Evp-6124: Safety, Tolerability And Cognitive Effects Of A Novel A7 Nicotinic Receptor Agonist In Alzheimer'S Disease Patients On Stable Donepezil Or Rivastigmine Therapy

Abstract

Approved symptomatic therapies for Alzheimer's disease (AD) provide modest relief. In the future, it is likely that symptomatic treatments will be utilized with AD modifying therapies, the development of which are currently a primary focus of research. The nicotinic a-7 receptor agonist may be an attractive drug candidate to potentially improve cognition in Alzheimer's disease patients either as a stand-alone therapy or in combination with other symptomatic treatments. EVP-6124 is a novel, potent, and selective alpha7 nicotinic receptor agonist. EVP-6124 has an excellent brain to plasma ratio and has shown excellent efficacy and potency in a number of animal models of cognition. Four clinical studies in healthy normal human subjects have been completed with EVP 6124. EVP-6124 exhibited linear kinetics over the range of 1 to 180mg and demonstrated a half-life suitable for once daily dosing. EVP 6124 appears to be safe and well-tolerated for up to 21 days as measured by adverse events, vital signs, continuous cardiac monitoring, physical examination, and clinical laboratory evaluations. In addition, in normal volunteers, EVP-6124 demonstrated pro-cognitive effects (CogState testing) in various cognitive domains including executive function. The safety and efficacy of EVP-6124 was assessed in a Phase 1b study of 48 mild to moderate AD patients 60-80 years of age, on stable donepezil or rivastigmine therapy. Patients were dosed with placebo or two different doses of EVP-6124 (0.3 or 1.0mg/d) for 28 days. Cognitive effects were measured by CogState computerized cognitive testing and a subset of NTB scales (category fluency, Trails A and B). EVP-6124 appeared to be safe and well tolerated with no significant adverse events reported more frequently in treated versus placebo patients; there were no SAEs reported. Subjects exposed to EVP-6124 in addition to donepezil or rivastigmine showed an increase in cognitive function, primarily in the domains of non-verbal learning, memory, and executive function. These data suggest that EVP-6124 administered to AD subjects on cholinesterase inhibitor therapies, may have a potential benefit. Larger phase II studies are currently being initiated in both Alzheimer's disease and schizophrenia.