CVL-231 · program

Emraclidine (CVL-231) for Schizophrenia

Phase 2ActiveAbbVie Inc. (ABBV)

Schizophrenia program for emraclidine (CVL-231), originally a once-daily oral MONOTHERAPY for adults with schizophrenia experiencing an acute exacerbation of psychosis. After a positive Phase 1b signal (NCT04787302; 30 mg QD LS-mean PANSS improvement of -12.7 vs placebo at Week 6, p=0.023), the Phase 2 EMPOWER program — EMPOWER-1 (NCT05227690; 10 & 30 mg) and EMPOWER-2 (NCT05227703; 15 & 30 mg), with an open-label extension EMPOWER-3 (NCT05443724) — BOTH MISSED the primary endpoint (change from baseline in PANSS total score at Week 6 vs placebo), reported 11 Nov 2024. AbbVie recorded a ~$3.5B impairment (disclosed Jan 2025). As of mid-2026 the company has de-prioritized schizophrenia monotherapy ('a more heavily risk-adjusted opportunity') and is instead pursuing emraclidine as an ADJUNCT to atypical antipsychotics in schizophrenia (planned Phase 2), alongside monotherapy programs in Alzheimer's and Parkinson's disease psychosis. Phase/status reflect the continued (adjunctive) Phase 2 pursuit in schizophrenia while capturing the failed monotherapy program.

Data current as of

Development timeline

Phase 2Jun 2022 – Nov 2024
  1. missedEMPOWER-1 and EMPOWER-2 both missed the primary PANSS endpoint at Week 6; emraclidine schizophrenia monotherapy fails Phase 2.↗
  2. AbbVie completed its ~$8.7B acquisition of Cerevel Therapeutics; emraclidine became an AbbVie asset while the EMPOWER Phase 2 trials were ongoing.↗
  3. Phase 2 EMPOWER monotherapy program initiated in acute schizophrenia: EMPOWER-1 (NCT05227690, started 30 Jun 2022) and EMPOWER-2 (NCT05227703, started 5 Jul 2022), plus open-label extension EMPOWER-3 (NCT05443724).
Phase 1Dec 2022
  1. Two-part Phase 1b (NCT04787302) published in The Lancet: emraclidine 30 mg QD and 20 mg BID each produced a statistically significant, clinically meaningful PANSS total improvement vs placebo at Week 6 in acute schizophrenia, with no EPS/weight signal — the proof-of-concept that drove the Phase 2 program.↗

Readouts

  • 2024-11-11ReportedTopline datamissedNCT05227690

    EMPOWER-1 and EMPOWER-2 both missed the primary PANSS endpoint at Week 6; emraclidine schizophrenia monotherapy fails Phase 2. ↗

Clinical trials in Schizophrenia

NCT05227703CVL-231-2002Phase 2Completedn=391

EMPOWER-2: A Phase 2, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Two Fixed Doses (15 mg and 30 mg QD) of CVL-231 (Emraclidine) in Participants With Schizophrenia Experiencing an Acute Exacerbation of Psychosis

Started Jul 2022· Primary completion Aug 2024· 📍 26 sites across 3 countries (United States, Bulgaria, Hungary)

missedprimaryPANSS total score change from baseline at Week 6 (30 mg QD vs placebo) — Emraclidine 30 mg -14.2 (95% CI -17.6, -10.8) vs placebo -16.1 (95% CI -19.4, -12.8) (0.3914)

30 mg arm performed numerically worse than placebo; did not meet the primary endpoint at Week 6. Reported 11 Nov 2024. LS-mean changes/CIs from the AbbVie PR; p-value from CT.gov results.

missedprimaryPANSS total score change from baseline at Week 6 (15 mg QD vs placebo) — Emraclidine 15 mg -18.5 (95% CI -22.0, -15.0) vs placebo -16.1 (95% CI -19.4, -12.8) (0.2925)

15 mg arm did not separate from placebo on the primary PANSS endpoint at Week 6. Reported 11 Nov 2024. LS-mean changes/CIs from the AbbVie PR; p-value from CT.gov results.

