AbbVie's emraclidine, an M4-selective positive allosteric modulator (PAM), failed to achieve its primary endpoint in two Phase 2 clinical trials (EMPOWER-1 and EMPOWER-2) for the treatment of schizophrenia. The trials assessed the efficacy of emraclidine as a once-daily, oral monotherapy in adult patients experiencing an acute exacerbation of psychotic symptoms. The primary endpoint was a statistically significant reduction in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo at week 6; however, neither trial met this goal.
Trial Details and Results
The EMPOWER trials were designed as placebo-controlled Phase 2 studies to evaluate multiple dosing options of emraclidine. EMPOWER-1 investigated 10mg and 30mg doses, while EMPOWER-2 assessed 15mg and 30mg doses. Although the primary endpoint was not met, detailed data from the trials provide insights into the drug's effects and tolerability. The baseline PANSS total scores were approximately 97-98 across all treatment and placebo groups, indicating a similar level of disease severity at the start of the trials.
| | EMPOWER-1 | | | EMPOWER-2 | |
|:----------------------|:--------------|:----------------------|:--------------|:--------------|:----------------------|
| | Placebo | Emraclidine 10mg | Emraclidine 30mg | Placebo | Emraclidine 15mg |
| N | 127 | 125 | 127 | 128 | 122 |
| Baseline (SD) | 98.3 (8.16) | 97.6 (7.65) | 97.9 (7.89) | 97.4 (8.22) | 98.0 (8.49) |
| LS Mean (95% CI) | -13.5 | -14.7 | -16.5 | -16.1 | -18.5 |
| | (-17.0, -10.0) | (-18.1, -11.2) | (-20.0, -13.1) | (-19.4, -12.8) | (-22.0, -15.0) |
Safety and Tolerability
Emraclidine demonstrated a favorable safety profile, consistent with observations from the Phase 1b trial. The most frequently reported adverse events included headache, dry mouth, and dyspepsia. Specifically, in EMPOWER-1, headache was reported in 9.4% of placebo patients, 14.1% of the 10mg emraclidine group, and 13.2% of the 30mg group. In EMPOWER-2, headache occurred in 10.8% of placebo patients, 14.6% of the 15mg emraclidine group, and 13.0% of the 30mg group. Dry mouth and dyspepsia also showed a dose-related increase in incidence compared to placebo.
Mechanism of Action and Potential
Emraclidine is designed as a highly selective PAM of centrally located M4 muscarinic acetylcholine receptors. The rationale behind this mechanism is to potentially reduce excess dopamine signaling in the striatum without directly blocking dopamine type 2 (D2) receptors. It is hypothesized that by selectively targeting M4 receptors, emraclidine could alleviate psychotic symptoms while minimizing the side effects often associated with traditional antipsychotics that affect dopamine, serotonin, and histamine receptors.
Schizophrenia Context
Schizophrenia is a chronic and severe mental disorder affecting approximately 24 million people worldwide. It is characterized by symptoms such as delusions, hallucinations, disorganized speech, and cognitive impairment. Current treatments often have limited efficacy and are associated with significant side effects, leading to poor medication adherence and high relapse rates. Only 20% of patients achieve favorable treatment outcomes, with a medication compliance rate of about 60% and a discontinuation rate of 74% within 18 months. Patients who discontinue medication face relapse rates of 77% at one year and 90% at two years. The development of new treatments with improved efficacy and tolerability remains a critical unmet need in schizophrenia management.
AbbVie's Neuroscience Pipeline
Despite the setback with emraclidine, AbbVie remains committed to neuroscience research. The company's neuroscience portfolio includes treatments for neurological conditions such as migraine, movement disorders, and psychiatric disorders. AbbVie's acquisition of Cerevel Therapeutics has further expanded its pipeline with multiple clinical-stage and preclinical candidates, complementing its existing offerings.
