy and as a treatment for psychosis in neurodegenerative diseases. While the initial vision for Emraclidine has collapsed, its demonstrated safety creates a credible, albeit more challenging and risk-adjusted, path forward.

B. Critical Assessment of Future Potential

The viability of AbbVie's revised strategy for Emraclidine warrants a critical and cautious assessment.

• Adjunctive Therapy for Schizophrenia: The rationale for using Emraclidine as an adjunctive agent is sound. Its novel mechanism and excellent tolerability make it an attractive candidate to combine with existing D2 antagonists. In this setting, it would not need to demonstrate robust standalone efficacy but rather a statistically significant improvement over and above the standard of care. However, the commercial landscape for adjunctive therapies is challenging, and demonstrating a clinically meaningful benefit that justifies its price will be a key hurdle.
• Psychosis in Neurodegenerative Disease: This indication represents the greatest potential for value creation but also carries the highest risk. The primary advantage of Emraclidine here is its safety profile. Elderly patients with Alzheimer's or Parkinson's are particularly vulnerable to the motor, metabolic, and sedative side effects of existing antipsychotics, making a well-tolerated agent highly desirable. The FDA's recent approval of brexpiprazole for agitation in Alzheimer's dementia sets a regulatory precedent, but also establishes a new competitor. The critical challenge for Emraclidine will be demonstrating clear efficacy in this notoriously difficult-to-treat and heterogeneous patient population, where the placebo response can be even more pronounced than in schizophrenia trials. The failure to show a strong effect in a younger, less complex population raises the bar for success in these more challenging indications.

C. Strategic Recommendations

Based on this comprehensive analysis, the following strategic recommendations are proposed for key stakeholders:

• For AbbVie:

1. Prioritize Robust Trial Design for Neurodegenerative Psychosis: The upcoming Phase 2 trials in Alzheimer's and Parkinson's disease psychosis are critical. These studies must incorporate rigorous design elements to mitigate the high anticipated placebo response. This should include stringent patient selection criteria, centralized rating and training, and potentially the use of a placebo run-in period or sequential parallel comparison designs.
2. Define a Clear Target Population for Adjunctive Schizophrenia: The Phase 2 study in adjunctive schizophrenia should be designed to target a specific patient sub-population where the unmet need is greatest, such as patients with persistent negative or cognitive symptoms despite adequate control of positive symptoms with a D2 antagonist. This could provide a clearer path to demonstrating clinical value.
3. Leverage the Tavapadon Narrative: In investor communications, AbbVie should continue to frame the Cerevel acquisition in the context of its entire pipeline, not just Emraclidine. The success of tavapadon provides a powerful counter-narrative to the Emraclidine setback and validates the overall strategic rationale of the acquisition.

• For Competitors (Bristol Myers Squibb):

1. Solidify Market Leadership: BMS should move aggressively to establish Cobenfy (KarXT) as the definitive standard of care for muscarinic-based antipsychotic therapy. This includes generating extensive long-term, real-world evidence on efficacy and safety to build prescriber confidence.
2. Highlight Mechanistic Differentiation: Marketing efforts should emphasize the potential synergistic benefits of dual M1/M4 agonism, implicitly contrasting it with the failed selective M4 PAM approach of Emraclidine. This narrative could help defend against future competitors targeting only one of the muscarinic receptor subtypes.

• For the Broader CNS Drug Development Field:

1. Re-evaluate the Placebo Response Challenge: The Emraclidine story should serve as a catalyst for the industry to invest in novel clinical trial methodologies aimed at reducing placebo effects in psychiatric studies.
2. Validate Novel Targets Cautiously: While the pursuit of novel, non-dopaminergic targets for psychosis is essential, the field must be cautious about over-interpreting early-phase data. The failure of Emraclidine suggests that a highly selective mechanism, while theoretically advantageous for safety, may not be sufficient to produce the robust efficacy required for regulatory approval in broad patient populations. A deeper understanding of the complex interplay between different neurotransmitter systems (e.g., M1 and M4) may be necessary for future success.

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