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Name: Encenicline
Synonyms: EVP-6124 , MT-4666, α7-nAChR agonist
Chemical Name: (R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease, Schizophrenia
U.S. FDA Status: Alzheimer's Disease (Discontinued), Schizophrenia (Discontinued)
Company: FORUM Pharmaceuticals Inc., Mitsubishi Tanabe Pharma
Approved for: None


Encenicline hydrochloride is a partial, selective agonist of the α-7 nicotinic acetylcholine receptor (α7-nAChR). It is being developed for the treatment of cognitive deficits in schizophrenia and Alzheimer's disease. Cholinergic function declines in Alzheimer's, and currently approved acetylcholinesterase inhibitor therapies modestly improve cognitive deficits in patients with AD by way of boosting cholinergic transmission. The rationale of selective α7-nAChR agonists is that they will enhance cognition without causing side effects associated with over-activation of other nAChRs such as α4β2, or muscarinic AChRs. In rats, encenicline penetrates the blood-brain barrier and improves memory performance by potentiating the acetylcholine response. Encenicline has been reported to act as a co-agonist with acetylcholine. It sensitizes the α-7 nACh receptor to its natural ligand and renders sub-efficacious doses of AChEI drugs effective in restoring memory function in an object recognition task (Prickaerts et al., 2012).


This compound was originally developed at Bayer Healthcare and in 2004 licensed to Envivo Pharmaceuticals, which subsequently licensed development in Asia to Mitsubishi Tanabe Pharma Corporation. In 2014, Envivo changed its name to FORUM Pharmaceuticals Inc.

Encenicline is being tested in Alzheimer's disease and schizophrenia. In Alzheimer's, an ascending-dose Phase 1/2 study showed 0.1 to 1 mg/day of EVP-6124 to be safe and well-tolerated when given to 49 people with mild to moderate AD for 28 days. No serious side effects were reported. Secondary efficacy endpoints suggested that EVP-6124 given in addition to therapy with the acetyl cholinesterase inhibitors donepezil or rivastigmine appeared to improve attention, verbal fluency, and executive function as measured on  tests in the CogState or NTB batteries (see Jul 2009 conference news). This study has posted results on

A 24-week Phase 2 trial conducted in 409 people with mild to moderate Alzheimer's disease in the United States and Eastern Europe compared 0.3, 1, and 2 mg of EVP-6124 per day to placebo, measuring cognition with ADAS-Cog as the primary outcome plus cognitive, functional, and psychiatric secondary outcomes. EVP 6124 was given as adjunct therapy to donepezil or rivastigmine. This trial was reported to have met its primary and most secondary endpoints, showing that people on the highest dose improved over baseline. EVP-6124 dose-dependently improved measures of attention, verbal and language fluency, and executive function. In this trial, all treatment groups initially improved, possibly due to a placebo effect, but by 12 weeks the groups separated and the placebo and low-dose groups declined (see Jul 2012 conference news). EVP-6124 was well-tolerated.

Mitsubishi Tanabe Pharma Corporation is conducting a Phase 2 trial for the treatment of Alzheimer's disease in Japan.

In October 2013, two international Phase 3 trials began enrolling what are to be 790 patients in each trial with mild to moderate Alzheimer's who are already taking an acetylcholinesterase inhibitor. The trials will compare two fixed, undisclosed add-on doses of EVP-6124 to placebo, all given as once-daily tablets for six months, for cognitive benefit as measured by the ADAS-Cog, clinical benefit as measured by the Clinical Dementia Rating Sum of Boxes (CDR-SB), as well as for safety and tolerability. Called COGNITIV AD, this Phase 3 program is set to run through 2016.

For schizophrenia, a Phase 1 study comparing 0.3 and 1 mg/day of EVP-6124 to placebo in 28 people with the disease gave preliminary evidence for the compound's safety, tolerability, and pharmacokinetics in this population. In addition, the compound yielded signals of bioactivity in the brain by way of EEG tests of evoked potentials, a measure of sensory gating affected in this disease. See study results on

A subsequent 12-week Phase 2 trial compared 0.3 and 1 mg/day of EVP-6124 to placebo in 317 people with schizophrenia and measured the compound's safety and efficacy on cognitive function. As presented at the American College of Neuropsychopharmacology meeting held in Hawaii December 2011, EVP 6124 met its primary endpoint of improvement on the CogState overall cognition index. The study also met secondary endpoints, showing improvement in clinical function as assessed by the Schizophrenia Cognition Rating Scale, and a decrease in negative symptoms. Two six-month, 700-patient Phase 3 studies, plus a six-month extension study, are ongoing. 

In September 2015, the FDA placed a clinical hold on three Phase 3 Alzheimer studies and one schizophrenia safety extension study following reports of gastrointestinal side effects (see Sep 2015 news). In November 2015, the FDA lifted a partial clinical hold on encenicline evaluation for cognitive impairment in schizophrenia; two global Phase 3 trials in this indication are expected to deliver results in the first half of 2016  (see company press release). As of January 2016, the clinical hold on the AD trials remained in place. 

In March 2016, Forum announced topline from the two cognitive function in schizophrenia phase 3 studies. Encenicline missed the co-primary endpoints in both trials (see company press release). Development of this compound has ended, and Forum Pharmaceuticals has been shut down.

For all clinical trials of encenicline, see

Clinical Trial Timeline

  • Phase 2
  • Phase 3
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034
FORUM Pharmaceuticals Inc. NCT01073228
FORUM Pharmaceuticals Inc. NCT01969123
FORUM Pharmaceuticals Inc. NCT01969136

Last Updated: 15 Jan 2016


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News Citations

  1. Vienna: New Shoot Among Ashes of Drug Trials
  2. Experimental α7 Agonist Meets Cognitive and Clinical Endpoints

Paper Citations

  1. . EVP-6124, a novel and selective α7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of α7 nicotinic acetylcholine receptors. Neuropharmacology. 2012 Feb;62(2):1099-110. Epub 2011 Nov 10 PubMed.

Other Citations

  1. Sep 2015 news

External Citations

  1. study results on
  2. see company press release).
  3. company press release

Further Reading