Safety and clinical effects of EVP-6124 in subjects with Alzheimer's disease currently or previously receiving an acetylcholinesterase inhibitor medication

Abstract

Alzheimer’s disease (AD) is a prevalent and currently incurable brain disease whose impact will continue to rise as the population ages. With limited treatment options, a variety of experimental therapies are currently in clinical trials. EVP-6124 (encenicline) is an α7 nicotinic acetylcholine receptor partial agonist under investigation for the symptomatic treatment of AD. EVP-6124 activates the α7 nicotinic acetylcholine receptor at low nanomolar brain concentrations and improves memory performance in rats. Treatment with EVP-6124 in Phase I and II trials involving patients with mild-to-moderate AD was well tolerated and showed statistically significant improvements compared with placebo on cognitive and functional measures. Two Phase III trials under the title COGNITIV AD will assess the efficacy and tolerability of EVP-6124 in patients with mild-to-moderate AD. Based on the completed clinical trials and proposed mechanism of action, EVP-6124 would appear to be a good candidate for therapy in combination with cholinesterase inhibitors.

Keywords:

• α-7 nicotinic acetylcholine receptor partial agonist
• Alzheimer’s disease
• cholinergic
• encenicline
• EVP-6124

Financial & competing interests disclosure

GT Grossberg serves as a consultant for Avanir, Forest, Novartis, Otsuka, Roche and Takeda. GT Grossberg also serves on monitoring boards for Merck and Newron and received research support from Accera, Avanir and Noven. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• EVP-6124 is a selective α7 nicotinic acetylcholine receptor (nAChR) partial agonist currently under evaluation for the treatment of mild-to-moderate Alzheimer’s disease (AD).

• Pre-clinical characterization showed that EVP-6124 has good selectively for the α7 nAChR, good brain penetration and improved memory performance in rat object recognition tasks. The results of these studies were similar to those reported with other α7 nAChR agonists.

• In clinical trials, EVP-6124 was safe and well tolerated with most adverse events being mild and gastrointestinal in nature.

• Phase I and Phase II trials with EVP-6124 have demonstrated improvements in cognitive and clinical functioning compared with placebo on measurements such as the ADAS-Cog, CDR-SB and NTB.

• Phase III trials under the title COGNITIV AD are currently being conducted to evaluate the safety and efficacy of two fixed doses in patients with mild-to-moderate Alzheimer’s disease currently receiving or previously treated with an acetylcholinesterase inhibitor.