NCT05227690CVL-231-2001Phase 2Completedn=385

EMPOWER-1: A Phase 2, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Two Fixed Doses (10 mg and 30 mg QD) of CVL-231 (Emraclidine) in Participants With Schizophrenia Experiencing an Acute Exacerbation of Psychosis

Started Jun 2022· Primary completion Aug 2024· 📍 25 sites across 2 countries (United States, Bulgaria)

missedprimaryPANSS total score change from baseline at Week 6 (30 mg QD vs placebo) — Emraclidine 30 mg -16.5 (95% CI -20.0, -13.1) vs placebo -13.5 (95% CI -17.0, -10.0) (0.1765)

30 mg arm numerically favored emraclidine but did not reach statistical significance vs placebo at Week 6. Reported 11 Nov 2024. LS-mean changes/CIs from the AbbVie PR; p-value from CT.gov results.

missedprimaryPANSS total score change from baseline at Week 6 (10 mg QD vs placebo) — Emraclidine 10 mg -14.7 (95% CI -18.1, -11.2) vs placebo -13.5 (95% CI -17.0, -10.0) (0.6007)

10 mg arm did not separate from placebo on the primary PANSS endpoint at Week 6. Reported 11 Nov 2024. LS-mean changes/CIs from the AbbVie PR; p-value from CT.gov results.

NCT04787302CVL-231-1003Phase 1Completedn=81

A Two-Part Phase 1b Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of CVL-231 in Participants With Schizophrenia

Started Feb 2021· Primary completion Aug 2021· 📍 2 sites across 2 countries (United States, Belgium)

metprimaryPANSS total score change from baseline at Week 6 (30 mg QD vs placebo) — LS-mean difference -12.7 (Cohen's d=0.68) (0.023)

Emraclidine 30 mg QD (n=27) produced a statistically significant, clinically meaningful PANSS total improvement vs placebo at Week 6; 20 mg BID (n=27) gave a -11.1 improvement (d=0.59, p=0.047). No EPS or clinically meaningful weight change. Proof-of-concept for Phase 2.

Formulations

FormulationRouteRegimenPharmacokinetics
Emraclidine oral (once-daily)
10, 15, or 30 mg once daily (Phase 2 EMPOWER); developed as once-daily, no titration
OralOnce daily—

Mechanism of action (compound-wide)

Selective positive allosteric modulator (PAM) of the M4 muscarinic acetylcholine receptor (CHRM4). Emraclidine potentiates acetylcholine-driven M4 signaling with reported selectivity of >100-fold over the related M2 subtype, and does not appreciably engage dopamine D2/D3 receptors. M4 is enriched in the striatum, where its activation is thought to indirectly reduce excess dopaminergic tone, providing an antipsychotic mechanism distinct from D2 blockade and predicting a lower extrapyramidal/metabolic burden. No clean single binding-affinity constant at human M4 is cleanly citable (allosteric modulator; literature reports relative selectivity, not a binding Ki/IC50).

TargetActionAffinity
M4primaryCHRM4PAM—ⓘ

← Full CVL-231 compound page (identity, identifiers, all indications)

Sources

  1. AbbVie completes $8.7 billion acquisition of Cerevel Therapeutics (closed 1 Aug 2024) — BioPharm International
  2. AbbVie Provides Update on Phase 2 Results for Emraclidine in Schizophrenia — once-daily oral, 10/15/30 mg QD EMPOWER doses — AbbVie / IR
  3. EMPOWER-1 Phase 2 of CVL-231 (emraclidine) 10/30 mg in schizophrenia (NCT05227690) — ClinicalTrials.gov
  4. EMPOWER-2 Phase 2 of CVL-231 (emraclidine) 15/30 mg in schizophrenia (NCT05227703) — ClinicalTrials.gov
  5. Emraclidine Phase 1b Lancet publication — once-daily development, no titration — Cerevel Therapeutics / AbbVie news
  6. Krystal et al. Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial — The Lancet
  7. M4 receptor (CHRM4), GtoPdb object 16 — IUPHAR/BPS Guide to Pharmacology
  8. Phase 1b trial of CVL-231 (emraclidine) in schizophrenia (NCT04787302) — ClinicalTrials.gov