emraclidine (CVL-231) / AbbVie - LARVOL DELTA

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

A Study to Assess Mass Balance, Pharmacokinetics, Metabolism, and Excretion of Emraclidine in Healthy Adult Male Participants (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: Cerevel Therapeutics, LLC | Recruiting ➔ Completed

Trial completion

A Multiple Dose Trial of Emraclidine in Elderly Participants and in Participants With Dementia Due to Alzheimer's Disease (clinicaltrials.gov) - P1 | N=78 | Recruiting | Sponsor: Cerevel Therapeutics, LLC | N=50 ➔ 78 | Trial completion date: Aug 2024 ➔ Apr 2025 | Trial primary completion date: Aug 2024 ➔ Mar 2025

Enrollment change • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Understanding the therapeutic action of antipsychotics: from molecular to cellular targets with focus on the islands of Calleja. (PubMed, Int J Neuropsychopharmacol) - "Here we discuss results suggesting a main role of the islands of Calleja, still poorly studied GABAergic granule cell clusters in the ventral striatum, as cellular targets of several innovative atypical antipsychotics (clozapine, cariprazine and xanomeline/emraclidine) effective in treating also negative symptoms of schizophrenia. We will emphasize the potential role of dopamine D3 and M4 muscarinic acetylcholine receptor expressed at highest level by the islands of Calleja, as well as their involvement in schizophrenia-associated neurocircuitries. Finally, we will discuss the implications of new data showing ongoing adult neurogenesis of the islands of Calleja, as a very promising antipsychotic target linking long-life neurodevelopment and dopaminergic dysfunction in the striatum."

Journal • CNS Disorders • Psychiatry • Schizophrenia • DRD2

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

New P1 trial

A Trial to Evaluate the Effects of Itraconazole and Carbamazepine on the Pharmacokinetics of Emraclidine and of Emraclidine on the Pharmacokinetics of Metformin in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=60 | Completed | Sponsor: Cerevel Therapeutics, LLC | Recruiting ➔ Completed

Trial completion

Dopaminergic Impairment in Schizophrenia: From Mechanisms to New Therapeutic Targets (SIRS 2024) - "He will present data about the occurrence of this process in rodents and primates and the ICj as preferential target for antipsychotics effective also against negative symptoms of SCZ (clozapine, cariprazine, xanomeline and emraclidine). Meeting Attendance I agree to be available for the entirety of the Congress. SIRS Role Limit Policy I have read and understand this policy."

CNS Disorders • Schizophrenia • DRD2

Postnatal Neurogenesis in the Striatum: Linking Neurodevelopmental to Dopaminergic Dysfunction in Schizophrenia With Focus on the Islands of Calleja (SIRS 2024) - "Moreover, they are preferentially targeted by efficient antipsychotics like clozapine, cariprazine and xanomelin/emraclidine. ECS strongly stimulates neurogenesis in the adult striatum. The implications for striatal neuroplasticity and the dopamine system, as well as for schizophrenia are discussed."

Neurodevelopmental • CNS Disorders • Schizophrenia

Muscarinic Receptor Agonists and Positive Allosteric Modulators in Animal Models of Schizophrenia: A Systematic Review and Meta-Analysis (SIRS 2024) - "Additionally, numerous muscarinic medications with different mechanisms of action (e.g., emraclidine, an M4 positive allosteric modulator) are undergoing clinical or preclinical development... The systematic review is ongoing, and we present our preliminary data at the conference. We expect that this review builds a body of evidence on the effects of muscarinic agonists in animal models of psychosis-like paradigm, which aims to provide insights into the search for innovative molecular targets and the development of novel antipsychotics."

Preclinical • Retrospective data • Review • CNS Disorders • Schizophrenia • DRD2

EMPOWERing the Next Generation: A Phase 2 Program to Evaluate Emraclidine, a Selective M4 Positive Allosteric Modulator (PAM), for the Treatment of Schizophrenia (SIRS 2024) - "Detailed study designs for the EMPOWER program will be presented. The primary outcome measure for EMPOWER 1 and 2 is change from baseline in PANSS total score at Week 6. Other outcome measures include change from baseline in CGI-S score at Week 6."

P2 data • CNS Disorders • Schizophrenia

Evaluation of M4 Muscarinic Receptor Occupancy by Emraclidine Using [11C]MK-6884 PET in Healthy Volunteers (SIRS 2024) - P1 | "Emraclidine showed favorable brain penetration and direct target engagement in preclinical rodent studies and exhibited robust in vivo antipsychotic-like activity in animal models (e.g., reversal of amphetamine-stimulated locomotion and prepulse inhibition). A total of 9 participants received a single dose of emraclidine 30 mg, 15 mg, or 5 mg (n=3 for each dose). Emraclidine PK exposure parameters decreased with decreasing emraclidine dose (median [range] average plasma concentration during the scan duration: 30-mg dose, 634 [425-888] ng/mL; 15 mg dose, 347 [186-374] ng/mL; 5 mg dose, 143 [128-167] mL). Mean (SD) M4 RO in the striatum was 52.7% (1.31%), 41.8% (11.9%), and 20.1% (7.30%) after a single 30-, 15-, or 5-mg dose of emraclidine, respectively."

Clinical • CNS Disorders • Schizophrenia