emraclidine (CVL-231) / AbbVie - LARVOL DELTA

Xanomeline-Trospium for the Treatment of Schizophrenia. (PubMed, Focus (Am Psychiatr Publ)) - "A search was conducted of all publicly available information (including press releases) and specifically within the databases MEDLINE, Embase, and PsycINFO, from their inception to May 1, 2025, noting the keywords "muscarinic," "schizophrenia," "xanomeline," and "emraclidine." A first-in-class medication approved for the treatment of schizophrenia in adults, XT possesses no direct action on dopamine D2 receptors. Post hoc analyses from the acute schizophrenia trials also indicate an impact on cognition among individuals with more significant baseline levels of cognitive impairment. Preliminary results of the adjunctive trial for adults with schizophrenia who are partial responders to other antipsychotics were not statistically significant, but ongoing studies are exploring XT for dementia-related psychosis and pediatric indications."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Movement Disorders • Pediatrics • Psychiatry • Schizophrenia • DRD2

Clinical Effects of Recently Developed Antipsychotic Drugs in Schizophrenia. (PubMed, Cent Nerv Syst Agents Med Chem) - "Promising new antipsychotic drugs include cariprazine, brexpiprazole, lumateperone, ulotaront, and xanomeline combined with trospium. Phase 3 clinical studies have shown therapeutic effects superior to those achieved with second-generation antipsychotic drugs."

Journal • CNS Disorders • Psychiatry • Schizophrenia

DISCOVERY OF IGS01, A HIGHLY SELECTIVE MUSCARINIC ACETYLCHOLINE M4 RECEPTOR POSITIVE ALLOSTERIC MODULATOR (PAM) WITH A FAVORABLE DDI RISK PROFILE FOR PSYCHOSIS (ADPD 2026) - "The selective M4 PAM emraclidine demonstrated efficacy signals in Phase 1b, but missed endpoints in two Phase 2 studies, triggering multifaceted re-thinking on better ways to harness the M4-PAM MoA...In preclinical studies, IGS01 dosedependently reversed amphetamine induced hyperlocomotion and rescued amphetamine induced sensory gating deficits in rats... IGS01 has completed GLP toxicology studies en route to an IND application. It represents a new opportunity to harness M4 activation for the treatment of psychosis in geriatric patients that demands a favorable DDI risk profile."

CNS Disorders • Geriatric Disorders • Psychiatry • CYP3A4

A Study to Assess the Adverse Events and How Oral Emraclidine Moves Through the Body of Healthy Elderly Adult Participants (clinicaltrials.gov) - P1 | N=32 | Recruiting | Sponsor: AbbVie

Adverse events • New P1 trial

Receptor subtype specific modulation of muscarinic pathways: a mechanistically distinct therapeutic strategy for schizophrenia (ECNP 2025) - "VU0152100, a selective M4 PAM, exhibits antipsychotic-like effects in rodent models, reducing amphetamine induced locomotor hyperactivity and reversing behavioral deficits...NBI-1117568, a selective M4 orthosteric agonist in Phase 2 trials for schizophrenia, attenuates dopaminergic hyperactivity and restores sensorimotor gating without sedative or motor impairments. Blarcamesine has shown neuroprotective and cognitive enhancing effects in multiple models... Targeting mAChRs, particularly M1 and M4, provides a receptor subtype specific strategy to address unmet needs in schizophrenia. KarXT and emraclidine represent leading agents in clinical development. Emerging modulators such as BQCA, AC-42, and the VU series highlight the diversity of mechanisms and potential for precision treatment tailored to receptor expression profiles and schizophrenia endophenotypes [3]."

CNS Disorders • Psychiatry • Schizophrenia

Enhancement of cognition in preclinical models by novel investigational M1/M4 agonist, ML-007 (ECNP 2025) - "Dose response testing of ML-007 revealed robust antipsychotic activity across a range of classical preclinical models of psychosis including amphetamine-induced hyperlocomotion, PCP-induced hyperlocomotion, and conditioned avoidance response (p<0.0001, 1-way ANOVA followed by Dunnett's multiple comparisons test, n=16 per group). Further consistent with the hypothesis that cognitive improvement is driven by strong activation of M1, the M4-selective positive allosteric modulator, emraclidine, was found to be inactive in the Y-maze memory assay. Together these studies suggest that M1 activity is critical for cognition in rodent models and that ML-007, due to its higher intrinsic activity at M1 receptors, could be ideally suited to address cognitive symptoms, in addition to treatment of psychosis in AD and schizophrenia."

