AbbVie's Phase 2 EMPOWER trials, EMPOWER-1 and EMPOWER-2, evaluating emraclidine as a once-daily, oral monotherapy for adults with schizophrenia experiencing acute psychotic symptoms, did not meet their primary endpoint. The trials failed to demonstrate a statistically significant reduction in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo at week 6.
The EMPOWER program included two Phase 2 trials designed to assess various dosing options to fully explore emraclidine's therapeutic dose range. EMPOWER-1 (NCT05227690) and EMPOWER-2 (NCT05227703) were placebo-controlled studies in patients experiencing an acute exacerbation of schizophrenia.
Trial Results and Safety
In EMPOWER-1, the least squares (LS) mean change from baseline in PANSS total score was -13.5 (95% CI: -17.0, -10.0) for placebo (n=127), -14.7 (95% CI: -18.1, -11.2) for emraclidine 10mg (n=125), and -16.5 (95% CI: -20.0, -13.1) for emraclidine 30mg (n=127). In EMPOWER-2, the LS mean change from baseline was -16.1 (95% CI: -19.4, -12.8) for placebo (n=128), -18.5 (95% CI: -22.0, -15.0) for emraclidine 15mg (n=122), and -14.2 (95% CI: -17.6, -10.8) for emraclidine 30mg (n=123).
Emraclidine was generally well-tolerated, with a safety profile consistent with the Phase 1b trial. The most common adverse events reported in EMPOWER-1 and EMPOWER-2 were headache, dry mouth, and dyspepsia. Specifically, headache was reported in 9.4% and 10.8% of placebo patients, 14.1% and 14.6% of emraclidine 10mg and 15mg patients respectively, and 13.2% and 13.0% of 30mg patients. Dry mouth occurred in 2.3% and 0.8% of placebo patients, 3.9% and 0.8% of emraclidine 10mg and 15mg patients, and 9.3% and 5.3% of 30mg patients. Dyspepsia was reported in 3.1% and 1.5% of placebo patients, 3.9% and 3.1% of emraclidine 10mg and 15mg patients, and 7.8% and 2.3% of 30mg patients.
Emraclidine's Mechanism of Action
Emraclidine is a potential novel M4-selective positive allosteric modulator (PAM) being developed for schizophrenia and Alzheimer's disease psychosis. It is designed to be administered once daily without the need for titration. As a highly selective PAM of centrally located M4 muscarinic acetylcholine receptors, emraclidine aims to reduce excess dopamine signaling in the striatum without directly blocking dopamine type 2 (D2) receptors. This selective targeting of M4 receptors is hypothesized to reduce psychotic symptoms while minimizing the side effects associated with current antipsychotics that interfere with dopamine, serotonin, and/or histamine receptors.
Future Directions
"While we are disappointed with the results, we are continuing to analyze the data to determine next steps," said Roopal Thakkar, M.D., executive vice president, research and development, chief scientific officer, AbbVie. AbbVie remains committed to its neuroscience portfolio, which includes treatments for migraine, movement disorders, and psychiatric disorders, and a pipeline of transformative therapies acquired through the Cerevel acquisition.
