Small Molecule · CVL-231
Emraclidine (CVL-231)
Oral, once-daily, brain-penetrant, highly selective positive allosteric modulator (PAM) of the M4 muscarinic acetylcholine receptor (CHRM4). Designed to dampen excess striatal dopamine signaling indirectly via M4 activation, without blocking dopamine D2/D3 receptors and without titration — aiming to avoid the extrapyramidal side effects, weight gain, and metabolic burden of conventional D2 antagonists. Originated at Cerevel Therapeutics (acquired by AbbVie, closed Aug 2024) and developed for schizophrenia and Alzheimer's/Parkinson's disease psychosis. After a positive Phase 1b signal, the Phase 2 EMPOWER monotherapy program in acute schizophrenia failed (Nov 2024); AbbVie subsequently de-prioritized schizophrenia monotherapy in favor of an adjunctive schizophrenia approach and psychosis indications.
Also known as: CVL-231, PF-06852231, emraclidine, 2170722-84-4
- Modality
- Small molecule
- Chemical class
- azetidine, ketone, trifluoromethylpyridine
- Chemistry
- Achiral
- Mechanism
- M4 PAM
- Highest phase
- Phase 2
- Lead indication
- Schizophrenia
- Developer
- Cerevel Therapeutics Holdings, Inc.
- Trials
- 3 tracked · 53 sites
Mechanism of action
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).
| Target | Action | Affinity |
|---|---|---|
| M4primaryCHRM4 | PAM | —ⓘ |
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Emraclidine oral (once-daily) 10, 15, or 30 mg once daily (Phase 2 EMPOWER); developed as once-daily, no titration | Oral | Once daily | — |
Development timeline
- missedEMPOWER-1 and EMPOWER-2 both missed the primary PANSS endpoint at Week 6; emraclidine schizophrenia monotherapy fails Phase 2.↗
- AbbVie completed its ~$8.7B acquisition of Cerevel Therapeutics; emraclidine became an AbbVie asset while the EMPOWER Phase 2 trials were ongoing.↗
- 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).
- 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.↗
Emraclidine (CVL-231) for Schizophrenia
Phase 2ActiveSchizophrenia indication →
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.
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
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
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
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
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.
Identifiers
- ChEMBL CHEMBL5314557
- PubChem CID 140830653
- FDA UNII J241Y80EEO
Sources
- AbbVie completes $8.7 billion acquisition of Cerevel Therapeutics (closed 1 Aug 2024) — BioPharm International
- AbbVie Provides Update on Phase 2 Results for Emraclidine in Schizophrenia — once-daily oral, 10/15/30 mg QD EMPOWER doses — AbbVie / IR
- EMPOWER-1 Phase 2 of CVL-231 (emraclidine) 10/30 mg in schizophrenia (NCT05227690) — ClinicalTrials.gov
- EMPOWER-2 Phase 2 of CVL-231 (emraclidine) 15/30 mg in schizophrenia (NCT05227703) — ClinicalTrials.gov
- Emraclidine Phase 1b Lancet publication — once-daily development, no titration — Cerevel Therapeutics / AbbVie news
- 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
- M4 receptor (CHRM4), GtoPdb object 16 — IUPHAR/BPS Guide to Pharmacology
- Phase 1b trial of CVL-231 (emraclidine) in schizophrenia (NCT04787302) — ClinicalTrials.gov