Emraclidine as a Novel Positive Allosteric Modulator Targeting M4 Muscarinic Receptors: Results From a Phase 1b Trial in Patients With Schizophrenia

Abstract: Background: Emraclidine is a novel, highly selective, M4 muscarinic receptor positive allosteric modulator in development for treating schizophrenia. Here, we describe safety, tolerability, and pharmacodynamic results from Part B of a two-part, phase 1b trial (NCT04136873). Methods: Adults with a primary diagnosis of schizophrenia experiencing acute symptom exacerbations within 2 months of screening, Positive and Negative Syndrome Scale (PANSS) score ≥80, and Clinical Global Impressions Scale (CGI-S) score ≥4 were eligible for Part B. Participants were randomized 1:1:1 to once-daily (QD) emraclidine 30 mg, twice-daily (BID) emraclidine 20 mg, or placebo for 6 weeks. Safety and tolerability were assessed. Pharmacodynamic assessments included change from baseline in the PANSS total and subscale scores, and the CGI-S score. Results: Of 81 randomized and treated participants, adverse events (AEs) were reported by 54% receiving emraclidine and 52% receiving placebo. Headache was the most commonly reported AE (placebo, 26%; all emraclidine, 28%). Modest increases in supine blood pressure and heart rate observed with emraclidine treatment initiation were not clinically meaningful vs placebo by Week 6. Weight changes and incidence of gastrointestinal AEs were comparable across groups. At Week 6, participants receiving emraclidine experienced significant reductions in PANSS total scores at both 30-mg QD (least squares mean [LSM] difference vs placebo, -12.7; nominal P=0.023) and 20-mg BID (LSM difference vs placebo, -11.1; nominal P=0.047) doses, with clinically meaningful reductions in PANSS subscales and CGI-S scores. Discussion: These data support further investigation of emraclidine as a once-daily treatment for schizophrenia without the need for titration.Short Description: In a phase 1b trial investigating emraclidine, a novel M4 muscarinic receptor positive allosteric modulator, in participants with schizophrenia, adverse events were comparable between treatment groups receiving 30 mg once daily, 20 mg twice daily, and placebo. Clinically meaningful improvements in the Positive and Negative Syndrome Scale scores and the Clinical Global Impressions Scale scores were observed in drug-treated groups compared with placebo, supporting further investigation of emraclidine for the treatment of schizophrenia.Name of Sponsoring Organization(s): Cerevel Therapeutics