Emraclidine for Schizophrenia Fails to Meet Primary Endpoints in Phase 2 EMPOWER Trials

MasterSergeant/AdobeStock

AbbVie announced that 2 of its phase 2 EMPOWER trials investigating emraclidine as a once-daily, oral monotherapy treatment for adults with schizophrenia experiencing acute psychotic symptoms, did not meet their primary endpoint of a statistically significant improvement in the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score compared with the placebo group at week 6.¹

"While we are disappointed with the results, we are continuing to analyze the data to determine next steps," said Roopal Thakkar, MD, executive vice president of research and development and chief scientific officer at AbbVie. "We would like to extend our gratitude to the study participants and their loved ones as well as to our network of clinical investigative sites for their participation in these trials. We are confident that our innovative pipeline will continue to bring meaningful therapies to patients, and we remain committed to finding better treatments for people living with psychiatric and neurological disorders."

According to new data from EMPOWER-1, those receiving placebo (n= 127), who had a baseline PANSS of 98.3 (8.16), saw an LS Mean (95% CI) change of -13.5 (-17.0, -10.0). Those receiving emraclidine 10 mg QD (n = 125), who had a baseline of 97.6 (7.65), saw an LS Mean change of -14.7 (-18.1, -11.2). Those receiving emraclidine 30 mg QD (n = 127), who had a baseline of 97.9 (7.89), saw an LS Mean change of -16.5 (-20.0, -13.1).

"Although understandably AbbVie is disappointed about the emraclidine negative phase 2 studies, the results are important for our continued understanding of how the muscarinic cholinergic receptors (mAChRs) interface with the symptoms of schizophrenia. There are several receptor binding differences between emraclidine and xanomeline, the active molecule in Cobenfy that was just FDA approved in September to treat individuals with schizophrenia. Specifically, emraclidine is a positive allosteric modulator of only one of the 5 mAChRs, M4. Xanomeline is an agonist at 2 specific mAChRs, M1 and M4. The emraclidine results suggest that M1 agonism contributes to the improvement in symptoms of schizophrenia, but this remains to be established," said John J. Miller, MD, Editor in Chief of Psychiatric Times.

In EMPOWER-2, those receiving placebo (n = 128), who had a baseline PANSS of 97.4 (8.22), saw an LS Mean change of -16.1 (-19.4, -12.8). Those receiving emraclidine 15 mg QD (n = 122), who had a basline of 98.0 (8.49), saw an LS Mean change of -18.5 (-22.0, -15.0). Those receiving emraclidine 30 mg QD (n = 123), who had a baseline of 97.2 (7.75), saw an LS Mean change of -14.2 (-17.6, -10.8).

In the EMPOWER trials, emraclidine was well-tolerated. Its safety profile is comparable to that observed in the phase 1b trial. The most commonly reported adverse events in EMPOWER-1 and EMPOWER-2, respectively, were headache (9.4% and 10.8% in placebo, 14.1% in EMPOWER-1 10mg and 14.6% in EMPOWER-2 15 mg, and 13.2% and 13.0% in 30 mg), dry mouth (2.3% and 0.8% in placebo, 3.9% in EMPOWER-1 10 mg and 0.8% in EMPOWER-2 15 mg, and 9.3% and 5.3% in 30mg), and dyspepsia (3.1% and 1.5% in placebo, 3.9% in EMPOWER-1 10 mg, and 3.1% in EMPOWER-2 15 mg, and 7.8% and 2.3% in 30 mg).

Emraclidine is a potential novel M4-selective positive allosteric modulator in development for schizophrenia and Alzheimer disease psychosis as a once-daily medication without the need for titration.²

References

1. AbbVie provides update on phase 2 results for emraclidine in schizophrenia. Abbvie. News release. November 11, 2024. https://news.abbvie.com/2024-11-11-AbbVie-Provides-Update-on-Phase-2-Results-for-Emraclidine-in-Schizophrenia

2. Miller JJ. Schizophrenia pharmacology: version 2.0. Psychiatric Times. 2024;41(11).