First in human trial of a type I positive allosteric modulator of alpha7-nicotinic acetylcholine receptors: Pharmacokinetics, safety, and evidence for neurocognitive effect of AVL-3288

• Published in: Journal of psychopharmacology (Oxford) Vol. 31; no. 4; p. 434
• Main Authors: Gee, Kelvin W, Olincy, Ann, Kanner, Richard, Johnson, Lynn, Hogenkamp, Derk, Harris, Josette, Tran, Minhtam, Edmonds, Stephen A, Sauer, William, Yoshimura, Ryan, Johnstone, Timothy, Freedman, Robert
• Format: Journal Article
• Language: English
• Published: United States 01.04.2017
• Subjects: Adult; Allosteric Regulation - drug effects; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Anilides - adverse effects; Anilides - pharmacokinetics; Anilides - therapeutic use; Biomarkers - metabolism; Cognition - drug effects; Double-Blind Method; Female; Humans; Isoxazoles - adverse effects; Isoxazoles - pharmacokinetics; Isoxazoles - therapeutic use; Male; Neurocognitive Disorders - drug therapy; Neurocognitive Disorders - metabolism; Nicotine - administration & dosage; Nicotinic Agonists - adverse effects; Nicotinic Agonists - pharmacokinetics; Nicotinic Agonists - therapeutic use; Receptors, Nicotinic - metabolism; Schizophrenia - drug therapy; Schizophrenia - metabolism; Synaptic Transmission - drug effects; Young Adult; Receptors; drug evaluation; schizophrenia; cognition; nicotinic; allosteric modulators
• DOI: 10.1177/0269881117691590

Type I positive allosteric modulators (PAMs) of the alpha7-nicotinic receptor enhance its cholinergic activation while preserving the spatiotemporal features of synaptic transmission and the receptor's characteristic rapid desensitization kinetics. Alpha7-nicotinic receptor agonists have shown promise for improving cognition in schizophrenia, but longer-term trials have been disappointing. Therefore, the type I PAM AVL-3288 was evaluated for safety and preliminary evidence of neurocognitive effect in healthy human subjects. Single-dose oral administration in ascending doses was conducted in a double-blind, placebo-controlled Phase I trial in non-smokers. The trial found indication of positive but non-significant effects on neurocognition at 10 and 30 mg, two doses that produced overlapping peak levels. There was also some evidence for effects on inhibition of the P50 auditory evoked potential to repeated stimuli, a biomarker that responds to alpha7-nicotinic receptor activation. The pharmacokinetic characteristics were consistent between subjects, and there were no safety concerns. The effects and safety profile were also assessed at 3 mg in a cohort of smokers, in whom concurrent nicotine administration did not alter either effects or safety. The trial demonstrates that a type I PAM can be safely administered to humans and that it has potential positive neurocognitive effects in central nervous system (CNS) disorders.