Preclinical • Alzheimer's Disease • CNS Disorders • Psychiatry • Schizophrenia

New Developments in the Treatments of Psychosis (WFSBP 2025) - "Objective: Despite the discovery of chlorpromazine over 70 years ago and substantial pharmacologic advances, postsynaptic dopamine blockade has remained the sole mechanism of action of approved drugs for schizophrenia... Newly/recently approved agents include vesicular monoamine transporter-2 inhibitors valbenazine and deutetrabenazine for tardive dyskinesia and, possibly, residual positive symptoms; olanzapine/samidorphan combination, lumateperone, new formulations, including subcutaneous injections, and ultra-long-acting injectable antipsychotics. Agents in development that have at least one positive phase 1B, 2 or 3 trial include the trace amine-associated receptor-1 (TAAR1) ulotaront, M1/M4 muscarinic agonist xanomeline plus peripherally restricted anticholinergic trospium, the M4 muscarinic positive allosteric modulator emraclidine, as well as multiple other muscarinic receptor modulators for total psychopathology, methylated amisulpride (LB-102), and evenamide, a..."

CNS Disorders • Movement Disorders • Psychiatry • Schizophrenia

A Study to Assess Adverse Events, Change in Disease Activity, and How Oral Emraclidine Moves Through the Body in Adult Participants With Schizophrenia (clinicaltrials.gov) - P2 | N=258 | Recruiting | Sponsor: AbbVie

Adverse events • New P2 trial • CNS Disorders • Psychiatry • Schizophrenia

A Study to Evaluate Safety and Tolerability of CVL-231 (Emraclidine) in Adult Participants With Schizophrenia (clinicaltrials.gov) - P2 | N=700 | Completed | Sponsor: AbbVie | Active, not recruiting ➔ Completed | Trial completion date: Feb 2026 ➔ Jun 2025 | Trial primary completion date: Feb 2026 ➔ Jun 2025

Trial completion • Trial completion date • Trial primary completion date • CNS Disorders • Psychiatry • Schizophrenia

CVL-231-1006: A Multiple Dose Trial of Emraclidine in Elderly Participants and in Participants With Dementia Due to Alzheimer's Disease (clinicaltrials.gov) - P1 | N=17 | Completed | Sponsor: AbbVie | Active, not recruiting ➔ Completed

Trial completion • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

CVL-231-1006: A Multiple Dose Trial of Emraclidine in Elderly Participants and in Participants With Dementia Due to Alzheimer's Disease (clinicaltrials.gov) - P1 | N=17 | Active, not recruiting | Sponsor: AbbVie | Recruiting ➔ Active, not recruiting | N=78 ➔ 17

Enrollment change • Enrollment closed • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

A Study to Evaluate the Effect of Hepatic Impairment on the Pharmacokinetics of Emraclidine (clinicaltrials.gov) - P1 | N=38 | Completed | Sponsor: Cerevel Therapeutics, LLC | Recruiting ➔ Completed

Trial completion • Hepatology

A Study to Evaluate Pharmacokinetic and Safety Trial of Emraclidine in Participants With Renal Impairment Compared With Participants With Normal Renal Function (clinicaltrials.gov) - P1 | N=58 | Completed | Sponsor: Cerevel Therapeutics, LLC | Active, not recruiting ➔ Completed | Trial completion date: Jun 2025 ➔ Dec 2024

Trial completion • Trial completion date • Renal Disease

Novel pharmaceutical treatment approaches for schizophrenia: a systematic literature review. (PubMed, Eur J Clin Pharmacol) - "Novel treatments for schizophrenia show promise in managing both positive and negative symptoms, with generally favorable safety profiles. Future studies should focus on large-scale, long-term trials to refine their efficacy, safety, and clinical applicability."

