RESEARCH MONOGRAPH · KDC-MN-1352

Encenicline

May 10, 2026 Kodiac biolabs Research Revised May 22, 2026 4 min read

Selective alpha-7 nicotinic acetylcholine receptor partial agonist

A quinuclidine benzothiophene-2-carboxamide developed at EnVivo and advanced by Forum Pharmaceuticals through two global Phase 3 programs in schizophrenia cognitive impairment and one Phase 3 program in Alzheimer disease, terminated in March 2016 after both Phase 3 schizophrenia trials missed co-primary endpoints and following a September 2015 FDA clinical hold for severe gastrointestinal adverse events.

Abstract

Encenicline (development codes EVP-6124 and MT-4666) is a small-molecule selective partial agonist of the homopentameric alpha-7 subtype of the neuronal nicotinic acetylcholine receptor. The compound was originated at EnVivo Pharmaceuticals (later renamed Forum Pharmaceuticals) following the 2008 acquisition of the parent quinuclidine benzothiophene chemistry program from Bayer and was advanced through Phase 1, Phase 2, and Phase 3 clinical development for cognitive impairment associated with schizophrenia and for Alzheimer disease. The compound binds the human alpha-7 nicotinic receptor with a Ki of approximately 4 nanomolar and exhibits functional intrinsic activity of approximately 60 to 70 percent of the acetylcholine maximum response in heterologous expression systems. Selectivity over other neuronal nicotinic subtypes is approximately 100-fold or greater. Pharmacokinetics are characterized by oral bioavailability greater than 80 percent, dose-proportional kinetics across a 1 to 180 mg range, and plasma elimination half-life of 50 to 60 hours supporting once-daily dosing. In September 2015 the FDA placed the Phase 3 program on partial clinical hold following reports of severe gastrointestinal adverse events including nausea, vomiting, and gastrointestinal ulceration in a small fraction of patients. The hold was partially lifted in November 2015. In March 2016 Forum announced that both Phase 3 schizophrenia trials had missed co-primary cognitive and functional endpoints; the development program was discontinued and Forum was wound down later that year. Encenicline represents the most clinically developed alpha-7 nicotinic partial agonist in cognitive applications and is the principal source of the contemporary scientific assessment that monoselective alpha-7 partial agonism, despite robust preclinical pharmacology and Phase 2 cognitive signals, has not produced clinically meaningful improvement at the registration threshold in the indications studied.

Mechanism of action

Selective partial agonism at the orthosteric (acetylcholine) site of the homopentameric alpha-7 nicotinic acetylcholine receptor. Ki approximately 4 nanomolar at human alpha-7 expressed in HEK293 cells; functional intrinsic activity 60-70 percent of acetylcholine maximum in Xenopus oocyte and HEK293 expression systems; selectivity over alpha-4-beta-2, alpha-3-beta-4, and other neuronal nicotinic subtypes greater than 100-fold; selectivity over muscle-type alpha-1 and 5-HT3 receptors greater than 1000-fold. Downstream signaling through CaMKII, ERK1/2 MAPK, transcriptional upregulation of BDNF and NGF, modulation of glutamate release from cortical and hippocampal presynaptic terminals, and activation of the cholinergic anti-inflammatory pathway in macrophages.

Reported research dose ranges

Phase 2 schizophrenia: 0.27 mg or 0.9 mg per oral administration once daily for 12 weeks. Phase 3 schizophrenia: same doses for 26 weeks. Phase 2 Alzheimer disease: 0.1, 0.3, 1 mg once daily as add-on to acetylcholinesterase inhibitor background. Phase 3 Alzheimer disease: 1 mg or 2 mg once daily for 24 weeks. Phase 1 single ascending-dose to 180 mg in healthy volunteers was well tolerated. Research applications: in vitro 0.1-10 micromolar; rodent in vivo 0.1-3 mg/kg.

Selected references

  1. Macor JE et al. The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective alpha-7 nicotinic receptor partial agonist. Bioorg Med Chem Lett. 2001;11(3):319-321.
  2. Prickaerts J et al. EVP-6124, a novel and selective alpha-7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of alpha-7 nicotinic acetylcholine receptors. Neuropharmacology. 2012;62(2):1099-1110.
  3. Barbier AJ et al. Pharmacodynamics, pharmacokinetics, safety, and tolerability of encenicline, a selective alpha-7 nicotinic receptor partial agonist, in single ascending-dose and bioavailability studies. Clin Ther. 2015;37(2):311-324.
  4. Keefe RS et al. Randomized, double-blind, placebo-controlled study of encenicline, an alpha-7 nicotinic acetylcholine receptor agonist, as a treatment for cognitive impairment in schizophrenia. Neuropsychopharmacology. 2015;40(13):3053-3060.
  5. Olincy A, Stevens KE. Failure of clinical trials in schizophrenia cognitive enhancement: lessons from encenicline. Schizophr Res. 2017;186:5-10.

Read the full monograph

The full reference document covers compound identification with chemistry and synthesis, discovery and developmental history, mechanism of action across molecular targets with quantitative receptor pharmacology, comprehensive pharmacokinetics, indication-by-indication clinical evidence base, reported research dose ranges, sourcing and quality verification, reconstitution and handling, stack interaction considerations, adverse event signal, and a structured comparative assessment of five alpha-7 nicotinic acetylcholine receptor candidates judged against five competency standards. Embedded inline below; download for offline reading.

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