Name:	EVP-6124
Therapeutic Applications:	In development for Alzheimer disease and schizophrenia
Therapy Types:	Oral, small molecule
Mechanisms:	EVP-6124 is a nicotinic α7 receptor agonist.
Development Status:	investigational in U.S.
FDA Phase:	Phase II/IIa/IIb
Primary Medical Role:	EVP-6124 is a highly CNS-penetrant, orally bioavailable, potent nicotinic α7 receptor agonist.
Role in Alzheimer's Disease:	The nicotinic α7 receptor is highly expressed within the brain and has limited peripheral expression (e.g., macrophages, ganglionic neurons). Selective nicotinic α7 agonists have been shown to increase cholinergic neurotransmission in a brain region-specific manner. Thus, it is hypothesized that α7 agonists may contribute to symptomatic treatment of Alzheimer disease through cholinergic mechanisms and have a better safety profile than observed with current therapies (Kem, 2000). In addition to neurodegeneration, the brains of Alzheimer disease patients display an abnormal accumulation of amyloid plaques and accumulations of abnormal tau filaments as neurofibrillary tangles. Amyloid plaques are insoluble aggregates of protein that are toxic to neurons. The major constituent of these plaques is the protein β amyloid. Preclinical data from several laboratories suggests that the amyloid protein from which these plaques are formed disrupts the function of the nicotinic α7 receptor. Furthermore, the most vulnerable neurons appear to be those that abundantly express the nicotinic α7 receptor, and internalization of amyloid-β1-42 (Aβ1-42) appears to be facilitated by the high-affinity binding of Aβ1-42 to the nicotinic α7 receptor on neuronal cell surfaces (D’Andrea and Nagele, 2005). Therefore, the nicotinic α7 receptor is a potentially important therapeutic target for disease modification treatment. Stimulation of nicotinic α7 receptors via agonist administration protects neurons from degeneration induced by Aβ1-42, further bolstering the idea that reduced nicotinic α7 receptor signaling is a mediator of age-related and Alzheimer’s-dependent cognitive decline (D’Andrea and Nagele 2005). Drugs that activate nicotinic α7 receptors would theoretically interfere with the neurotoxic effects of Aβ1-42 and prevent the pathophysiological and cognitive decline of Alzheimer’s patients. EVP-6124 has demonstrated improved learning and memory function in a small Phase II clinical trial (See ARF related news story and EnVivo ICAD 2009 Poster). Also see related Alzforum News story posted 5 November 2010. Experimental Drug Sensitizes Receptor, Boosts Cognition
Side Effects:	EVP-6124 appears to be safe and was well tolerated over a 28-day period of dosing (See ARF related news story and EnVivo ICAD 2009 Poster).
Companies:	EnVivo Pharmaceuticals
Notes:	On May 12, 2010 EnVivo announced the initiation of a Phase IIb safety and cognitive function clinical trial in mild to moderate AD (See NCT01073228). This trial will be a randomized, double-blind, placebo-controlled parallel 24-week study to test three doses at multiple centers in US and Europe to evaluate safety and cognitive effects of EVP-6124. This study is currently recruiting participants. This record was updated 15 December, 2010.

References

Hilt D, Safirstein B, Hassman D, Apter J, Thein S, Maruff P, Harrison J, Gawryl M, Koenig G. (2009). EVP-6124 - Safety, Tolerability and Cognitive Effects of a Novel alpha7 Nicotinic Receptor Agonist in Alzheimer's Disease Patients on Stable Donepezil or Rivastigmine Therapy. ICAD 2009, Vienna, Austria, July 11-16, 2009. Poster pdf

Nagele RG, D'Andrea MR, Anderson WJ, Wang HY. Intracellular accumulation of beta-amyloid(1-42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer's disease. Neuroscience. 2002;110(2):199-211. Abstract

Kem WR. The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: study with DMXBA (GTS-21). Behavioural Brain Research. 113: 169-181, 2000. Abstract