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Encenicline (EVP-6124) is an investigational, orally active, selective partial agonist of the alpha7 nicotinic acetylcholine receptor developed for cognitive impairment in schizophrenia and Alzheimer disease. Late-stage clinical development was halted after serious gastrointestinal adverse events, and it is not approved for any use.
- Enhances alpha7-mediated cholinergic transmission tied to attention and memory
- Improved cognition on some measures in early schizophrenia and Alzheimer trials
- Normalizes P50 auditory sensory gating deficits
- Active orally at low once-daily doses
- Long receptor residence enabling sustained target engagement
- 5-HT3-related nausea and altered gut motility
Overview
Encenicline reached later-stage clinical development than almost any other alpha7 nicotinic agonist. In a randomized, double-blind, placebo-controlled study in schizophrenia it was tested as a treatment for cognitive impairment, with early signals on cognition and clinical measures that motivated larger trials. Human pharmacology studies established that it is orally bioavailable and active at low, once-daily doses, with a pharmacokinetic profile suited to sustained receptor engagement.
Mechanistically the compound is a selective high-affinity partial agonist of the alpha7 receptor, and its rationale rests heavily on the receptor's role in attention, working memory and sensory gating; the P50 auditory sensory gating deficit seen in schizophrenia has been used as a translational biomarker for alpha7-targeted drugs like encenicline.
Positron emission tomography work in the pig has directly characterized encenicline binding at the alpha7 receptor, supporting central target engagement. Despite this, its development ultimately failed. Phase 3 programs were suspended after reports of serious gastrointestinal adverse events, an effect widely attributed in part to activity at 5-HT3 receptors in addition to alpha7. Encenicline therefore stands as an instructive example of a mechanistically promising cognitive enhancer whose tolerability, not its target, ended its clinical prospects.
- It is one of very few alpha7 nicotinic agonists ever to reach phase 3 trials.
- Encenicline also acts at 5-HT3 receptors, which likely drove the gastrointestinal side effects that ended its development.
- Its long receptor engagement allowed simple once-daily oral dosing.
Mechanism
Encenicline is a selective partial at the alpha7 receptor, active at low nanomolar concentrations, enhancing cholinergic transmission implicated in attention, memory and sensory gating. It also interacts with 5-HT3 receptors, an off-target action linked to its gastrointestinal effects.
receptor fingerprint
Alpha7 receptorselective partial agonist
5-HT3 receptoroff-target ligand
Dosingtypical ranges, not medical advice
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Safetyrisks and cautions, not medical advice
Encenicline is investigational and unapproved. Its phase 3 development in schizophrenia and Alzheimer cognition was halted after serious gastrointestinal adverse events emerged, likely related to 5-HT3 activity. Efficacy across large trials was inconsistent, and its overall risk-benefit profile proved unfavorable.
History
Encenicline (EVP-6124) was developed by EnVivo Pharmaceuticals, later FORUM Pharmaceuticals, and partnered with Mitsubishi Tanabe (codename MT-4666). It advanced through phase 3 before being discontinued.
Reputation
It is remembered as one of the most advanced alpha7 clinical candidates for cognition, and as a cautionary case where gastrointestinal tolerability sank an otherwise mechanistically attractive drug.
Subjective profileweighing the evidence above
Development was halted in Phase 3 over serious gastrointestinal adverse events, most likely from its 5-HT3 activity, and efficacy across the large trials was inconsistent anyway. The alpha7 target is still worth pursuing; this particular molecule is not, and it is approved for nothing.
Resources
This entry is here for reference.
Research
- 2015first citedRandomized, Double-Blind, Placebo-Controlled Study of Encenicline, an alpha7 Nicotinic Acetylch…
- 2024most recentCharacterizing the binding of TC-5619 and encenicline on the alpha7 nicotinic acetylcholine rec…
- 1.Randomized, Double-Blind, Placebo-Controlled Study of Encenicline, an alpha7 Nicotinic Acetylcholine Receptor Agonist, as a Treatment for Cognitive Impairment in Schizophrenia
- 2.Pharmacodynamics, pharmacokinetics, safety, and tolerability of encenicline, a selective alpha7 nicotinic receptor partial agonist, in single ascending-dose and bioavailability studies
- 3.Targeting of alpha7 Nicotinic Acetylcholine Receptors in the Treatment of Schizophrenia and the Use of Auditory Sensory Gating as a Translational Biomarker
- 4.Characterizing the binding of TC-5619 and encenicline on the alpha7 nicotinic acetylcholine receptor using PET imaging in the pig
4 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Is encenicline approved anywhere?
No. Its late-stage trials were halted and it never reached market.
Why did development stop?
Serious gastrointestinal adverse events, likely tied to 5-HT3 activity, outweighed the cognitive benefit.
What was it meant to treat?
Cognitive impairment in schizophrenia and Alzheimer disease.
How is it different from an acetylcholinesterase inhibitor?
It directly and selectively partially activates the alpha7 nicotinic receptor rather than raising acetylcholine broadly.
Is it selective for alpha7?
It is selective at alpha7 but also engages 5-HT3 receptors, which contributed to its side effects.
Adverse effects
- 5-HT3-related nausea and altered gut motility
Notes and cautions
- Serious gastrointestinal adverse events that ended phase 3 development
- Inconsistent efficacy across large trials
- Not approved; overall risk-benefit ultimately unfavorable