Featured Article A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects

Introduction: Pyroglutamate-amyloid-b (pE-Ab) peptides are major components of Ab-oligomers and Ab-plaques,whichareregardedaskeyculpritsofAlzheimer’sdisease(AD)pathology.PQ912isacompetitive inhibitor of the enzyme glutaminyl cyclase (QC), essential for the formation of pE-Ab peptides. Methods: A randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study investigated the safety, pharmacokinetics, and pharmacodynamics of PQ912 in healthy nonelderly and elderly subjects. Results: PQ912 was considered safe and well tolerated with dose-proportional pharmacokinetics up to doses of 200 mg. At higher doses up to 1800 mg, exposure was supraproportional and exposure in elderly subjects was approximately 1.5- to 2.1-fold higher. Exposure in cerebrospinalfluid (CSF) was approximately 20% of the unbound drug in plasma, and both serum and CSF QC activity was inhibited in a dose-related manner. Discussion: This first-in-man study of a compound-targeting QC inhibition justifies further development of PQ912 for the treatment of AD. 2015 Probiodrug AG, Germany. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).