Journal • Review • CNS Disorders • Constipation • Gastroenterology • Gastrointestinal Disorder • Mental Retardation • Psychiatry • Schizophrenia

The mechanism of action of clozapine. (PubMed, J Psychopharmacol) - "Here we describe how the unique pharmacology of clozapine in the peripheral nervous system held clues for solving the puzzle of clozapine in the central nervous system. Clozapine appears to have been the prototype for a new class of antipsychotics, now entering clinical psychiatry, which activates muscarinic acetylcholine receptors."

Journal • CNS Disorders • Psychiatry • Schizophrenia

A Study to Evaluate Safety and Tolerability of CVL-231 (Emraclidine) in Adult Participants With Schizophrenia (clinicaltrials.gov) - P2 | N=850 | Active, not recruiting | Sponsor: Cerevel Therapeutics, LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Psychiatry • Schizophrenia

A Study to Evaluate Pharmacokinetic and Safety Trial of Emraclidine in Participants With Renal Impairment Compared With Participants With Normal Renal Function (clinicaltrials.gov) - P1 | N=60 | Active, not recruiting | Sponsor: Cerevel Therapeutics, LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Renal Disease

A Trial of 15 and 30 mg Doses of CVL-231 (Emraclidine) in Participants With Schizophrenia (clinicaltrials.gov) - P2 | N=391 | Completed | Sponsor: Cerevel Therapeutics, LLC | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Psychiatry • Schizophrenia

A Trial of 10 and 30 mg Doses of CVL-231 (Emraclidine) in Participants With Schizophrenia (clinicaltrials.gov) - P2 | N=385 | Completed | Sponsor: Cerevel Therapeutics, LLC | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ Aug 2024

Trial completion • Trial completion date • CNS Disorders • Psychiatry • Schizophrenia

A Trial of 10 and 30 mg Doses of CVL-231 (Emraclidine) in Participants With Schizophrenia (clinicaltrials.gov) - P2 | N=372 | Active, not recruiting | Sponsor: Cerevel Therapeutics, LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Psychiatry • Schizophrenia

A Trial of 15 and 30 mg Doses of CVL-231 (Emraclidine) in Participants With Schizophrenia (clinicaltrials.gov) - P2 | N=372 | Active, not recruiting | Sponsor: Cerevel Therapeutics, LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Psychiatry • Schizophrenia

AbbVie Completes Acquisition of Cerevel Therapeutics (PRNewswire) - "AbbVie...today announced that it has completed its acquisition of Cerevel Therapeutics...With the completion of the acquisition, Cerevel is now part of AbbVie...There are multiple programs in Cerevel's pipeline across several neurological and psychiatric conditions such as schizophrenia, Parkinson's disease and mood disorders, where there continues to be significant unmet need for patients."

M&A • CNS Disorders • Parkinson's Disease

A Trial to Evaluate the Effect of Esomeprazole on the Pharmacokinetics of Emraclidine in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=20 | Completed | Sponsor: Cerevel Therapeutics, LLC | Not yet recruiting ➔ Completed

Trial completion

Design and Synthesis of Clinical Candidate PF-06852231 (CVL-231): A Brain Penetrant, Selective, Positive Allosteric Modulator of the M4 Muscarinic Acetylcholine Receptor. (PubMed, J Med Chem) - "A major challenge in capitalizing on this allosteric site to date has been achieving a balance of suitable potency and brain penetration. Herein, we describe the design of a brain penetrant series of M4 selective positive allosteric modulators (PAMs), ultimately culminating in the identification of 21 (PF-06852231, now CVL-231/emraclidine), which is under active clinical development as a novel mechanism and approach for the treatment of schizophrenia."

Journal • CNS Disorders • Psychiatry • Schizophrenia

Reflections on the Future of Psychiatry Drug Discovery (WFSBP 2024) - "Objective: To review challenges that have traditionally plagued the development of medications for psychiatry indications and to highlight two areas of exciting recent developments: 1) ketamine and psychedelics and 2) antipsychotics that may work via targets other than the dopamine D2 receptor. This presentation will conclude by raising remaining challenges as we grapple with the complexity of the neurobiology of psychiatric disorders, particularly the opportunities and challenges that emerge as we try to translate the genetics of psychiatric disorders to novel therapeutics."

CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia