Nicotinic Alpha7 Acetylcholine Receptor Agonist Program

Compounds that improve cholinergic functioning, e.g. acetylcholinesterase inhibitors (AChE-I), ameliorate the cognitive deficits in patients suffering from AD. However, AChE-I only provide suboptimal palliative treatment. Currently, the most widely used AChE-I is Aricept. The positive impact on other behavioral impairments that represent a major factor increasing the care burden is rather low. Therefore, more efficacious drugs are urgently needed to improve the treatment of AD patients in order to reduce the high and growing direct (loss of patient health) and indirect (caregiver) costs.

Nicotine enhances cognitive functions, such as learning, memory, and retention through activation of brain nicotinic acetylcholine receptors (nAChRs). The most common nicotinic receptors found in the brain are the low affinity a ₇-nAChR and the high affinity a ₄b₂-nAChR. a ₇- and a ₄b₂-nAChR agonists possess cognitive-enhancing properties. The ß₂-subunit but not the a ₇-nAChRs mediates the addictive properties and some of the side-effects of nicotine. a 7-nAChRs are located in brain areas important for cognition. Selective activation of a 7-nAChRs may thus alleviate the cholinergic deficit present in AD without the undesirable side-effects caused by overactivation of other nAChRs or muscarinic acetylcholine receptors involved in addiction, cardiovascular or gastrointestinal functions. These side effects limit the doses of AChE-I tolerated and thus the level of cholinergic activation mediated by these compounds. Similarly nicotinic agonists without selective actions on a 7-nAChRs have been associated with dose limiting side effects. Various studies have reported modest reductions or no changes of a 7-nAChR levels in AD brain. a 7-nAChR agonists should therefore still active in the later stages of the disease, when cholinergic neurons have died and AChE-I loose their therapeutic efficacy. Like AChE-I such as donepezil (Aricept), selective a 7-nAChR agonists are expected to improve both acquisition and retention processes. In addition, a 7-nAChR agonists may have beneficial effects on other behavioral parameters, such as the psychiatric status of AD and other patients with hallucinations, anxiety or disturbed circadian rhythms.

EnVivo’s Cholinergic Nicotinic Agonist Program

In November of 2004, EnVivo Pharmaceuticals, Inc. licensed from Bayer Healthcare the exclusive rights to their alpha 7 agonist program and considerable patent estate. At EnVivo we identified EVP-6124 as a highly CNS-penetrant, orally bio-available, potent nicotinic alpha 7 agonists. EVP-6124 successfully completed clinical phase I studies in healthy young volunteers and Ib/IIa studies for Schizophrenia. Phase Ib/IIa studies in AD are ongoing.