spec sheet8 rows
Emraclidine A selective M4 positive allosteric modulator built at Pfizer and carried into schizophrenia trials by Cerevel and then AbbVie, whose phase 2 programme failed to beat placebo in November 2024.
- highly selective for M4 over the other muscarinic subtypes
- brain penetrant and once daily without titration
- no dopamine D2 receptor blockade
- tolerability comparable to placebo in the trials so far
- headache
- transient rise in blood pressure at treatment initiation
- transient rise in heart rate at treatment initiation
- no demonstrated benefit over placebo on the primary endpoint
Overview
The most instructive failure in the muscarinic field. The molecule is genuinely good: clean, brain penetrant, once daily, and about as selective for M4 as anyone has managed. The trials still missed, and the reason is not settled. What the result really shows is that the muscarinic case rests on more than an elegant target, and that a promising phase 1b in 81 patients can be an artefact of small numbers. Worth watching rather than writing off, because AbbVie is still running it.
- Both phase 2 trials missed, but they missed in different ways: in EMPOWER-1 both doses beat placebo without reaching significance, while in EMPOWER-2 the 30 mg dose actually did worse than placebo and the 15 mg dose did better, which is not the pattern a real dose response produces.
- The placebo arms tell much of the story. Placebo improved by 13.5 points in one trial and 16.1 in the other, which is close to the drug effect reported in successful antipsychotic trials.
- Emraclidine has no meaningful activity at M1, M3 or M5 at concentrations up to 10 micromolar, which is a far cleaner subtype profile than xanomeline achieves, and it still did not beat placebo.
Mechanism
Emraclidine does not activate the M4 receptor by itself; it binds an site and amplifies the receptor's response to the already present, which is how it achieves subtype selectivity that orthosteric agonists cannot. In the discovery paper it modulated human M4 with an EC50 of 12.2 nM and an Emax of 104 percent, was about 390-fold weaker at M2, and produced no measurable positive modulation at M1, M3 or M5 up to 10 micromolar [2].
The therapeutic reasoning is that M4 receptors on striatal cholinergic interneurons and medium spiny neurons hold release in check, so raising M4 tone should reduce psychosis without blocking receptors at all. PET imaging in rhesus macaques with the M4 tracer carbon 11 MK-6884 showed dose dependent occupancy of M4 receptors in the caudate and putamen after emraclidine, confirming the molecule reaches its target in a primate brain [3].
receptor fingerprint
M4 (CHRM4)Positive allosteric modulator
M2 (CHRM2)Weak positive allosteric modulator
M1 (CHRM1)No measurable modulation
M3 (CHRM3)No measurable modulation
M5 (CHRM5)No measurable modulation
Safetyrisks and cautions, not medical advice
In the phase 1b trial, adverse events occurred in about half of participants on emraclidine and about half on placebo, with headache the most common in both arms, and the modest rises in blood pressure and heart rate seen at treatment initiation faded and were judged not clinically meaningful by week 6 [1]. Weight change, clinical assessments and extrapyramidal measures did not separate from placebo in that trial. AbbVie reported the same tolerability picture across the much larger phase 2 programme. What is not established is anything about long term safety; a 52 week open label safety study in about 700 patients (NCT05443724) has completed but its results have not been published, so the durable safety profile remains an open question rather than a reassuring one.
History
The molecule was designed at Pfizer as PF-06852231 and moved to Cerevel Therapeutics, the neuroscience company formed in July 2018 from Pfizer assets and Bain Capital funding, where it became CVL-231 and then emraclidine. A two part phase 1b in 130 patients reported clean tolerability and encouraging symptom reductions in 2022, and AbbVie bought Cerevel for 8.7 billion dollars, completing the acquisition on 1 August 2024, with emraclidine as the headline asset. On 11 November 2024 AbbVie announced that both phase 2 trials had missed. AbbVie did not shelve it; a new adaptive two part phase 2 (NCT07145918) with a multiple ascending dose stage and pharmacokinetic primary endpoints began recruiting in August 2025.
Reputation
Widely and wrongly remembered as a success, because the 2022 phase 1b results were celebrated and the phase 2 failure got a fraction of the coverage. Among people who follow the field it is now the standard cautionary example about reading too much into a small phase 1b; AbbVie shares fell sharply on the day of the announcement. Interest in M4 as a target survived the result largely intact, since the failure has not been shown to be a target failure.
Subjective profileweighing the evidence above
The most instructive failure in the muscarinic field. The molecule is genuinely good: clean, brain penetrant, once daily, and about as selective for M4 as anyone has managed. The trials still missed, and the reason is not settled. What the result really shows is that the muscarinic case rests on more than an elegant target, and that a promising phase 1b in 81 patients can be an artefact of small numbers. Worth watching rather than writing off, because AbbVie is still running it.
Resources
This entry is here for reference.
Research
- 1.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.
- 2.Design and Synthesis of Clinical Candidate PF-06852231 (CVL-231): A Brain Penetrant, Selective, Positive Allosteric Modulator of the M4 Muscarinic Acetylcholine Receptor.
- 3.PET imaging of M4 muscarinic acetylcholine receptors in rhesus macaques using [11C]MK-6884: Quantification with kinetic modeling and receptor occupancy by CVL-231 (emraclidine), a novel positive allosteric modulator.
3 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Did emraclidine work?
No, not in the trials designed to show it. The two phase 2 EMPOWER trials, run in about 750 adults with schizophrenia in an acute psychotic episode, both missed their primary endpoint of a statistically significant reduction in PANSS total score against placebo at week 6. AbbVie announced this on 11 November 2024. The earlier phase 1b looked promising, but it was a safety study in 81 randomised patients and was never powered to prove efficacy.
Is it the same kind of drug as Cobenfy?
Same receptor family, different way of engaging it. Cobenfy's xanomeline is an orthosteric agonist that switches muscarinic receptors on directly and hits M1, M4 and everything else. Emraclidine only amplifies the signal from acetylcholine that is already there, and only at M4. That should in principle be gentler and more selective, which is part of why the failure was a surprise.
Is development over?
No. AbbVie started a new adaptive phase 2 study in August 2025 that begins with a multiple ascending dose stage and pharmacokinetic primary endpoints before an efficacy stage, which is the design a company runs when it suspects the dose or the exposure, not the target, was the problem. Whether that reading is right is not yet known.
Can I get it?
Only through a clinical trial. Emraclidine is not approved anywhere and has no established human dose.
Adverse effects
- headache
- transient rise in blood pressure at treatment initiation
- transient rise in heart rate at treatment initiation
- no demonstrated benefit over placebo on the primary endpoint