AbbVie's emraclidine, a once-daily, oral, M4-selective positive allosteric modulator being investigated as a monotherapy for schizophrenia, failed to meet its primary endpoints in two Phase 2 EMPOWER trials. The trials assessed emraclidine's efficacy in reducing acute psychotic symptoms in adults with schizophrenia, measuring the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at week 6 compared to placebo.
The EMPOWER-1 and EMPOWER-2 trials did not demonstrate a statistically significant improvement in PANSS total score compared to placebo. In EMPOWER-1, the placebo group (n=127) with a baseline PANSS of 98.3 (8.16) showed an LS Mean change of -13.5 (-17.0, -10.0), while the emraclidine 10 mg QD group (n=125, baseline 97.6 (7.65)) had an LS Mean change of -14.7 (-18.1, -11.2), and the 30 mg QD group (n=127, baseline 97.9 (7.89)) had an LS Mean change of -16.5 (-20.0, -13.1). Similarly, in EMPOWER-2, the placebo group (n=128, baseline 97.4 (8.22)) showed an LS Mean change of -16.1 (-19.4, -12.8), the emraclidine 15 mg QD group (n=122, baseline 98.0 (8.49)) had an LS Mean change of -18.5 (-22.0, -15.0), and the 30 mg QD group (n=123, baseline 97.2 (7.75)) had an LS Mean change of -14.2 (-17.6, -10.8).
Safety and Tolerability
Emraclidine was reported to be well-tolerated in both EMPOWER trials, with a safety profile consistent with that observed in the Phase 1b trial. The most commonly reported adverse events included headache, dry mouth, and dyspepsia. Specifically, headache was reported in 9.4% and 10.8% of patients in the placebo groups, 14.1% in the EMPOWER-1 10mg group and 14.6% in the EMPOWER-2 15 mg group, and 13.2% and 13.0% in the 30 mg groups. Dry mouth was reported in 2.3% and 0.8% of patients in the placebo groups, 3.9% in the EMPOWER-1 10 mg group and 0.8% in the EMPOWER-2 15 mg group, and 9.3% and 5.3% in the 30mg groups. Dyspepsia was reported in 3.1% and 1.5% of patients in the placebo groups, 3.9% in the EMPOWER-1 10 mg group, and 3.1% in the EMPOWER-2 15 mg group, and 7.8% and 2.3% in the 30 mg groups.
Implications and Future Directions
"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. The company remains committed to finding better treatments for people living with psychiatric and neurological disorders.
John J. Miller, MD, Editor in Chief of Psychiatric Times, commented on the trial results, stating, "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... The emraclidine results suggest that M1 agonism contributes to the improvement in symptoms of schizophrenia, but this remains to be established."
