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

This work was sponsored by Cerevel Therapeutics 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, emraclidine may reduce excess dopamine signaling in the striatum, potentially leading to a reduction in psychotic symptoms. The phase 2 EMPOWER program will fully evaluate the efficacy, safety, tolerability, and dose-range of once-daily (QD) emraclidine in schizophrenia. EMPOWER-1 and EMPOWER-2 are two adequately powered, multicenter, randomized, double-blind, placebo-controlled, parallel group, 6-week inpatient studies of emraclidine monotherapy (10mg, 15mg, and 30mg QD). The trials are enrolling adult participants with schizophrenia who are experiencing an acute exacerbation of psychosis with 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. De novo participants and those who complete EMPOWER-1 or EMPOWER-2 are eligible to participate in EMPOWER-3, a 52-week open label extension trial evaluating the long-term safety and tolerability of emraclidine in adults with stable schizophrenia. 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 safety and tolerability evaluation of emraclidine in adults with schizophrenia. The EMPOWER program aims to establish the efficacy, safety, tolerability, and appropriate dose-range of emraclidine in the treatment of schizophrenia.