Nicotine has been shown to enhance cognitive functions, such as learning, memory, and retention through the activation of nicotinic acetylcholine receptors in the brain. Alpha-7 nicotinic acetylcholine receptors are located in the areas of the brain that are important for cognition. EnVivo has developed a selective alpha-7 agonist program with compounds possessing cognitive-enhancing properties but that are also able to mediate the addictive properties and side effects of nicotine.
The lead compound in EnVivo’s alpha-7 agonist program, EVP-6124, is a selective, potent, brain penetrant oral compound that offers a novel mechanism of action – it enhances synaptic transmission in the brain and acts as a co-agonist in combination with Acetylcholine (ACh) to enhance cognition. By sensitizing the alpha-7 receptor, EVP-6124 makes it possible for smaller amounts of naturally occurring ACh to be effective in activating the A7 receptor. This mechanism could potentially alleviate the undesirable side effects caused by other systemic compounds (for example, Acetylcholinesterase inhibitors- AChE-Is), which are dose-limited by toxic side effects.
EnVivo’s preclinical research has demonstrated that memory deficits can be minimized or entirely reversed by activating the alpha-7 receptor with EVP-6124 alone or in combination with other AChE-Is in low doses (for example, donepezil). EVP-6124 has also been shown to increase the release of important neurotransmitters, notably glutamate, which is believed to be important in the pathology of schizophrenia.
EVP-6124 is being developed as a long-term treatment to restore and improve cognitive function with sustained effect in Alzheimer’s disease and schizophrenia.
In July 2012, EnVivo announced positive results of its six-month, double-blind Phase 2b clinical trial that evaluated EVP-6124 against placebo in patients with mild to moderate Alzheimer’s disease. Results demonstrated that dosing with EVP-6124 resulted in statistically significant improvements in cognition and clinical function, meeting both of the trial’s primary endpoints. The data also showed statistically significant results across secondary endpoints of other cognitive and clinical measures. In October 2012, EnVivo announced additional pharmacokinetic and pharmacodynamic data from the Phase 2b trial, which demonstrated a significant relationship (p=0.003) between EVP-6124 plasma concentrations and the probability of experiencing an improvement in cognition. Based on the Phase 2b trial results, EnVivo plans to initiate a Phase 3 clinical trial program in Alzheimer’s disease in 2013.
EnVivo announced positive topline data from its double-blind, placebo-controlled Phase 2b clinical trial of EVP-6124 in schizophrenia in May 2011 and presented a comprehensive analysis of these findings in December 2011. Results demonstrated EVP-6124’s statistically significant and clinically meaningful effects on both cognition and functional symptoms, including global cognitive function. In February 2013, EnVivo announced the initiation of its Phase 3 clinical trial program for EVP-6124. The two trials are designed to assess the safety and efficacy of EVP-6124 compared to placebo in patients with schizophrenia when added to chronic, stable, atypical antipsychotic therapy.