EMPOWERing the Next-Generation: A Phase 2 Program to Evaluate Emraclidine, a Selective M4 Positive Allosteric Modulator (PAM), for the Treatment of Schizophrenia

Background Emraclidine is a novel, highly selective positive allosteric modulator of M4 muscarinic acetylcholine receptors currently in development for the treatment of schizophrenia and Alzheimer’s disease psychosis. By selectively activating M4 receptors, emraclidine may reduce excess dopamine signaling in the striatum, potentially leading to a reduction in psychotic symptoms. Unlike current antipsychotics, emraclidine does not interfere with signaling at dopamine, serotonin, or histamine receptors, which can lead to adverse events. A previous phase 1b study supports further investigation of emraclidine. The phase 2 EMPOWER program will fully evaluate the efficacy, safety, tolerability, and dose-range of once-daily (QD) emraclidine in schizophrenia. Methods EMPOWER-1 and EMPOWER-2 are two adequately powered, multicenter, randomized, double-blind, placebo-controlled, parallel group, 6-week inpatient studies of emraclidine monotherapy (10 mg QD, 15 mg QD, 30 mg QD). The trials are enrolling adult participants with schizophrenia who are experiencing an acute exacerbation of psychosis. Eligible participants will have a Positive and Negative Syndrome Scale (PANSS) Total Score between ≥85 and ≤120 and a Clinical Global Impression – Severity (CGI-S) score ≥4 at baseline. Both de novo participants and those who complete EMPOWER-1 or EMPOWER-2 will be eligible to participate in EMPOWER-3, a 52-week open label extension trial to evaluate the long-term safety and tolerability of emraclidine in adult participants with stable schizophrenia. Results Detailed study designs for the EMPOWER program will be presented. 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. Data from EMPOWER-3 will contribute to the overall evaluation of safety and tolerability of emraclidine in adult participants with schizophrenia. Conclusions The development of emraclidine is promising, as it selectively activates M4, a novel target that has been implicated in reducing psychotic symptoms while potentially avoiding many of the side effects currently associated with antipsychotics. The EMPOWER program aims to establish the efficacy, safety, tolerability, and appropriate dose-range of emraclidine in the treatment of schizophrenia. Funding Cerevel Therapeutics